Abstract 3209: Numerical modeling of intracellular mechanisms in tumor-treating fields
Notice bibliographique
Résumé
Abstract Tumor Treating Fields (TTFields) are 100-500 kHz electric fields with intensities of about 1-4 V/cm. They are known to exert an antimitotic effect on cancer cells, most likely by exerting forces on highly polar tubulin dimers, thereby disrupting spindle formation. Calculations show that TTFields-tubulin interaction energy is negligible compared to the thermal energy in the cell (1). Therefore, this interaction is unlikely to disrupt cellular function. Conductivity of polymerized tubulin, microtubules (MTs), was measured to be 20 S/m, which is 400 times higher than that of the ambient cytosol (0.05 S/m) (2). Thus when TTFields penetrate the cytosol, they may induce electric currents along MTs that are strong enough to disrupt key cellular functions. In particular, if the power (energy per unit time) deposited by these currents is on par with that the power consumed by the molecular motor kinesin, then TTFields may disrupt the forces needed for cell division, thereby disrupting mitosis. To test this hypothesis, we performed numerical simulations evaluating the magnitude of the electric current along MTs exposed to TTFields at 200 kHz. Based on studies of MTs and their microenvironment, we model the MT as a layered cylindrical structure (1): Innermost is the lumen (15 nm in thickness), surrounded by 13 strands of alpha-beta tubulin dimers linked in a helix (4.5 nm). C-termini extend out from the helix with a thickness of 3.5 nm. MTs carry net negative charge; thus they are surrounded by a counter-ion layer (2 nm), and an outer nonconductive Bjerrum layer (3 nm). We built a finite element model in COMSOL Multiphysics (tm) incorporating these layers and examined the current density induced in each layer by TTFields for MTs varying in length from 1-10 µm within an ambient 200 kHz AC electric field of 1-4 V/cm. Our model shows that MTs act as electrical "shunts" that conduct electric current within them. The highest current flows through the counter-ion layer surrounding the C-termini. The current density in this layer exceeds the level likely to disrupt the motor protein kinesin "walk" along the C-termini. The current density is highest when both the field and the MTs are aligned with the cell axis, in accord with in vitro experiments (3). Our model is consistent with the hypothesis that when cells are exposed to TTFields, MTs act as cables carrying high-density electric currents strong enough to disrupt the function of molecular motors, ultimately disrupting mitosis. References: 1. Tuszynski JA et al. An overview of sub-cellular mechanisms involved in the action of TTFields. Int J Environ Res Public Health 2016. 2. Santelices IB et al. Response to alternating electric fields of tubulin dimers and microtubule ensembles in electrolytic solutions. Sci Rep 2017. 3. Kirson ED et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A 2007. Citation Format: Kristen W. Carlson, Jack A. Tuszynski, Socrates Dokos. Numerical modeling of intracellular mechanisms in tumor-treating fields [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3209.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».