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European Radiology Experimental Nov 2023Malignant tumors routinely present with irregular shapes and complex configurations. The lack of customization to individual tumor shapes and standardization of...
BACKGROUND
Malignant tumors routinely present with irregular shapes and complex configurations. The lack of customization to individual tumor shapes and standardization of procedures limits the success and application of thermal ablation.
METHODS
We introduced an automated treatment model consisting of (i) trajectory and ablation profile planning, (ii) ablation probe insertion, (iii) dynamic energy delivery (including robotically driven control of the energy source power and location over time, according to a treatment plan bespoke to the tumor shape), and (iv) quantitative ablation margin verification. We used a microwave ablation system and a liver phantom (acrylamide polymer with a thermochromic ink) to mimic coagulation and measure the ablation volume. We estimated the ablation width as a function of power and velocity following a probabilistic model. Four representative shapes of liver tumors < 5 cm were selected from two publicly available databases. The ablated specimens were cut along the ablation probe axis and photographed. The shape of the ablated volume was extracted using a color-based segmentation method.
RESULTS
The uncertainty (standard deviation) of the ablation width increased with increasing power by ± 0.03 mm (95% credible interval [0.02, 0.043]) per watt increase in power and by ± 0.85 mm (95% credible interval [0, 2.5]) per mm/s increase in velocity. Continuous ablation along a straight-line trajectory resulted in elongated rotationally symmetric ablation shapes. Simultaneous regulation of the power and/or translation velocity allowed to modulate the ablation width at specific locations.
CONCLUSIONS
This study offers the proof-of-principle of the dynamic energy delivery system using ablation shapes from clinical cases of malignant liver tumors.
RELEVANCE STATEMENT
The proposed automated treatment model could favor the customization and standardization of thermal ablation for complex tumor shapes.
KEY POINTS
• Current thermal ablation systems are limited to ellipsoidal or spherical shapes. • Dynamic energy delivery produces elongated rotationally symmetric ablation shapes with varying widths. • For complex tumor shapes, multiple customized ablation shapes could be combined.
Topics: Humans; Microwaves; Liver Neoplasms; Ablation Techniques; Models, Theoretical
PubMed: 37932631
DOI: 10.1186/s41747-023-00381-6 -
Heart Rhythm Dec 2023Myocardial calcium (Ca) signaling plays a crucial role in contractile function and membrane electrophysiology. An abnormal myocardial Ca transient is linked to heart... (Review)
Review
Myocardial calcium (Ca) signaling plays a crucial role in contractile function and membrane electrophysiology. An abnormal myocardial Ca transient is linked to heart failure and ventricular arrhythmias. At the subcellular level, the synchronous release of Ca sparks from sarcoplasmic Ca release units determines the configuration and amplitude of the global Ca transient. This narrative review evaluates the role of aberrant Ca release synchrony in the pathophysiology of cardiomyopathies and ventricular arrhythmias. The potential therapeutic benefits of restoration of Ca release synchrony in heart failure and ventricular arrhythmias are also discussed.
Topics: Humans; Calcium; Myocytes, Cardiac; Arrhythmias, Cardiac; Heart Failure; Myocardium; Calcium Signaling; Sarcoplasmic Reticulum; Ryanodine Receptor Calcium Release Channel
PubMed: 37678492
DOI: 10.1016/j.hrthm.2023.08.040 -
Biophysical Journal Sep 2023Ryanodine receptors (RyRs) are Ca release channels, gated by Ca in the cytosol and the sarcoplasmic reticulum lumen. Their regulation is impaired in certain cardiac and...
Ryanodine receptors (RyRs) are Ca release channels, gated by Ca in the cytosol and the sarcoplasmic reticulum lumen. Their regulation is impaired in certain cardiac and muscle diseases. Although a lot of data is available on the luminal Ca regulation of RyR, its interpretation is complicated by the possibility that the divalent ions used to probe the luminal binding sites may contaminate the cytoplasmic sites by crossing the channel pore. In this study, we used Eu, an impermeable agonist of Ca binding sites, as a probe to avoid this complication and to gain more specific information about the function of the luminal Ca sensor. Single-channel currents were measured from skeletal muscle and cardiac RyRs (RyR1 and RyR2) using the lipid bilayer technique. We show that RyR2 is activated by the luminal addition of Ca, whereas RyR1 is inhibited. These results were qualitatively reproducible using Eu. The luminal regulation of RyR1 carrying a mutation associated with malignant hyperthermia was not different from that of the wild-type. RyR1 inhibition by Eu was extremely voltage dependent, whereas RyR2 activation did not depend on the membrane potential. These results suggest that the RyR1 inhibition site is in the membrane's electric field (channel pore), whereas the RyR2 activation site is outside. Using in silico analysis and previous results, we predicted putative Ca binding site sequences. We propose that RyR2 bears an activation site, which is missing in RyR1, but both isoforms share the same inhibitory Ca binding site near the channel gate.
Topics: Ryanodine Receptor Calcium Release Channel; Cytoplasm; Cytosol; Muscle, Skeletal; Binding Sites; Calcium
PubMed: 37533257
DOI: 10.1016/j.bpj.2023.07.029 -
Small (Weinheim An Der Bergstrasse,... Jan 2024Nanotechnology-based strategy has recently drawn extensive attention for the therapy of malignant tumors due to its distinct strengths in cancer diagnosis and treatment....
Nanotechnology-based strategy has recently drawn extensive attention for the therapy of malignant tumors due to its distinct strengths in cancer diagnosis and treatment. However, the limited intratumoral permeability of nanoparticles is a major hurdle to achieving the desired effect of cancer treatment. Due to their superior cargo towing and reliable penetrating property, micro-/nanomotors (MNMs) are considered as one of the most potential candidates for the coming generation of drug delivery platforms. Here, near-infrared (NIR)-actuated biomimetic nanomotors (4T1-JPGSs-IND) are fabricated successfully and we demonstrate that 4T1-JPGSs-IND selectively accumulate in homologous tumor regions due to the effective homing ability. Upon laser irradiation, hyperthermia generated by 4T1-JPGSs-IND leads to self-thermophoretic motion and photothermal therapy (PTT) to ablate tumors with a deep depth, thereby improving the photothermal therapeutic effect for cancer management. The developed nanomotor system with multifunctionalities exhibits promising potential in biomedical applications to fight against various diseases.
Topics: Humans; Photothermal Therapy; Phototherapy; Biomimetics; Hyperthermia, Induced; Nanoparticles; Neoplasms; Cell Line, Tumor
PubMed: 37670543
DOI: 10.1002/smll.202306208 -
Clinical and Experimental Medicine Nov 2023Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this... (Review)
Review
Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy.
Topics: Animals; Humans; Hydra; Hyperthermia, Induced; Neoplasms; Cell Differentiation; Neoplastic Stem Cells
PubMed: 37093450
DOI: 10.1007/s10238-023-01066-5 -
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 -
BMC Pediatrics Oct 2023The CACNA1S gene encodes the alpha 1 S-subunit of the voltage-gated calcium channel, which is primarily expressed in the skeletal muscle cells. Pathogenic variants of... (Review)
Review
BACKGROUND
The CACNA1S gene encodes the alpha 1 S-subunit of the voltage-gated calcium channel, which is primarily expressed in the skeletal muscle cells. Pathogenic variants of CACNA1S can cause hypokalemic periodic paralysis (HypoPP), malignant hyperthermia susceptibility, and congenital myopathy. We aimed to study the clinical and molecular features of a male child with a CACNA1S variant and depict the molecular sub-regional characteristics of different phenotypes associated with CACNA1S variants.
CASE PRESENTATION
We presented a case of HypoPP with recurrent muscle weakness and hypokalemia. Genetic analyses of the family members revealed that the proband had a novel c.497 C > A (p.Ala166Asp) variant of CACNA1S, which was inherited from his father. The diagnosis of HypoPP was established in the proband as he met the consensus diagnostic criteria. The patient and his parents were informed to avoid the classical triggers of HypoPP. The attacks of the patient are prevented by lifestyle changes and nutritional counseling. We also showed the molecular sub-regional location of the variants of CACNA1S which was associated with different phenotypes.
CONCLUSIONS
Our results identified a new variant of CACNA1S and expanded the spectrum of variants associated with HypoPP. Early genetic diagnosis can help avoid diagnostic delays, perform genetic counseling, provide proper treatment, and reduce morbidity and mortality.
Topics: Humans; Male; Child; Hypokalemic Periodic Paralysis; Mutation; Phenotype; Muscle Weakness; Family; Calcium Channels, L-Type
PubMed: 37784084
DOI: 10.1186/s12887-023-04326-1 -
Revista Espanola de Anestesiologia Y... Feb 2024
PubMed: 38342304
DOI: 10.1016/j.redare.2024.02.005 -
JA Clinical Reports Jul 2023Freeman-Sheldon syndrome (FSS) is a rare disorder characterized by specific deformities of the extremities and face. There have been no reports of open-heart surgery in...
BACKGROUND
Freeman-Sheldon syndrome (FSS) is a rare disorder characterized by specific deformities of the extremities and face. There have been no reports of open-heart surgery in pediatric patients with FSS.
CASE PRESENTATION
We present the case of an 8-year-old girl with FSS who underwent atrial septal defect closure. Tracheal intubation was uncomplicated, although the patient had microstomia. Inhalational anesthetics and dopamine antagonists were avoided intraoperatively and perioperatively. We chose dexmedetomidine as an adjuvant for postoperative pain management contributing to adequate analgesia and early extubation without causing respiratory depression.
CONCLUSIONS
Anesthetic management of FSS requires consideration for airway management and prevention of malignant hyperthermia and respiratory complications. We successfully managed the case avoiding the use of malignant hyperthermia-triggering drugs.
PubMed: 37438578
DOI: 10.1186/s40981-023-00633-9 -
Advanced Science (Weinheim,... May 2024Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate...
Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel "two birds with one stone" technique for amplifying enzyme-mediated tumor apoptosis and enzyme-promoted metabolic clearance is proposed and achieved using GOx-functionalized rhenium nanoclusters-doped polypyrrole (Re@ReP-G). Re@ReP-G reduces ATP production while increasing HO concentrations in the tumor microenvironment through GOx-induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti-apoptotic Bcl-2 proteins, the upregulation of pro-apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser-induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, HO catalyzes the conversion of rhenium nanoclusters in Re@ReP-G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP-G-based "two birds with one stone" therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms.
Topics: Animals; Apoptosis; Mice; Glucose Oxidase; Neoplasms; Humans; Disease Models, Animal; Cell Line, Tumor; Nanomedicine; Tumor Microenvironment; Hydrogen Peroxide; Polymers
PubMed: 38447152
DOI: 10.1002/advs.202308251