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Neuromuscular Disorders : NMD Dec 2023Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these...
Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these individuals carry mutations in RYR1, the gene encoding the ryanodine receptor calcium channel of skeletal muscle. In this study, we performed functional analysis of 5 RYR1 variants identified in members from 8 families who had been diagnosed by the IVCT. Of the 68 individuals enrolled in the study, 43 were diagnosed as MHS, 23 as MHN, and 2 individuals were not tested. Here we demonstrate that the 5 RyR1 variants cause hypersensitivity to RyR1 agonist-mediated calcium release. According to the EMHG scoring matrix these five genetic variants can be classified as follows: c.8638G>A (p.E2880K) and c.11314C>T (p.R3772W) likely pathogenic, c.11416G>A (p.G3806R), c.14627A>G (p.K4876R) and c.14813T>C (p.I4938T), pathogenic (RefSeq NM_000540.3). We propose that the newly functionally characterized RYR1 variants, be included in the panel of variants to be used for the molecular diagnosis of MHS.
Topics: Humans; Calcium; Genetic Predisposition to Disease; Malignant Hyperthermia; Muscle, Skeletal; Mutation; Ryanodine Receptor Calcium Release Channel
PubMed: 37996280
DOI: 10.1016/j.nmd.2023.10.019 -
The Journal of Biological Chemistry Aug 2023Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to...
Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca channel Ca1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, Ca1.1-R174W. Heterozygous (HET) and homozygous (HOM) Ca1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of Ca1.1 by quantitative PCR, Western blot, [H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible Ca1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the Ca1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca and Na measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. Ca1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.
Topics: Animals; Mice; Calcium; Halothane; Heat-Shock Response; Malignant Hyperthermia; Muscle, Skeletal; Mutation; Ryanodine Receptor Calcium Release Channel; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
PubMed: 37392848
DOI: 10.1016/j.jbc.2023.104992 -
Materials Today. Bio Dec 2023Aggressive benign, malignant and metastatic bone tumors can greatly decrease the quality of patients' lives and even lead to substantial mortality. Several clinical... (Review)
Review
Aggressive benign, malignant and metastatic bone tumors can greatly decrease the quality of patients' lives and even lead to substantial mortality. Several clinical therapeutic strategies have been developed to treat bone tumors, including preoperative chemotherapy, surgical resection of the tumor tissue, and subsequent systemic chemo- or radiotherapy. However, those strategies are associated with inevitable drawbacks, such as severe side effects, substantial local tumor recurrence, and difficult-to-treat bone defects after tumor resection. To overcome these shortcomings and achieve satisfactory clinical outcomes, advanced bifunctional biomaterials which simultaneously promote bone regeneration and combat bone tumor growth are increasingly advocated. These bifunctional bone substitute materials fill bone defects following bone tumor resection and subsequently exert local anticancer effects. Here we describe various types of the most prevalent bone tumors and provide an overview of common treatment options. Subsequently, we review current progress regarding the development of bifunctional bone substitute materials combining osteogenic and anticancer efficacy. To this end, we categorize these biomaterials based on their anticancer mechanism deriving from i) intrinsic biomaterial properties, ii) local drug release of anticancer agents, and iii) oxidative stress-inducing and iv) hyperthermia-inducing biomaterials. Consequently, this review offers researchers, surgeons and oncologists an up-to-date overview of our current knowledge on bone tumors, their treatment options, and design of advanced bifunctional biomaterials with strong potential for clinical application in oncological orthopedics.
PubMed: 38149015
DOI: 10.1016/j.mtbio.2023.100889 -
Biomaterials Research Nov 2023Malignant bone tumors are characterized by severe disability rate, mortality rate, and heavy recurrence rate owing to the complex pathogenesis and insidious disease... (Review)
Review
Malignant bone tumors are characterized by severe disability rate, mortality rate, and heavy recurrence rate owing to the complex pathogenesis and insidious disease progression, which seriously affect the terminal quality of patients' lives. Photothermal therapy (PTT) has emerged as an attractive adjunctive treatment offering prominent hyperthermal therapeutic effects to enhance the effectiveness of surgical treatment and avoid recurrence. Simultaneously, various advanced biomaterials with photothermal capacity are currently created to address malignant bone tumors, performing distinctive biological functions, including nanomaterials, bioceramics (BC), polymers, and hydrogels et al. Furthermore, PTT-related combination therapeutic strategies can provide more significant curative benefits by reducing drug toxicity, improving tumor-killing efficiency, stimulating anti-cancer immunity, and improving immune sensitivity relative to monotherapy, even in complex tumor microenvironments (TME). This review summarizes the current advanced biomaterials applicable in PTT and relevant combination therapies on malignant bone tumors for the first time. The multiple choices of advanced biomaterials, treatment methods, and new prospects for future research in treating malignant bone tumors with PTT are generalized to provide guidance. Malignant bone tumors seriously affect the terminal quality of patients' lives. Photothermal therapy (PTT) has emerged as an attractive adjunctive treatment enhancing the effectiveness of surgical treatment and avoiding recurrence. In this review, advanced biomaterials applicable in the PTT of malignant bone tumors and their distinctive biological functions are comprehensively summarized for the first time. Simultaneously, multiple PTT-related combination therapeutic strategies are classified to optimize practical clinical issues, contributing to the selection of biomaterials, therapeutic alternatives, and research perspectives for the adjuvant treatment of malignant bone tumors with PTT in the future.
PubMed: 37968707
DOI: 10.1186/s40824-023-00453-z -
Cureus Apr 2024As a result of the widespread prevalence of anesthetic usage, anesthesia-related complications are well studied, ranging from benign postoperative nausea and vomiting to... (Review)
Review
As a result of the widespread prevalence of anesthetic usage, anesthesia-related complications are well studied, ranging from benign postoperative nausea and vomiting to potentially fatal complications, such as paralysis, malignant hyperthermia, and death. However, one intersection that still needs further analysis is the relationship between vector-borne illnesses (VBIs) and anesthetic complications. With the advent of climate change and global warming, what were previously endemic vectors have spread far beyond their typical regions, resulting in the spread of VBI. As the incidence of VBIs rapidly increases in the United States, operations for diagnostic testing, and thus the identification and treatments of these VBIs, have significantly diminished. A literature review was conducted to analyze case reports of patients with VBIs and anesthetic concerns with sources from PubMed and Google Scholar databases, and a wide range of complications were found.
PubMed: 38586230
DOI: 10.7759/cureus.57517 -
Advanced Science (Weinheim,... Jul 2023Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the...
Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the tumor. Combination therapy can efficiently enhance tumor treatment by stimulating multiple pathways and regulating the tumor immune microenvironment. Nanodrug delivery systems have become attractive candidates for combined strategies for liver cancer treatment. This study reports a nano ultrasound contrast agent (arsenic trioxide (ATO)/PFH NPs@Au-cRGD) to integrate diagnosis and treatment for efficient ultrasound imaging and liver cancer therapy. This nanodrug delivery system promotes tumor-associated antigens release through ATO-induced ferroptosis and photothermal-induced immunogenic cell death, enhancing the synergistic effects of ATO and photothermal therapy in human Huh7 and mouse Hepa1-6 cells. This drug delivery system successfully activates the antitumor immune response and promotes macrophage M1 polarization in tumor microenvironment with low side effects in subcutaneous and orthotopic liver cancer. Furthermore, tumor metastasis is inhibited and long-term immunological memory is also established in orthotopic liver cancer when the nanodrug delivery system is combined with anti-programmed death-ligand 1 (PD-L1) immunotherapy. This safe nanodrug delivery system can enhance antitumor therapy, inhibit lung metastasis, and achieve visual assessment of therapeutic efficacy, providing substantial potential in clinic applications for liver cancer.
Topics: Mice; Humans; Animals; Contrast Media; Photothermal Therapy; Phototherapy; Hyperthermia, Induced; Mice, Inbred Strains; Ultrasonography; Liver Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37162268
DOI: 10.1002/advs.202300878 -
International Journal of Nanomedicine 2023Radiotherapy is a pivotal method for treating malignant tumors, and enhancing the therapeutic gain ratio of radiotherapy through physical techniques is the direction of... (Review)
Review
The Refined Application and Evolution of Nanotechnology in Enhancing Radiosensitivity During Radiotherapy: Transitioning from Gold Nanoparticles to Multifunctional Nanomaterials.
Radiotherapy is a pivotal method for treating malignant tumors, and enhancing the therapeutic gain ratio of radiotherapy through physical techniques is the direction of modern precision radiotherapy. Due to the inherent physical properties of high-energy radiation, enhancing the therapeutic gain ratio of radiotherapy through radiophysical techniques inevitably encounters challenges. The combination of hyperthermia and radiotherapy can enhance the radiosensitivity of tumor cells, reduce their radioresistance, and holds significant clinical utility in radiotherapy. Multifunctional nanomaterials with excellent biocompatibility and safety have garnered widespread attention in tumor hyperthermia research, demonstrating promising potential. Utilizing nanotechnology as a sensitizing carrier in conjunction with radiotherapy, and high atomic number nanomaterials can also serve independently as radiosensitizing carriers. This synergy between tumor hyperthermia and radiotherapy may overcome many challenges currently limiting tumor radiotherapy, offering new opportunities for its further advancement. In recent years, the continuous progress in the synthesis and design of novel nanomaterials will propel the future development of medical imaging and cancer treatment. This article summarizes the radiosensitizing mechanisms and effects based on gold nanotechnology and provides an overview of the advancements of other nanoparticles (such as bismuth-based nanomaterials, magnetic nanomaterials, selenium nanomaterials, etc.) in the process of radiation therapy.
Topics: Humans; Gold; Metal Nanoparticles; Nanostructures; Nanotechnology; Radiation Tolerance; Neoplasms
PubMed: 37936951
DOI: 10.2147/IJN.S436268 -
Journal of Clinical Medicine May 2024Patients with neuromuscular diseases are particularly vulnerable in the perioperative period to the development of pulmonary and cardiac complications, or medication... (Review)
Review
Patients with neuromuscular diseases are particularly vulnerable in the perioperative period to the development of pulmonary and cardiac complications, or medication side effects. These risks could include hypoventilation, aspiration pneumonia, exacerbation of underlying cardiomyopathy, arrhythmias, adrenal insufficiency, prolonged neuromuscular blockade, issues related to thermoregulation, rhabdomyolysis, malignant hyperthermia, or prolonged mechanical ventilation. Interventions at each of the perioperative stages can be implemented to mitigate these risks. A careful pre-operative evaluation may help identify risk factors so that appropriate interventions are initiated, including cardiology consultation, pulmonary function tests, initiation of noninvasive ventilation, or implementation of preventive measures. Important intraoperative issues include positioning, airway and anesthetic management, and adequate ventilation. The postoperative period may require correction of electrolyte abnormalities, control of secretions with medications, manual or mechanical cough assistance, avoiding the risk of reintubation, judicious pain control, and appropriate medication management. The aim of this review is to increase awareness of the particular surgical challenges in this vulnerable population, and guide the clinician on the various evaluations and interventions that may result in a favorable surgical outcome.
PubMed: 38792504
DOI: 10.3390/jcm13102963 -
Biomolecules Nov 2023Calsequestrin (CASQ) is a key intra-sarcoplasmic reticulum Ca-handling protein that plays a pivotal role in the contraction of cardiac and skeletal muscles. Its... (Review)
Review
Calsequestrin (CASQ) is a key intra-sarcoplasmic reticulum Ca-handling protein that plays a pivotal role in the contraction of cardiac and skeletal muscles. Its Ca-dependent polymerization dynamics shape the translation of electric excitation signals to the Ca-induced contraction of the actin-myosin architecture. Mutations in CASQ are linked to life-threatening pathological conditions, including tubular aggregate myopathy, malignant hyperthermia, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The variability in the penetrance of these phenotypes and the lack of a clear understanding of the disease mechanisms associated with CASQ mutations pose a major challenge to the development of effective therapeutic strategies. In vitro studies have mainly focused on the polymerization and Ca-buffering properties of CASQ but have provided little insight into the complex interplay of structural and functional changes that underlie disease. In this review, the biochemical and structural natures of CASQ are explored in-depth, while emphasizing their direct and indirect consequences for muscle Ca physiology. We propose a novel functional classification of CASQ pathological missense mutations based on the structural stability of the monomer, dimer, or linear polymer conformation. We also highlight emerging similarities between polymeric CASQ and polyelectrolyte systems, emphasizing the potential for the use of this paradigm to guide further research.
Topics: Humans; Calsequestrin; Heart; Tachycardia, Ventricular; Sarcoplasmic Reticulum; Mutation, Missense; Calcium
PubMed: 38136565
DOI: 10.3390/biom13121693