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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 -
Radiologic Clinics of North America May 2024The visceral vasculature is inextricably intertwined with abdominopelvic disease staging, spread, and management in routine and emergent cases. Comprehensive evaluation... (Review)
Review
The visceral vasculature is inextricably intertwined with abdominopelvic disease staging, spread, and management in routine and emergent cases. Comprehensive evaluation requires specialized imaging techniques for abnormality detection and characterization. Vascular pathology is often encountered on nondedicated routine imaging examinations, which may obscure, mimic, or confound many vascular diagnoses. This review highlights normal arterial, portal venous, and systemic venous anatomy and clinically relevant variants; diagnostic pitfalls related to image-acquisition technique and disease mimics; and characteristics of common and rare vascular diseases to empower radiologists to confidently interpret the vascular findings and avoid misdiagnosis.
Topics: Humans; Portal Vein; Diagnostic Imaging; Diagnostic Errors
PubMed: 38553185
DOI: 10.1016/j.rcl.2023.12.003 -
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 -
Journal of Orthopaedic Research :... May 2024Biplane radiography has emerged as the gold standard for accurately measuring in vivo skeletal kinematics during physiological loading. The purpose of this scoping... (Review)
Review
Biplane radiography has emerged as the gold standard for accurately measuring in vivo skeletal kinematics during physiological loading. The purpose of this scoping review was to map the extent, range, and nature of biplane radiography research on humans from 2004 through 2022. A literature search was performed using the terms biplane radiography, dual fluoroscopy, dynamic stereo X-ray, and biplane videoradiography. All articles referenced in included publications were also assessed for inclusion. A secondary search was then performed using the names of the most frequently appearing principal investigators among included papers. A total of 379 manuscripts were identified and included. The first studies published in 2004 focused on the native knee, followed by studies of the ankle joint complex in 2006, the shoulder in 2007, and the spine in 2008. Nearly half (180, 47.5%) of all manuscripts investigated knee kinematics. The average number of publications increased from 21.6 per year from 2012 to 2017 to 34.6 per year from 2017 to 2022. The average number of participants per study was 16, with a range from 1 to 101. A total of 90.2% of studies featured cohorts of 30 or less. The most prolific research groups for each joint were: Mass General Hospital (lumbar spine and knee), Henry Ford Hospital (shoulder), the University of Utah (ankle and hip), The University of Pittsburgh (cervical spine), and Brown University (hand/wrist/elbow). Future advancements in biplane radiography research are dependent upon increased availability of these imaging systems, standardization of data collection protocols, and the development of automated approaches to expedite data processing.
Topics: Humans; Biomechanical Phenomena; Radiography; Fluoroscopy; Knee Joint; X-Rays
PubMed: 38366965
DOI: 10.1002/jor.25806 -
Radiology. Cardiothoracic Imaging Feb 2024Purpose To achieve ultra-high temporal resolution (approximately 20 msec) in free-breathing, real-time cardiac cine MRI using golden-angle radial sparse parallel (GRASP)...
Purpose To achieve ultra-high temporal resolution (approximately 20 msec) in free-breathing, real-time cardiac cine MRI using golden-angle radial sparse parallel (GRASP) reconstruction amplified with view sharing (VS) and k-space-weighted image contrast (KWIC) filtering. Materials and Methods Fourteen pediatric patients with congenital heart disease (mean age [SD], 9 years ± 2; 13 male) and 10 adult patients with arrhythmia (mean age, 62 years ± 8; nine male) who underwent both standard breath-hold cine and free-breathing real-time cine using GRASP were retrospectively identified. To achieve high temporal resolution, each time frame was reconstructed using six radial spokes, corresponding to acceleration factors ranging from 24 to 32. To compensate for loss in spatial resolution resulting from over-regularization in GRASP, VS and KWIC filtering were incorporated. The blur metric, visual image quality scores, and biventricular parameters were compared between clinical and real-time cine images. Results In pediatric patients, the incorporation of VS and KWIC into GRASP (ie, GRASP + VS + KWIC) produced significantly ( < .05) sharper x-y-t (blur metric: 0.36 ± 0.03, 0.41 ± 0.03, 0.48 ± 0.03, respectively) and x-y-f (blur metric: 0.28 ± 0.02, 0.31 ± 0.03, 0.37 ± 0.03, respectively) component images compared with GRASP + VS and conventional GRASP. Only the noise score differed significantly between GRASP + VS + KWIC and clinical cine; all visual scores were above the clinically acceptable (3.0) cutoff point. Biventricular volumetric parameters strongly correlated ( > 0.85) between clinical and real-time cine images reconstructed with GRASP + VS + KWIC and were in good agreement (relative error < 6% for all parameters). In adult patients, the visual scores of all categories were significantly lower ( < .05) for clinical cine compared with real-time cine with GRASP + VS + KWIC, except for noise ( = .08). Conclusion Incorporating VS and KWIC filtering into GRASP reconstruction enables ultra-high temporal resolution (approximately 20 msec) without significant loss in spatial resolution. Cine, View Sharing, k-Space-weighted Image Contrast Filtering, Radial k-Space, Pediatrics, Arrhythmia, GRASP, Compressed Sensing, Real-Time, Free-Breathing © RSNA, 2024.
Topics: Adult; Humans; Male; Child; Middle Aged; Magnetic Resonance Imaging, Cine; Retrospective Studies; Magnetic Resonance Imaging; Tachypnea; Hyperventilation; Arrhythmias, Cardiac
PubMed: 38358330
DOI: 10.1148/ryct.230107 -
Nucleic Acids Research Mar 2024Arginine/R methylation (R-met) of proteins is a widespread post-translational modification (PTM), deposited by a family of protein arginine/R methyl transferase enzymes...
Arginine/R methylation (R-met) of proteins is a widespread post-translational modification (PTM), deposited by a family of protein arginine/R methyl transferase enzymes (PRMT). Regulations by R-met are involved in key biological processes deeply studied in metazoan. Among those, post-transcriptional gene silencing (PTGS) can be regulated by R-met in animals and in plants. It mainly contributes to safeguard processes as protection of genome integrity in germlines through the regulation of piRNA pathway in metazoan, or response to bacterial infection through the control of AGO2 in plants. So far, only PRMT5 has been identified as the AGO/PIWI R-met writer in higher eukaryotes. We uncovered that AGO1, the main PTGS effector regulating plant development, contains unique R-met features among the AGO/PIWI superfamily, and outstanding in eukaryotes. Indeed, AGO1 contains both symmetric (sDMA) and asymmetric (aDMA) R-dimethylations and is dually targeted by PRMT5 and by another type I PRMT in Arabidopsis thaliana. We showed also that loss of sDMA didn't compromise AtAGO1 subcellular trafficking in planta. Interestingly, we underscored that AtPRMT5 specifically promotes the loading of phasiRNA in AtAGO1. All our observations bring to consider this dual regulation of AtAGO1 in plant development and response to environment, and pinpoint the complexity of AGO1 post-translational regulation.
Topics: Animals; Arabidopsis; Arabidopsis Proteins; Arginine; Argonaute Proteins; Eukaryota; Plants; RNA Interference; Protein-Arginine N-Methyltransferases
PubMed: 38321923
DOI: 10.1093/nar/gkae045 -
Trends in Endocrinology and Metabolism:... Apr 2024Mitochondria play multiple critical roles in cellular activity. In particular, mitochondrial translation is pivotal in the regulation of mitochondrial and cellular...
Mitochondria play multiple critical roles in cellular activity. In particular, mitochondrial translation is pivotal in the regulation of mitochondrial and cellular homeostasis. In this forum article, we discuss human mitochondrial tRNA metabolism and highlight its tight connection with various mitochondrial diseases caused by mutations in aminoacyl-tRNA synthetases, tRNAs, and tRNA-modifying enzymes.
Topics: Humans; Mitochondria; Amino Acyl-tRNA Synthetases; RNA, Transfer
PubMed: 38307811
DOI: 10.1016/j.tem.2024.01.002