scholarly journals Tumor Treating Fields Suppression of Ciliogenesis Enhances Temozolomide Toxicity

2021 ◽  
Author(s):  
Ping Shi ◽  
Jia Tian ◽  
Brittany S. Ulm ◽  
Julianne C. Mallinger ◽  
Habibeh Khoshbouei ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Ex Vivo ◽  
Electrical Field Stimulation ◽  
Intermediate Frequency ◽  
Ependymal Cells ◽  
Relative Timing ◽  
Inhibitory Effects ◽  
Electrical Field ◽  
Electrical Fields ◽  
Tumor Treating Fields

AbstractTumor Treating Fields (TTFields) are low intensity, alternating intermediate frequency (200kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer over normal cells, or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation, and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low and high grade patient glioma cell lines that TTFields ablated cilia within 24 hours. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons, and multiciliated/ependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Moreover, the inhibitory effects of TTFields and TMZ on tumor cell recurrence correlated with the relative timing of TMZ exposure to TTFields and ARL13B+ cilia. Finally, TTFields disrupted cilia in patient tumors treated ex vivo. Our findings suggest TTFields efficacy may depend on the degree of tumor ciliogenesis and relative timing of TMZ treatment.

Inhibition of cholinergic neurotransmission in human airways by beta 2-adrenoceptors

1988 ◽  
Vol 65 (2) ◽  
pp. 700-705 ◽  
Author(s):  
K. J. Rhoden ◽  
L. A. Meldrum ◽  
P. J. Barnes
Keyword(s):  
Electrical Field Stimulation ◽  
Inhibitory Effects ◽  
Human Airway Smooth Muscle ◽  
Electrical Field ◽  
Cholinergic Neurotransmission ◽  
Beta Agonists ◽  
Dependent Inhibition ◽  
Beta 2 ◽  
Human Airways ◽  
Human Bronchi

The purpose of the study was to determine whether catecholamines modulate cholinergic neurotransmission in isolated human airway smooth muscle. Bronchial rings were suspended in organ baths for isometric measurement of tension, and contractions were induced by either electrical field stimulation (EFS) or exogenous acetylcholine (ACh). Isoproterenol, epinephrine, and norepinephrine in that order of potency produced concentration-dependent inhibition of comparable responses to EFS and ACh. However a potency difference of 100-fold for isoproterenol (IC50 = 4.80 X 10(-8) M for EFS and 3.70 X 10(-6) M for ACh) and 10-fold for both epinephrine and norepinephrine was observed for inhibition of responses to EFS compared with responses to ACh. The inhibitory effects of isoproterenol on responses to EFS were prevented by propranolol and ICI 118551 (a beta 2-antagonist) but not by betaxolol (a beta 1-antagonist). Tyramine had no effect on contractions elicited by EFS. These experiments demonstrate that beta-agonists inhibit cholinergic nerve-induced contractions of human bronchi more potently than contractions induced by exogenous ACh, suggesting modulation of cholinergic neurotransmission by prejunctional beta 2-receptors.

Nonadrenergic inhibitory nerves attenuate neurally mediated contraction in cat bronchi

1990 ◽  
Vol 69 (5) ◽  
pp. 1594-1598 ◽  
Author(s):  
T. Aikawa ◽  
K. Sekizawa ◽  
S. Itabashi ◽  
H. Sasaki ◽  
T. Takishima
Keyword(s):  
Contractile Response ◽  
Stimulus Frequency ◽  
Electrical Field Stimulation ◽  
Inhibitory Effect ◽  
Field Stimulation ◽  
Inhibitory Effects ◽  
Electrical Field ◽  
Calcitonin Gene ◽  
Contraction And Relaxation ◽  
Biphasic Responses

Effects of nonadrenergic and noncholinergic (NANC) inhibitory nerves on cholinergic neurotransmission were examined in isolated bronchial segments from cats in the presence of propranolol (10(-6) M) and indomethacin (10(-6) M) by use of electrical field stimulation (EFS) techniques. EFS caused contraction alone in tissues at the baseline tension and biphasic responses (contraction and relaxation) in tissues precontracted with 5-hydroxytryptamine. Contraction was abolished by atropine (10(-6) M), and relaxation was abolished by tetrodotoxin (10(-6) M). At the baseline tension, EFS at frequencies greater than 10 Hz inhibited the subsequent (4 min later) contraction induced by EFS at 1-5 Hz. EFS-induced inhibition was stimulus frequency dependent and reached maximum at 20 Hz. However, EFS at 20 Hz did not inhibit the subsequent contractile response to acetylcholine (10(-7) to 10(-3) M). Exogenously applied vasoactive intestinal peptide mimicked EFS-induced inhibitory effects, but substance P and calcitonin gene-related peptide did not. The inhibitory effect of EFS at 20 Hz was not altered by pyrilamine, cimetidine, naloxone, methysergide, phentolamine, BW755C, AF-DX 116, or removal of epithelium. These results imply that the NANC transmitter acts via presynaptic cholinergic receptors.

Somatostatin excites canine ileum ex vivo: role for nitric oxide?

1995 ◽  
Vol 269 (1) ◽  
pp. G12-G21 ◽  
Author(s):  
P. Vergara ◽  
Z. Woskowska ◽  
S. Cipris ◽  
J. E. Fox-Threlkeld ◽  
E. E. Daniel
Keyword(s):  
Nitric Oxide ◽  
Motor Activity ◽  
Ex Vivo ◽  
Direct Action ◽  
Low Frequency ◽  
Electrical Field Stimulation ◽  
Electrical Field ◽  
Similar Motor ◽  
Motor Effects ◽  
Artificial Restoration

Isolated perfused segments of canine ileum have no spontaneous motor activity and release large quantities of vasoactive intestinal polypeptide (VIP) continuously. Somatostatin perfusion was shown to decrease VIP release, accompanied by increased contractions and amplification of responses to low-frequency electrical field stimulation. After perfusion of higher somatostatin concentrations, the VIP output did not recover but quiescence returned. The actions of somatostatin on motor activity were not modified by hexamethonium, slightly reduced by atropine, and markedly reduced by tetrodotoxin. Inhibition of VIP output was not the major determinant of motor activity in the ileum because 1) a second infusion of somatostatin had similar motor effects despite markedly reduced VIP output, 2) abolition of tonic VIP output did not prevent induction of motor activity by somatostatin, and 3) artificial restoration of VIP levels did not prevent or antagonize somatostatin-induced ileal contractions. In contrast, the increment in motor responses induced by somatostatin was not apparent after N omega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase, but recovered after reversal by L-arginine. We conclude that the mode of somatostatin activation of intestinal motor activity involves reduced NO output, enhanced excitatory mediator action or release, a direct action on smooth muscle, and possibly inhibition of VIP output. Of these, reduced NO output plays the most important role.

scholarly journals Primary cilia are sensors of electrical field stimulation to induce osteogenesis of human adipose‐derived stem cells

2016 ◽  
Vol 31 (1) ◽  
pp. 346-355 ◽  
Author(s):  
Shaobo Cai ◽  
Josephine C. Bodle ◽  
Pattie S. Mathieu ◽  
Alison Amos ◽  
Mehdi Hamouda ◽  
...  
Keyword(s):  
Stem Cells ◽  
Primary Cilia ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Adipose Derived Stem Cells ◽  
Electrical Field

scholarly journals New waves: Rhythmic electrical field stimulation systematically alters spontaneous slow dynamics across mouse neocortex

2017 ◽  
Author(s):  
Anastasia Greenberg ◽  
Javad Karimi Abadchi ◽  
Clayton T. Dickson ◽  
Majid H. Mohajerani
Keyword(s):  
Neural Activity ◽  
Medial Axis ◽  
Memory Performance ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Methodological Issues ◽  
Electrical Field ◽  
Cortical Dynamics ◽  
Electrical Fields ◽  
Lateral Posterior

AbstractThe signature rhythm of slow-wave forebrain activity is the large amplitude, slow oscillation (SO: ~1 Hz) made up of alternating synchronous periods of depolarizing and hyperpolarizing states at the single cell and network levels. On each wave, the SO originates at a unique location and propagates across the neocortex. Attempts to manipulate SO activity using electrical fields have been shown to entrain cortical networks and enhance memory performance. However, neural activity during this manipulation has remained elusive due to methodological issues in typical electrical recordings. Here we use voltage-sensitive dye (VSD) imaging in a bilateral cortical preparation of urethane-anesthetized mice to track SO cortical activity and its modulation by sinusoidal electrical field stimulation applied to frontal regions. We show that under spontaneous conditions, the SO propagates in two main opposing directional patterns along an anterior lateral – posterior medial axis. Rhythmic field stimulation alters spontaneous propagation to reflect activity that repeats cycle after cycle with distributed and varied anterior initiation zones and a consistent termination zone in the posterior somatosensory cortex. Our results show that slow electrical field stimulation stereotypes ongoing slow cortical dynamics during sleep-like states.Author ContributionsA.G., J.K.A., M.H.M. and C.T.D. designed the study. A.G. and J.K.A. performed the experiments. A.G. analyzed the data. A.G. wrote the manuscript, which all authors commented on and edited. C.T.D. and M.H.M. supervised the study.

An ultrastructural analysis of the sympathetic innervation of the rabbit ear artery and middle cerebral artery and their branches

1992 ◽  
Vol 50 (1) ◽  
pp. 934-935
Author(s):  
John T. Dodge ◽  
John A. Bevan
Keyword(s):  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Sympathetic Innervation ◽  
Electrical Field Stimulation ◽  
Rabbit Ear Artery ◽  
Electrical Field ◽  
Functional Differences ◽  
Ear Artery ◽  
Rabbit Ear ◽  
Vascular Beds

Unlike many peripheral vascular beds, the sympathetic nervous system exerts little control on cerebral blood flow. The contractile response of isolated rabbit middle cerebral artery (MCA) segments to electrical field stimulation of its intramural nerves is less than in a similar-sized artery from the ear. This study was undertaken to characterize and compare the perivascular neuromuscular relationships and innervation density of similar-sized arteries varying in diameter from these two different regional arterial beds to see if there were structural correlates for these functional differences.

scholarly journals Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise

2021 ◽  
Author(s):  
Sophie N Saxton ◽  
Lauren K Toms ◽  
Robert G Aldous ◽  
Sarah B Withers ◽  
Jacqueline Ohanian ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Contractile Function ◽  
Ex Vivo ◽  
Vascular Complications ◽  
Electrical Field Stimulation ◽  
Organic Cation Transporter ◽  
Nervous Stimulation ◽  
Perivascular Adipose Tissue ◽  
Contractile Effect ◽  
Organic Cation Transporter 3

AbstractPurposePerivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function.MethodsVascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT.ResultsHigh fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored.ConclusionLoss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

Tetrodotoxin-resistant release of ATP from superfused rabbit detrusor muscle during electrical field stimulation in the presence of luciferin–luciferase

1984 ◽  
Vol 62 (1) ◽  
pp. 153-156 ◽  
Author(s):  
Archana Chaudhry ◽  
John W. Downie ◽  
Thomas D. White
Keyword(s):  
Action Potentials ◽  
Electrical Field Stimulation ◽  
Detrusor Muscle ◽  
Electrical Field ◽  
Stimulation Parameters ◽  
Rabbit Bladder ◽  
Firefly Luciferin ◽  
Rabbit Urinary Bladder ◽  
Stimulation Of

The present study was carried out to assess the possible role of ATP in the noncholinergic, nonadrenergic transmission in the rabbit urinary bladder. When rabbit detrusor muscle strips were superfused with medium containing firefly luciferin–luciferase and stimulated transmurally at low stimulation parameters, tetrodotoxin-sensitive contractions were obtained but no release of ATP could be detected. However, at somewhat higher stimulation parameters, release of ATP was observed. This release of ATP was not diminished by tetrodotoxin indicating that ATP was not likely released as a result of propagated action potentials in nerves. Because contractions persisted in the presence of tetrodotoxin, it is possible that the ATP might have been released as a result of direct electrical stimulation of the muscle. These results do not support the idea that ATP is released as a neurotransmitter in the rabbit bladder.

scholarly journals ES-1 Clinical results of tumor treating fields in patients with glioblastoma in Japan, compared with global surveillance

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii3-ii3
Author(s):  
Yoshihiro Muragaki ◽  
Masayuki Nitta ◽  
Taiichi Saito ◽  
Shunichi Tutsuki ◽  
Atsushi Fukui ◽  
...  
Keyword(s):  
Side Effects ◽  
Insurance Coverage ◽  
Intermediate Frequency ◽  
Clinical Results ◽  
Tumor Treating Fields ◽  
Post Marketing Surveillance ◽  
Post Marketing ◽  
Us Fda ◽  
Medical University

Abstract INTRODUCTION: The tumor treatment field induces apoptosis of tumor cells by providing a low intensity, intermediate frequency, alternating current electric field via a transducer array. TTFields is based on Phase 3 EF-11 and EF-14 trials for glioblastoma in the US FDA and Japan PMDA. Therefore, I will report the statistics of TTFields use in Japan along with recent papers. METHODS: 410 patients were treated with TTFields in Japan (December 2017-), of which 17 were at Tokyo Women’s Medical University. We also referred to papers about global post-marketing surveillance and recent studies. RESULTS: Of the 410 patients, 409 (99.8%) were diagnosed with ndGBM(male: female, 66.8%: 33.2%). As of June 2020, 222 patients (54.1%) were on treatment and 188 (45.9%) were discontinued. In 17 cases at TWMU, the average age was 46.3 years. The average treatment period was 218 days, with 6 patients (35%) continuing treatment, 6 patients (35%) discontinuing due to patient wishes, and 5 patients (30%) discontinuing treatment due to recurrence. Side effects were contact dermatitis under the array in 9 patients (57%) and mild malaise in 7 patients (43%). We experienced long-term progression-free cases with TTF use of 25 months (survival 30 months after surgery) with a glioma partially resected and 21 months (survival 27 months after surgery) with a biopsied glioma. In the biopsy case, bevacizumab was used in combination during the treatment. Conclusion: In global surveillance, use for rGBM accounts for 39%, but Japan is limited to use for ndGBM due to insurance coverage. In terms of side effects, it showed a good safety profile comparable to previous trials. Long-term progression-free cases have been observed, and it is necessary to examine the characteristics of patients who respond to treatment and the effect of concomitant use with bevacizumab by prospective studies

Vascular effects of free radicals generated by electrical stimulation

1984 ◽  
Vol 247 (5) ◽  
pp. H709-H714 ◽  
Author(s):  
F. S. Lamb ◽  
R. C. Webb
Keyword(s):  
Electrical Stimulation ◽  
Free Radical ◽  
Experimental System ◽  
Electrical Field Stimulation ◽  
Oxygen Metabolism ◽  
Inhibitory Effect ◽  
Oxygen Free Radical ◽  
Vascular Effects ◽  
Electrical Field ◽  
Rat Tail

Electrical field stimulation (9 V, 1.0 ms, 4 Hz) of isolated segments of rat tail arteries and dog coronary arteries inhibits contractile responses to exogenous norepinephrine and elevated potassium concentration. This inhibitory effect of electrical stimulation is blocked by various agents that alter oxygen metabolism: superoxide dismutase, catalase, glutathione, ascorbate, and dimethyl sulfoxide. The observations suggest that the inhibitory effect is due to an action of oxygen free radical metabolites that are generated by the electrical stimulation of the oxygen-rich buffer. These free radical metabolites have two actions: 1) they oxidize drugs in the experimental system, and 2) they exert a direct inhibitory action on vascular smooth muscle.

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