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Biomedicines Jun 2024Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients.... (Review)
Review
Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients. Conventional treatment options such as surgery and endovascular therapy often are insufficient for cure. There is a growing body of knowledge on the genetic and molecular underpinnings of AVM development and maintenance, making the future of precision medicine a real possibility for AVM management. Here, we review the pathophysiology of AVM development across various cell types, with a focus on current and potential druggable targets and their therapeutic potentials in both sporadic and familial AVM populations.
PubMed: 38927496
DOI: 10.3390/biomedicines12061289 -
Biomolecules Jun 2024Bacterial peptidyl tRNA hydrolase (Pth) or Pth1 emerges as a pivotal enzyme involved in the maintenance of cellular homeostasis by catalyzing the release of peptidyl... (Review)
Review
Bacterial peptidyl tRNA hydrolase (Pth) or Pth1 emerges as a pivotal enzyme involved in the maintenance of cellular homeostasis by catalyzing the release of peptidyl moieties from peptidyl-tRNA molecules and the maintenance of a free pool of specific tRNAs. This enzyme is vital for bacterial cells and an emerging drug target for various bacterial infections. Understanding the enzymatic mechanisms and structural intricacies of bacterial Pth is pivotal in designing novel therapeutics to combat antibiotic resistance. This review provides a comprehensive analysis of the multifaceted roles of Pth in bacterial physiology, shedding light on its significance as a potential drug target. This article delves into the diverse functions of Pth, encompassing its involvement in ribosome rescue, the maintenance of a free tRNA pool in bacterial systems, the regulation of translation fidelity, and stress response pathways within bacterial systems. Moreover, it also explores the druggability of bacterial Pth, emphasizing its promise as a target for antibacterial agents and highlighting the challenges associated with developing specific inhibitors against this enzyme. Structural elucidation represents a cornerstone in unraveling the catalytic mechanisms and substrate recognition of Pth. This review encapsulates the current structural insights of Pth garnered through various biophysical techniques, such as X-ray crystallography and NMR spectroscopy, providing a detailed understanding of the enzyme's architecture and conformational dynamics. Additionally, biophysical aspects, including its interaction with ligands, inhibitors, and substrates, are discussed, elucidating the molecular basis of bacterial Pth's function and its potential use in drug design strategies. Through this review article, we aim to put together all the available information on bacterial Pth and emphasize its potential in advancing innovative therapeutic interventions and combating bacterial infections.
Topics: Bacteria; Anti-Bacterial Agents; Carboxylic Ester Hydrolases; Humans; Bacterial Proteins; Bacterial Infections
PubMed: 38927071
DOI: 10.3390/biom14060668 -
Biomolecules May 2024Insomnia, also known as sleeplessness, is a sleep disorder due to which people have trouble sleeping, followed by daytime sleepiness, low energy, irritability, and a...
Insomnia, also known as sleeplessness, is a sleep disorder due to which people have trouble sleeping, followed by daytime sleepiness, low energy, irritability, and a depressed mood. It may result in an increased risk of accidents of all kinds as well as problems focusing and learning. Dietary supplements have become popular products for alleviating insomnia, while the lenient requirements for pre-market research result in unintelligible mechanisms of different combinations of dietary supplements. In this study, we aim to systematically identify the molecular mechanisms of a sleep cocktail's pharmacological effects based on findings from network pharmacology and molecular docking. A total of 249 targets of the sleep cocktail for the treatment of insomnia were identified and enrichment analysis revealed multiple pathways involved in the nervous system and inflammation. Protein-protein interaction (PPI) network analysis and molecular complex detection (MCODE) analysis yielded 10 hub genes, including AKT1, ADORA1, BCL2, CREB1, IL6, JUN, RELA, STAT3, TNF, and TP53. Results from weighted correlation network analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of insomnia-related transcriptome data from peripheral blood mononuclear cells (PBMCs) showed that a sleep cocktail may also ease insomnia via regulating the inflammatory response. Molecular docking results reveal good affinity of Sleep Cocktail to 9 selected key targets. It is noteworthy that the crucial target HSP90AA1 binds to melatonin most stably, which was further validated by MD simulation.
Topics: Humans; Molecular Docking Simulation; Network Pharmacology; Protein Interaction Maps; Sleep Initiation and Maintenance Disorders; Dietary Supplements; Sleep
PubMed: 38927034
DOI: 10.3390/biom14060630 -
BMC Cardiovascular Disorders Jun 2024The relationships among left heart remodeling, cardiac function, and cardiovascular events (CEs) in patients with heart failure (HF) with preserved ejection fraction...
BACKGROUND
The relationships among left heart remodeling, cardiac function, and cardiovascular events (CEs) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) undergoing maintenance hemodialysis (MHD) remain unclear. We evaluated the echocardiographic characteristics and clinical outcomes of such patients with diverse left ventricular geometric (LVG) configurations.
METHODS
Overall, 210 patients with HFpEF undergoing MHD (cases) and 60 healthy controls were enrolled. Cases were divided into four subgroups based on LVG and were followed up for three years. The primary outcomes were the first CEs and all-cause mortality.
RESULTS
Left ventricular ejection fraction (LVEF) and right ventricular systolic function did significantly differ between cases and controls, whereas echocardiographic parameters of cardiac structure, diastolic function, and left ventricular global longitudinal strain (LVGLS) differed significantly. The proportion of cases with left ventricular hypertrophy (LVH) was 67.1%. In addition, 2.38%, 21.90%, 12.86%, and 62.86% of cases presented with normal geometry (NG), concentric remodeling (CR), eccentric hypertrophy (EH), and concentric hypertrophy (CH), respectively. The left atrial diameter (LAD) was the largest and cardiac output index was the lowest in the EH subgroup. The score of Acute Dialysis Quality Initiative Workgroup (ADQI) HF class was worse in the EH subgroup than in other subgroups at baseline. The proportions of cases free of adverse CEs in the EH subgroup at 12, 24, and 36 months were 40.2%, 14.8%, and 0%, respectively, and the survival rates were 85.2%, 29.6%, 3.7%, respectively, which were significantly lower than those in other subgroups. Multivariate Cox regression revealed that age, TNI (Troponin I), EH, left ventricular mass index (LVMI), age and EH configuration were independent risk factors for adverse CEs and all-cause mortality in the cases.
CONCLUSION
Most patients with HFpEF receiving MHD have LVH and diastolic dysfunction. Among the four LVGs, patients with HFpEF undergoing MHD who exhibited EH had the highest risk of adverse CEs and all-cause mortality.
Topics: Humans; Male; Renal Dialysis; Female; Stroke Volume; Heart Failure; Ventricular Remodeling; Middle Aged; Ventricular Function, Left; Aged; Hypertrophy, Left Ventricular; Time Factors; Treatment Outcome; Risk Factors; Risk Assessment; Case-Control Studies
PubMed: 38926680
DOI: 10.1186/s12872-024-03985-x -
Nature Communications Jun 2024Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of...
Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.
Topics: Animals; Oxidative Stress; Interferon-gamma; Myositis; Humans; Female; Reactive Oxygen Species; Mice; Mice, Inbred NOD; Mitochondria; Muscle, Skeletal; Disease Models, Animal; Mitochondria, Muscle; Mice, Knockout; Myoblasts
PubMed: 38926363
DOI: 10.1038/s41467-024-49460-1 -
Bulletin Du Cancer Jun 2024Treatment of pediatric high-risk acute myeloid leukemia (AML), defined either on molecular or cytogenetic features, relies on bone marrow transplant after cytologic...
Treatment of pediatric high-risk acute myeloid leukemia (AML), defined either on molecular or cytogenetic features, relies on bone marrow transplant after cytologic remission. However, relapse remains the first post-transplant cause of mortality. In this 13 session of practice harmonization of the francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), our group worked on recommendations regarding the management of post-transplant relapse in AML pediatric patients based on international literature, national survey and expert opinion. Overall, immunomodulation strategy relying on both measurable residual disease (MRD) and chimerism evaluation should be used for high-risk AML. In very high-risk (VHR) AML with a 5-year overall survival ≤30 %, a post-transplant maintenance should be proposed using either hypomethylating agents, combined with DLI whenever possible, or FLT3 tyrosine kinase inhibitors if this target is present on leukemia cells. In the pre-emptive or early relapse settings (< 6 months post-transplant), treatments combining DLI, Azacytidine and Venetoclax should be considered. Access to phase I/II trails for targeted therapies (menin, IDH or JAK inhibitors) should be discussed in each patient according to the underlying molecular abnormalities of the disease.
PubMed: 38926053
DOI: 10.1016/j.bulcan.2024.02.006 -
Journal of Prosthodontic Research Jun 2024Marginal bone loss (MBL) occurs in the periapical cervical bone after dental implant placement and abutment connection. MBL may not result in peri-implantitis; however,...
PURPOSE
Marginal bone loss (MBL) occurs in the periapical cervical bone after dental implant placement and abutment connection. MBL may not result in peri-implantitis; however, it is always accompanied by MBL. Recent studies have demonstrated that early MBL is a predictor of peri-implantitis. In this narrative review, we aimed to provide an evidence base for recommended treatment strategies for clinicians to prevent MBL.
STUDY SELECTION
We reviewed the recent literature and performed a narrative synthesis of the evidence, focusing on available systematic reviews and meta-analyses of implant marginal bone resorption.
RESULTS
The available evidence indicates that certain biological, material, and technical factors can influence MBL and consequently dictate the risk of developing peri-implant disease in later years. The order of the impact of the strength of each factor is unknown. Current recommendations to prevent MBL include controlling patients' smoking and hemoglobin A1c levels to sufficiently low levels before surgery and throughout their lifetime. Regarding the material, a platform-switching, conical-connecting implant system, and an abutment with a height of at least 2 mm should be selected. Placement should be performed using techniques that ensure sufficient soft tissue (keratinized gingival width > 2 mm, supracrestal tissue height > 3 mm), and non-undersized preparations in the cortical bone should be made with connected concave abutments during primary or secondary surgery. Patients should receive supportive peri-implant therapy during maintenance.
CONCLUSIONS
MBL development is multifactorial and can be reduced by considering the biological, material, and technical factors.
PubMed: 38925986
DOI: 10.2186/jpr.JPR_D_23_00223 -
Ceska a Slovenska Oftalmologie :... 2024This article presents an overview of treatment regimens of drugs containing antivascular endothelial growth factor for the treatment of neovascular form of age-related... (Review)
Review
This article presents an overview of treatment regimens of drugs containing antivascular endothelial growth factor for the treatment of neovascular form of age-related macular degeneration. Currently, drugs containing antivascular endothelial growth factor are the only effective treatment for this chronic and progressive disease. The treatment regimens for this disease in the last two decades have seen a shift from a simple endeavor to stabilize the disease to achieving maximum improvement of visual acuity and its maintenance, with improvement of the patient's quality of life and a minimal treatment burden on patients and their families. Other goals of the alternative dosing regimens that have replaced the original fixed regimens were greater individualization of the dosing regimen, better patient cooperation, saving financial costs and reducing the burden on application centers. Age-related macular degeneration, whether dry form or wet form, represents a serious health and socioeconomic problem, as the disease is one of the most common causes of severe and irreversible central visual acuity disorders up to the degree of practical blindness of one or both eyes in people over 50 years of age in developed industrialized countries. The most important issue is to ensure early diagnosis of this disease, followed by prompt and continuous treatment with an individualized proactive treatment regimen, with the aim of stabilizing and improving anatomical and functional results.
Topics: Humans; Angiogenesis Inhibitors; Macular Degeneration; Vascular Endothelial Growth Factor A; Bevacizumab
PubMed: 38925899
DOI: 10.31348/2024/25 -
BMJ Open Jun 2024Patients with cirrhosis awaiting liver transplantation (LT) are often frail, and malnourished. The period of time on the waitlist provides an opportunity to improve...
INTRODUCTION
Patients with cirrhosis awaiting liver transplantation (LT) are often frail, and malnourished. The period of time on the waitlist provides an opportunity to improve their physical fitness. Prehabilitation appears to improve the physical fitness of patients before major surgery. Little is known about prehabilitation in patients with cirrhosis. The aim of this feasibility study will be to investigate the feasibility, safety, and effectiveness of a multimodal prehabilitation programme in this patient population.
METHODS AND ANALYSIS
This is an open-label single-arm feasibility trial recruiting 25 consecutive adult patients with cirrhosis active on the LT waiting list of the McGill University Health Centre (MUHC). Individuals will be excluded based on criteria developed for the safe exercise training in patients with cirrhosis. Enrolled individuals will participate in a multimodal prehabilitation programme conducted at the PeriOperative Programme complex of the MUHC. It includes exercise training with a certified kinesiologist (aerobic and resistance training), nutritional optimisation with a registered dietician and psychological support with a nurse specialist. The exercise training programme is divided into an induction phase with three sessions per week for 4 weeks followed by a maintenance phase with one session every other week for 20 weeks. Aerobic training will be individualised based on result from cardiopulmonary exercise testing (CPET) and will include a high-intensity interval training on a cycle ergometer. Feasibility, adherence and acceptability of the intervention will be assessed. Adverse events will be reviewed before each visit. Changes in exercise capacity (6-minute walk test, CPET, liver frailty index), nutritional status and health-related quality of life will be assessed during the study. Post-transplantation outcomes will be recorded.
ETHICS AND DISSEMINATION
The research ethics board of the MUHC has approved this study (2021-7646). Our findings will be submitted for presentation at national and international conferences, and for peer-reviewed publication.
TRIAL REGISTRATION NUMBER
NCT05237583.
Topics: Humans; Liver Transplantation; Feasibility Studies; Liver Cirrhosis; Preoperative Exercise; Waiting Lists; Quality of Life; Physical Fitness; Adult; Exercise Therapy; Male; Female
PubMed: 38925705
DOI: 10.1136/bmjopen-2023-081362 -
BMJ Open Jun 2024Insomnia is a common health problem and cognitive-behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Insomnia is a common health problem and cognitive-behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we developed a digital CBT application (IIIP MED: Sleepy Med) as Software as a Medical Device for insomnia. This paper describes the study protocol for an exploratory randomised controlled trial (RCT) to evaluate effectiveness and safety of our developed digital CBT (dCBT) for 5 weeks compared with zolpidem tartrate for patients with insomnia disorder.
METHODS AND ANALYSIS
This proposed multicentre exploratory RCT will be conducted at the outpatient clinic of Chiba University Hospital, Akita University Hospital and Yoyogi Sleep Disorder Center, Japan. The study population comprises two parallel groups (dCBT and zolpidem) consisting of 15 participants each (n=30 in total) diagnosed with insomnia disorder who remain symptomatic at 4 weeks after sleep hygiene education. We will evaluate the effectiveness at baseline, week 5 (post-intervention) and week 10 (follow-up). The primary outcome will be the change of subjective sleep onset latency at week 5 from baseline. Secondary outcomes include sleep-related outcomes, such as objective sleep onset latency measured by mobile electroencephalography, functional improvement during the daytime and quality of life.
ETHICS AND DISSEMINATION
Ethics approval was granted by the Institutional Review Board of Chiba University Hospital (K2023001). All participants will be required to provide written informed consent. Results will be published in international journals.
TRIAL REGISTRATION NUMBER
jRCT2032230353.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Zolpidem; Cognitive Behavioral Therapy; Hypnotics and Sedatives; Adult; Randomized Controlled Trials as Topic; Female; Male; Treatment Outcome; Japan; Middle Aged
PubMed: 38925698
DOI: 10.1136/bmjopen-2023-081205