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Scientific Reports Feb 2021Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism characterized by generalized muscle rigidity, increased body temperature,... (Clinical Trial)
Clinical Trial
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, hyperkalemia and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca release from myotubes via the ryanodine receptor type 1 (RYR1) and the voltage-dependent L-type calcium channel (CACNA1S). As more than 300 variants of unknown significance have been detected to date, we examined whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants. In this diagnostic accuracy study, blood samples from 235 individuals with a history of a clinical malignant hyperthermia or their close relatives were genetically screened for RYR1 variants of all 106 RYR1 exons and additionally for known variants of CACNA1S. In vitro contracture tests were conducted on muscle biopsies obtained from all individuals, independently of whether a pathogenic variant, a variant of unknown significance or no variant was detected. Comparisons were made to three established bioinformatic pathogenicity detection tools to identify the clinical impact of the variants of unknown significance. All detected genetic variants were tested for pathogenicity by three in silico approaches and compared to the in vitro contracture test. Sensitivity and specificity of exon screening of all individuals listed in our MH database was analyzed. Exon screening identified 97 (41%) of the 235 individuals as carriers of pathogenic variants. Variants of unknown significance were detected in 21 individuals. Variants of unknown significance were subdivided into 19 malignant-hyperthermia-susceptible individuals and 2 non-malignant-hyperthermia-susceptible individuals. All pathogenic variants as well as the malignant-hyperthermia-suspectible variants were correctly identified by the bioinformatic prediction tools. Sensitivity of in silico approaches ranged between 0.71 and 0.98 (Polyphen 0.94 [CI 95% 0.75; 0.99]; Sift 0.98 [CI 95% 0.81; 0.99]; MutationTaster 0.92 [CI 95% 0.75; 0.99]). Specificity differed depending on the used tool (Polphen 0.98 [CI 95% 0.32; 0.99]; Sift 0.98 [CI 95% 0.32; 0.99]; MutationTaster 0.00 [CI 95% 0.00; 0.60]). All pathogenic variants and variants of unknown significance were scored as probably damaging in individuals, demonstrating a high sensitivity. Specificity was very low in one of the three tested programs. However, due to potential genotype-phenotype discordance, bioinformatic prediction tools are currently of limited value in diagnosing pathogenicity of MH-susceptible variants.
Topics: Adult; Calcium Channels, L-Type; Databases, Nucleic Acid; Exons; Female; Genetic Variation; Humans; Male; Malignant Hyperthermia; Middle Aged; Predictive Value of Tests; Retrospective Studies; Ryanodine Receptor Calcium Release Channel
PubMed: 33564012
DOI: 10.1038/s41598-021-82024-7 -
Anesthesiology Nov 2019
Topics: Genetic Predisposition to Disease; Humans; Malignant Hyperthermia; Mutation; Penetrance; Ryanodine Receptor Calcium Release Channel
PubMed: 31335544
DOI: 10.1097/ALN.0000000000002884 -
Cells Jun 2022The role of Heat Shock Proteins (HSPs) is a "double-edged sword" with regards to tumors. The location and interactions of HSPs determine their pro- or antitumor... (Review)
Review
The role of Heat Shock Proteins (HSPs) is a "double-edged sword" with regards to tumors. The location and interactions of HSPs determine their pro- or antitumor activity. The present review includes an overview of the relevant functions of HSPs, which could improve their antitumor activity. Promoting the antitumor processes could assist in the local and systemic management of cancer. We explore the possibility of achieving this by manipulating the electromagnetic interactions within the tumor microenvironment. An appropriate electric field may select and affect the cancer cells using the electric heterogeneity of the tumor tissue. This review describes the method proposed to effect such changes: amplitude-modulated radiofrequency (amRF) applied with a 13.56 MHz carrier frequency. We summarize the preclinical investigations of the amRF on the HSPs in malignant cells. The preclinical studies show the promotion of the expression of HSP70 on the plasma membrane, participating in the immunogenic cell death (ICD) pathway. The sequence of guided molecular changes triggers innate and adaptive immune reactions. The amRF promotes the secretion of HSP70 also in the extracellular matrix. The extracellular HSP70 accompanied by free HMGB1 and membrane-expressed calreticulin (CRT) form damage-associated molecular patterns encouraging the dendritic cells' maturing for antigen presentation. The process promotes CD8 killer T-cells. Clinical results demonstrate the potential of this immune process to trigger a systemic effect. We conclude that the properly applied amRF promotes antitumor HSP activity, and in situ, it could support the tumor-specific immune effects produced locally but acting systemically for disseminated cells and metastatic lesions.
Topics: Antigen Presentation; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Immunotherapy; Neoplasms; Tumor Microenvironment
PubMed: 35681533
DOI: 10.3390/cells11111838 -
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 -
Frontiers in Cell and Developmental... 2022Cancer is still one of the world's deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost... (Review)
Review
Cancer is still one of the world's deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost worldwide. Although chemotherapy is most widely used methodology to treat cancer, poor pharmacokinetic parameters of anticancer drugs render them less effective. Novel nano-drug delivery systems have the caliber to improve the solubility and biocompatibility of various such chemical compounds. In this regard, cyclodextrins (CD), a group of natural nano-oligosaccharide possessing unique physicochemical characteristics has been highly exploited for drug delivery and other pharmaceutical purposes. Their cup-like structure and amphiphilic nature allows better accumulation of drugs, improved solubility, and stability, whereas CDs supramolecular chemical compatibility renders it to be highly receptive to various kinds of functionalization. Therefore combining physical, chemical, and bio-engineering approaches at nanoscale to specifically target the tumor cells can help in maximizing the tumor damage without harming non-malignant cells. Numerous combinations of CD nanocomposites were developed over the years, which employed photodynamic, photothermal therapy, chemotherapy, and hyperthermia methods, particularly targeting cancer cells. In this review, we discuss the vivid roles of cyclodextrin nanocomposites developed for the treatment and theranostics of most important cancers to highlight its clinical significance and potential as a medical tool.
PubMed: 36158215
DOI: 10.3389/fcell.2022.984311 -
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 -
Nature Communications Apr 2023The survival of malignant tumors is highly dependent on their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy. However, precisely...
The survival of malignant tumors is highly dependent on their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy. However, precisely dismantling self-defenses to amplify antitumor potency remains unexplored. Herein, we demonstrate that nanoparticle-mediated transient receptor potential vanilloid member 1 (TRPV1) channel blockade potentiates thermo-immunotherapy via suppressing heat shock factor 1 (HSF1)-mediated dual self-defense pathways. TRPV1 blockade inhibits hyperthermia-induced calcium influx and subsequent nuclear translocation of HSF1, which selectively suppresses stressfully overexpressed HSP70 for enhancing thermotherapeutic efficacy against a variety of primary, metastatic and recurrent tumor models. Particularly, the suppression of HSF1 translocation further restrains the transforming growth factor β (TGFβ) pathway to degrade the tumor stroma, which improves the infiltration of antitumor therapeutics (e.g. anti-PD-L1 antibody) and immune cells into highly fibrotic and immunosuppressive pancreatic cancers. As a result, TRPV1 blockade retrieves thermo-immunotherapy with tumor-eradicable and immune memory effects. The nanoparticle-mediated TRPV1 blockade represents as an effective approach to dismantle self-defenses for potent cancer therapy.
Topics: Humans; Transient Receptor Potential Channels; Hyperthermia, Induced; Neoplasm Recurrence, Local; Antineoplastic Agents; Heat-Shock Response; Immunotherapy; Heat Shock Transcription Factors; TRPV Cation Channels
PubMed: 37120615
DOI: 10.1038/s41467-023-38128-x -
Boletin Medico Del Hospital Infantil de... 2020Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile...
BACKGROUND
Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures).
CASE REPORT
We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment.
CONCLUSIONS
Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.
Topics: Adenoidectomy; Anesthetics, Inhalation; Child; Dantrolene; Female; Humans; Malignant Hyperthermia; Sevoflurane
PubMed: 33186346
DOI: 10.24875/BMHIM.20000047 -
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 -
Orphanet Journal of Rare Diseases Jul 2022Malignant hyperthermia (MH) is a rare, hereditary disease with a hypermetabolic response to volatile anesthetics/succinylcholine. Susceptible patients face difficulties...
BACKGROUND
Malignant hyperthermia (MH) is a rare, hereditary disease with a hypermetabolic response to volatile anesthetics/succinylcholine. Susceptible patients face difficulties due to a lack of knowledge about MH. As informational materials could increase knowledge and adherence to prevention/therapy, digital information about rare diseases validated for patients is needed. Our objective was to evaluate the following: (1) the impact of digital manuals on the knowledge/quality of life of MH patients and (2) access to MH services.
MATERIALS AND METHODS
Fifty MH-susceptible patients filled out a virtual questionnaire twice (demographic/economic/clinical data, MH knowledge and impact on daily life, and SF-36 quality of life). Test groups 1 (n = 17) and 2 (n = 16) were evaluated 30 and 180 days after receiving a digital manual, and the control group (n = 17; without manual) was evaluated after 180 days. We collected the MH service data about the number of contacts.
RESULTS
Twenty-four (48%) patients reported problems in personal/professional life, sports, clinical/surgical/dental treatments, and military service, in addition to concerns about emergency care and complaints of sequelae. The percentage of correct answers in the second MH knowledge questionnaire increased for test group 2 (62% vs. 74.1%; unpaired t test, p < 0.01), was significantly greater in test groups 1 (68.1%) and 2 (74.1%) than in the control group (56.5%; Kruskal-Wallis, p < 0.05), and correlated with more time studying the manual and reports of MH-related problems (multiple regression, p < 0.05).
CONCLUSIONS
The digital manual improved patients' MH knowledge. Online contacts with the MH service increased, allowing greater information dissemination. As informational materials could increase knowledge/adherence to prevention/therapy, digital information about MH validated for patients should be implemented.
Topics: Humans; Malignant Hyperthermia; Patient Education as Topic; Quality of Life; Succinylcholine
PubMed: 35841058
DOI: 10.1186/s13023-022-02435-1