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ENeuro Aug 2023Volatile anesthetics reduce excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms which include inhibition of depolarization-evoked increases...
Volatile anesthetics reduce excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms which include inhibition of depolarization-evoked increases in presynaptic Ca concentration and blockade of postsynaptic excitatory glutamate receptors. The presynaptic sites of action leading to reduced electrically evoked increases in presynaptic Ca concentration and Ca-dependent exocytosis are unknown. Endoplasmic reticulum (ER) of Ca release via ryanodine receptor 1 (RyR1) and uptake by SERCA are essential for regulation intracellular Ca and are potential targets for anesthetic action. Mutations in sarcoplasmic reticulum (SR) release channels mediate volatile anesthetic-induced malignant hyperthermia (MH), a potentially fatal pharmacogenetic condition characterized by unregulated Ca release and muscle hypermetabolism. However, the impact of MH mutations on neuronal function are unknown. We used primary cultures of postnatal hippocampal neurons to analyze volatile anesthetic-induced changes in ER Ca dynamics using a genetically encoded ER-targeted fluorescent Ca sensor in both rat and mouse wild-type (WT) neurons and in mouse mutant neurons harboring the T4826I MH-susceptibility mutation. The volatile anesthetic isoflurane reduced both baseline and electrical stimulation-evoked increases in ER Ca concentration in neurons independent of its depression of presynaptic cytoplasmic Ca concentrations. Isoflurane and sevoflurane, but not propofol, depressed depolarization-evoked increases in ER Ca concentration significantly more in mouse T4826I mutant neurons than in wild-type neurons. The T4826I mutant neurons also showed markedly greater isoflurane-induced reductions in presynaptic cytosolic Ca concentration and synaptic vesicle (SV) exocytosis. These findings implicate RyR1 as a molecular target for the effects of isoflurane on presynaptic Ca handling.
Topics: Rats; Mice; Animals; Calcium; Isoflurane; Malignant Hyperthermia; Ryanodine Receptor Calcium Release Channel; Rodentia; Endoplasmic Reticulum; Neurons; Hippocampus
PubMed: 37591734
DOI: 10.1523/ENEURO.0114-23.2023 -
Journal For Immunotherapy of Cancer Aug 2023Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy...
Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial.
BACKGROUND
Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC.
METHODS
This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4-6 weeks before CRS-HIPEC leukapheresis was performed. 8-10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment.
RESULTS
All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5-23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation.
CONCLUSIONS
Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells was more pronounced in patients with longer PFS. These data provide rationale for future combination treatment strategies.
TRIAL REGISTRATION NUMBER
NTR7060; Dutch Trial Register (NTR).
Topics: Humans; Hyperthermic Intraperitoneal Chemotherapy; Cytoreduction Surgical Procedures; Antineoplastic Combined Chemotherapy Protocols; Hyperthermia, Induced; Mesothelioma, Malignant; Mesothelioma; Peritoneal Neoplasms; Adjuvants, Immunologic; Immunotherapy; Dendritic Cells
PubMed: 37536940
DOI: 10.1136/jitc-2023-007070 -
Anesthesiology Jan 2024Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering...
BACKGROUND
Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering anesthesia agents. Genomic screening for variants in MH-associated genes RYR1 and CACNA1S provides an opportunity to prevent morbidity and mortality. There are limited outcomes data from disclosing variants in RYR1, the most common MH susceptibility gene, in unselected populations. The authors sought to identify the rate of MH features or fulminant episodes after triggering agent exposure in an unselected population undergoing genomic screening including actionable RYR1 variants.
METHODS
The MyCode Community Health Initiative by Geisinger (USA) is an electronic health record-linked biobank that discloses pathogenic and likely pathogenic variants in clinically actionable genes to patient-participants. Available electronic anesthesia and ambulatory records for participants with actionable RYR1 results returned through December 2020 were evaluated for pertinent findings via double-coded chart reviews and reconciliation. Descriptive statistics for observed phenotypes were calculated.
RESULTS
One hundred fifty-two participants had an actionable RYR1 variant disclosed during the study period. None had previous documented genetic testing for MH susceptibility; one had previous contracture testing diagnosing MH susceptibility. Sixty-eight participants (44.7%) had anesthesia records documenting triggering agent exposure during at least one procedure. None received dantrolene treatment or had documented muscle rigidity, myoglobinuria, hyperkalemia, elevated creatine kinase, severe myalgia, or tea-colored urine. Of 120 possibly MH-related findings (postoperative intensive care unit admissions, hyperthermia, arterial blood gas evaluation, hypercapnia, or tachycardia), 112 (93.3%) were deemed unlikely to be MH events; 8 (6.7%) had insufficient records to determine etiology.
CONCLUSIONS
Results demonstrate a low frequency of classic intraanesthetic hypermetabolic phenotypes in an unselected population with actionable RYR1 variants. Further research on the actionability of screening for MH susceptibility in unselected populations, including economic impact, predictors of MH episodes, and expanded clinical phenotypes, is necessary.
Topics: Humans; Genetic Testing; Malignant Hyperthermia; Metagenomics; Mutation; Phenotype; Ryanodine Receptor Calcium Release Channel
PubMed: 37787745
DOI: 10.1097/ALN.0000000000004786 -
Risk Management and Healthcare Policy 2024Malignant hyperthermia (MH) is a hypermetabolic syndrome with high mortality rates. Early detection and prompt intravenous administration of dantrolene are crucial for...
BACKGROUND
Malignant hyperthermia (MH) is a hypermetabolic syndrome with high mortality rates. Early detection and prompt intravenous administration of dantrolene are crucial for effective management of MH. However, there is currently a lack of comprehensive nationwide surveys on the availability of dantrolene and anesthesiologists' understanding of MH in China.
METHODS
A nationwide survey was conducted between January 2022 and June 2022. Online questionnaires on the cognition of MH among anesthesiologists in China were sent through social platforms to anesthesiologists in mainland China. Data regarding participants' perception of MH-related knowledge, availability of domestic dantrolene, and reported MH cases were collected in this study.
RESULTS
Responses were collected from a total of 11,354 anesthesiologists representing 31 provinces across the Chinese mainland. Among the 11 scoring questions, the highest accuracy rates were observed for the question regarding therapeutic drugs for MH (99.3%) and the characteristics of MH (98.0%). Conversely, the question pertaining to the earliest clinical signs of MH had the lowest accuracy rate (23.5%). Significant variations were observed in the scores among different professional titles (=0.003), academic degree (<0.001), hospital classification (<0.001), and urban hierarchy (<0.001). Of the respondents, 919 (8.1%) anesthesiologists reported dantrolene availability in their hospitals, and 631 (5.6%) indicated unclear. A total of 136 hospitals in this survey reported at least one previous case of MH.
CONCLUSION
Mainland China faces challenges such as insufficient experience in diagnosing and treating MH, as well as difficulty in obtaining dantrolene. To improve the public awareness of MH, it is imperative to establish and promote a refined MH training system. Additionally, a streamlined and rapid dantrolene linkage emergency system should be implemented to ensure prompt access to the drug.
PubMed: 38562250
DOI: 10.2147/RMHP.S454895 -
Asian Journal of Surgery Aug 2023
PubMed: 37625965
DOI: 10.1016/j.asjsur.2023.08.016 -
Nanomaterials (Basel, Switzerland) Aug 2023Magnetic nanoparticles (MNPs) with various shapes and special (magnetic and thermal) properties are promising for magnetic hyperthermia. The efficiency of this therapy...
Magnetic nanoparticles (MNPs) with various shapes and special (magnetic and thermal) properties are promising for magnetic hyperthermia. The efficiency of this therapy depends mainly on the MNPs' physical characteristics: types, sizes and shapes. This paper presents the hyperthermic temperature values induced by cubic/sphere-shaped MNPs injected within a concentric tissue configuration (malignant and healthy tissues) when an external time-dependent magnetic field was applied. The space-time distribution of the nanoparticles as a result of their injection within a tumoral (benign/malign) tissue was simulated with the bioheat transport equation (Pennes equation). A complex thermo-fluid model that considers the space-time MNP transport and its heating was developed in Comsol Multiphysics. The cubic-shaped MNPs give a larger spatial distribution of the therapeutic temperature in the tumoral volume compared to the spherical-shaped ones. MNP doses that induce the therapeutic (hyperthermic) values of the temperature (40 ÷ 45 °C) in smaller volumes from the tumoral region were analyzed. The size of these regions (covered by the hyperthermic temperature values) was computed for different magnetite cubic/sphere-shaped MNP doses. Lower doses of the cubic-shaped MNPs give the hyperthermic values of the temperature in a larger volume from the tumoral region compared with the spheric-shaped MNPs. The MNP doses were expressed as a ratio between mass concentration and the maximum clinical accepted doses. This thermo-fluid analysis is an important computational instrument that allows the computations of the MNP doses that give therapeutic temperature values within tissues.
PubMed: 37630968
DOI: 10.3390/nano13162383 -
Cureus Sep 2023Purpose The diagnosis of malignant hyperthermia susceptibility (MHS) has significant implications for the perioperative period that may persist for generations....
Purpose The diagnosis of malignant hyperthermia susceptibility (MHS) has significant implications for the perioperative period that may persist for generations. Anesthetic medication options are reduced, anesthetic workstations require preparation to reduce exposure to inhaled volatile anesthetics, and patients may be excluded from surgery at ambulatory centers. In this study, we sought to better characterize the etiology of MHS diagnoses in our health system and the downstream effects of this diagnosis on anesthetic care. Methods We retrospectively reviewed the electronic medical records of 55 patients with a documented concern for MHS who received care at University of Florida (UF) Health between 2014 and 2020. We characterized the etiology of the patient's MHS diagnosis, whether this diagnosis was supported by formal genetic or muscle contracture testing, and the details of the recorded anesthetics that were delivered to these patients. Results The 55 patients with suspected MHS were evenly split between those with a family history of malignant hyperthermia (MH) (28/55) and those with a concern for MHS in their personal medical history (27/55). Of the 28 patients with a family history of MH, 16 reported that the affected family member was a first-degree relative, and two of these 16 reported that the affected family member had undergone confirmatory muscle contracture testing. Of the 27 patients with a personal history suspicious for MHS, two had undergone confirmatory genetic testing, and two patients had anesthetic records available for review where intraoperative MH was suspected and treated with dantrolene. An additional four patients were told of a concern about MHS due to another underlying diagnosis. No patients with a personal history suspicious of MHS had undergone confirmatory muscle contracture testing. These 55 patients underwent 87 anesthetics, and exclusively non-triggering anesthetic techniques were utilized in nearly all cases. In pediatric patients, some perioperative challenges were identified, related to the avoidance of mask inhalational induction. Only six of these 87 anesthetics occurred at our ambulatory surgery centers, a proportion (6.9%) lower than that of the general surgical population at UF Health (20.0%). Conclusions Among patients suspected to be MH susceptible in our health system over a six-year period, a minority (8/55) were supported by clear records of a prior MH event, confirmatory genetic or muscle contracture testing, or an underlying diagnosis closely linked to MH. The vast majority had limited documentation supporting their MH risk but continued to be treated with non-triggering anesthetics and were less likely to have surgery at an ambulatory surgery center than our overall surgical population. Among pediatric patients, some anesthetic challenges related to delivering non-triggering anesthetics were identified. Improving the documentation of index cases of MH and increasing referrals to clinical geneticists and genetic testing may be a viable route to decreasing the proportion of suspected MHS patients with a poorly characterized risk profile.
PubMed: 37799222
DOI: 10.7759/cureus.44661 -
Journal of Nanobiotechnology Oct 2023The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this...
BACKGROUND
The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC).
RESULTS
In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts.
CONCLUSION
This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.
Topics: Humans; B7 Antigens; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Doxorubicin; Drug Liberation; Gold; Hydrogen-Ion Concentration; Hyperthermia, Induced; Lung Neoplasms; Nanoparticles; Phototherapy; Photothermal Therapy; Tumor Microenvironment; Antineoplastic Agents; Animals; Mice; Xenograft Model Antitumor Assays
PubMed: 37848956
DOI: 10.1186/s12951-023-02078-9 -
The Journal of Clinical Investigation Aug 2023BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.
Topics: Adult; Animals; Child; Humans; Fragile X Syndrome; Single-Blind Method; Learning; Language; Cleft Palate; Indoles; Malignant Hyperthermia; Myotonia Congenita
PubMed: 37651202
DOI: 10.1172/JCI171723 -
World Journal of Emergency Medicine 2024
PubMed: 38188551
DOI: 10.5847/wjem.j.1920-8642.2024.006