Building a 3D Virtual Liver: Methods for Simulating Blood Flow and Hepatic Clearance on 3D Structures.

1 year 2 months ago
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Building a 3D Virtual Liver: Methods for Simulating Blood Flow and Hepatic Clearance on 3D Structures.

PLoS One. 2016;11(9):e0162215

Authors: White D, Coombe D, Rezania V, Tuszynski J

Abstract
In this paper, we develop a spatio-temporal modeling approach to describe blood and drug flow, as well as drug uptake and elimination, on an approximation of the liver. Extending on previously developed computational approaches, we generate an approximation of a liver, which consists of a portal and hepatic vein vasculature structure, embedded in the surrounding liver tissue. The vasculature is generated via constrained constructive optimization, and then converted to a spatial grid of a selected grid size. Estimates for surrounding upscaled lobule tissue properties are then presented appropriate to the same grid size. Simulation of fluid flow and drug metabolism (hepatic clearance) are completed using discretized forms of the relevant convective-diffusive-reactive partial differential equations for these processes. This results in a single stage, uniformly consistent method to simulate equations for blood and drug flow, as well as drug metabolism, on a 3D structure representative of a liver.

PMID: 27649537 [PubMed - indexed for MEDLINE]

Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism.

1 year 2 months ago
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Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism.

J Med Chem. 2016 Oct 27;59(20):9532-9540

Authors: Ayoub AT, Abou El-Magd RM, Xiao J, Lewis CW, Tilli TM, Arakawa K, Nindita Y, Chan G, Sun L, Glover M, Klobukowski M, Tuszynski J

Abstract
Lankacidin group antibiotics show strong antimicrobial activity against various Gram-positive bacteria. In addition, they were shown to have considerable antitumor activity against certain cell line models. For decades, the antitumor activity of lankacidin was associated with the mechanism of its antimicrobial action, which is interference with peptide bond formation during protein synthesis. This, however, was never confirmed experimentally. Due to significant similarity to paclitaxel-like hits in a previous computational virtual screening study, we suggested that the cytotoxic effect of lankacidin is due to a paclitaxel-like action. In this study, we tested this hypothesis computationally and experimentally and confirmed that lankacidin is a microtubule stabilizer that enhances tubulin assembly and displaces taxoids from their binding site. This study serves as a starting point for optimization of lankacidin derivatives for better antitumor activities. It also highlights the power of computational predictions and their aid in guiding experiments and formulating rigorous hypotheses.

PMID: 27718573 [PubMed - indexed for MEDLINE]

A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation.

1 year 2 months ago
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A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation.

Oncotarget. 2016 Jun 28;7(26):40518-40530

Authors: Ghaly PE, Abou El-Magd RM, Churchill CD, Tuszynski JA, West FG

Abstract
Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug.

PMID: 27777381 [PubMed - indexed for MEDLINE]

Personalized anticancer therapy selection using molecular landscape topology and thermodynamics.

1 year 2 months ago
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Personalized anticancer therapy selection using molecular landscape topology and thermodynamics.

Oncotarget. 2017 Mar 21;8(12):18735-18745

Authors: Rietman EA, Scott JG, Tuszynski JA, Klement GL

Abstract
Personalized anticancer therapy requires continuous consolidation of emerging bioinformatics data into meaningful and accurate information streams. The use of novel mathematical and physical approaches, namely topology and thermodynamics can enable merging differing data types for improved accuracy in selecting therapeutic targets. We describe a method that uses chemical thermodynamics and two topology measures to link RNA-seq data from individual patients with academically curated protein-protein interaction networks to select clinically relevant targets for treatment of low-grade glioma (LGG). We show that while these three histologically distinct tumor types (astrocytoma, oligoastrocytoma, and oligodendroglioma) may share potential therapeutic targets, the majority of patients would benefit from more individualized therapies. The method involves computing Gibbs free energy of the protein-protein interaction network and applying a topological filtration on the energy landscape to produce a subnetwork known as persistent homology. We then determine the most likely best target for therapeutic intervention using a topological measure of the network known as Betti number. We describe the algorithm and discuss its application to several patients.

PMID: 27793055 [PubMed - indexed for MEDLINE]

Possible existence of optical communication channels in the brain.

1 year 2 months ago
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Possible existence of optical communication channels in the brain.

Sci Rep. 2016 11 07;6:36508

Authors: Kumar S, Boone K, Tuszyński J, Barclay P, Simon C

Abstract
Given that many fundamental questions in neuroscience are still open, it seems pertinent to explore whether the brain might use other physical modalities than the ones that have been discovered so far. In particular it is well established that neurons can emit photons, which prompts the question whether these biophotons could serve as signals between neurons, in addition to the well-known electro-chemical signals. For such communication to be targeted, the photons would need to travel in waveguides. Here we show, based on detailed theoretical modeling, that myelinated axons could serve as photonic waveguides, taking into account realistic optical imperfections. We propose experiments, both in vivo and in vitro, to test our hypothesis. We discuss the implications of our results, including the question whether photons could mediate long-range quantum entanglement in the brain.

PMID: 27819310 [PubMed - indexed for MEDLINE]

An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields.

1 year 2 months ago
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An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields.

Int J Environ Res Public Health. 2016 Nov 12;13(11):

Authors: Tuszynski JA, Wenger C, Friesen DE, Preto J

Abstract
Long-standing research on electric and electromagnetic field interactions with biological cells and their subcellular structures has mainly focused on the low- and high-frequency regimes. Biological effects at intermediate frequencies between 100 and 300 kHz have been recently discovered and applied to cancer cells as a therapeutic modality called Tumor Treating Fields (TTFields). TTFields are clinically applied to disrupt cell division, primarily for the treatment of glioblastoma multiforme (GBM). In this review, we provide an assessment of possible physical interactions between 100 kHz range alternating electric fields and biological cells in general and their nano-scale subcellular structures in particular. This is intended to mechanistically elucidate the observed strong disruptive effects in cancer cells. Computational models of isolated cells subject to TTFields predict that for intermediate frequencies the intracellular electric field strength significantly increases and that peak dielectrophoretic forces develop in dividing cells. These findings are in agreement with in vitro observations of TTFields' disruptive effects on cellular function. We conclude that the most likely candidates to provide a quantitative explanation of these effects are ionic condensation waves around microtubules as well as dielectrophoretic effects on the dipole moments of microtubules. A less likely possibility is the involvement of actin filaments or ion channels.

PMID: 27845746 [PubMed - indexed for MEDLINE]

Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer.

1 year 2 months ago
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Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer.

Protoplasma. 2017 May;254(3):1163-1173

Authors: Wang W, Zhang H, Wang X, Patterson J, Winter P, Graham K, Ghosh S, Lee JC, Katsetos CD, Mackey JR, Tuszynski JA, Wong GK, Ludueña RF

Abstract
Tubulin is the target for very widely used anti-tumor drugs, including Vinca alkaloids, taxanes, and epothilones, which are an important component of chemotherapy in breast cancer and other malignancies. Paclitaxel and other tubulin-targeting drugs bind to the β subunit of tubulin, which is a heterodimer of α and β subunits. β-Tubulin exists in the form of multiple isotypes, which are differentially expressed in normal and neoplastic cells and differ in their ability to bind to drugs. Among them, the βIII isotype is overexpressed in many aggressive and metastatic cancers and may serve as a prognostic marker in certain types of cancer. The underpinning mechanisms accounting for the overexpression of this isotype in cancer cells are unclear. To better understand the role of β-tubulin isotypes in cancer, we analyzed over 1000 clones from 90 breast cancer patients, sequencing their β-tubulin isotypes, in search of novel mutations. We have elucidated two putative emerging molecular subgroups of invasive breast cancer, each of which involve mutations in the βI-, βIIA-, or βIVB isotypes of tubulin that increase their structural, and possibly functional, resemblance to the βIII isotype. A unifying feature of the first of the two subgroups is the mutation of the highly reactive C239 residue of βI- or βIVB-tubulin to L239, R239, Y239, or P239, culminating in probable conversion of these isotypes from ROS-sensitive to ROS-resistant species. In the second subgroup, βI, βIIA, and βIVB have up to seven mutations to the corresponding residues in βIII-tubulin. Given that βIII-tubulin has emerged as a pro-survival factor, overexpression of this isotype may confer survival advantages to certain cancer cell types. In this mini-review, we bring attention to a novel mechanism by which cancer cells may undergo adaptive mutational changes involving alternate β-tubulin isotypes to make them acquire some of the pro-survival properties of βIII-tubulin. These "hybrid" tubulins, combining the sequences and/or properties of two wild-type tubulins (βIII and either βI, βIIA, or βIVB), are novel isotypes expressed solely in cancer cells and may contribute to the molecular understanding and stratification of invasive breast cancer and provide novel molecular targets for rational drug development.

PMID: 27943021 [PubMed - indexed for MEDLINE]

Novel Colchicine Derivatives and their Anti-cancer Activity.

1 year 2 months ago
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Novel Colchicine Derivatives and their Anti-cancer Activity.

Curr Top Med Chem. 2017;17(22):2538-2558

Authors: Johnson L, Goping IS, Rieger A, Mane JY, Huzil T, Banerjee A, Luduena R, Hassani B, Winter P, Tuszynski JA

Abstract
In this paper we provide an overview of the status of various colchicine derivatives in preclinical development with special focus on their anti-cancer activity. We discuss several groups of compounds that have been designed to differentially bind with specific affinities for tubulin β isotypes, especially in regard to βIII, which is commonly over-expressed in cancer. Computational prediction, protein-based and cell-based assays are summarized as well as some animal tests conducted on these compounds. It is concluded that an untapped potential exists for exploiting the colchicine scaffold as a pharmacophore with the possibility of increasing its affinity for tubulin isotypes overexpressed in cancer and decreasing it for normal cells thereby widening the therapeutic window.

PMID: 28056740 [PubMed - indexed for MEDLINE]

Novel Allosteric Pathway of Eg5 Regulation Identified through Multivariate Statistical Analysis of Hydrogen-Exchange Mass Spectrometry (HX-MS) Ligand Screening Data.

1 year 2 months ago
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Novel Allosteric Pathway of Eg5 Regulation Identified through Multivariate Statistical Analysis of Hydrogen-Exchange Mass Spectrometry (HX-MS) Ligand Screening Data.

Mol Cell Proteomics. 2017 Mar;16(3):428-437

Authors: Sheff JG, Farshidfar F, Bathe OF, Kopciuk K, Gentile F, Tuszynski J, Barakat K, Schriemer DC

Abstract
The mitotic kinesin Eg5 is an important target in cancer chemotherapy. A structurally diverse collection of canonical loop L5 inhibitors engage an allosteric pathway that includes elements of its microtubule binding region. However, recent evidence suggests that Eg5 may permit alternative allosteric mechanisms. Terpendole E, a natural-product Eg5 inhibitor, is active against mutants resistant to canonical loop L5 inhibitors and appears to offer a unique mode of inhibition. To investigate the variety of inhibitor responses, the structure-function properties of eighteen kinesin inhibitors were quantified with hydrogen-exchange mass spectrometry (HX-MS), functional analysis and molecular modeling. A unique strategy for high-density data analysis was implemented, based on a scalable multivariate statistical method, as current HX-MS routines have a limited capacity to guide a characterization of ligands when additional functional data is available. Inhibitor evaluation was achieved using orthogonal partial least squares projection to latent structures discriminant analysis (OPLS-DA). The strategy generated a model that identified functionally-significant conformational elements involved in kinesin inhibition, confirming the canonical allosteric pathway and identifying a novel response pathway. Terpendole E is demonstrated to be an atypical L5 site inhibitor, where binding induces an allosteric effect mediated by a destabilization in the β-sheet core of the molecular motor, an element involved in mechanochemical coupling for structurally-related kinesins. The analysis suggests that a different approach to inhibitor development may be fruitful.

PMID: 28062800 [PubMed - indexed for MEDLINE]

Automatic prediction of tumour malignancy in breast cancer with fractal dimension.

1 year 2 months ago
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Automatic prediction of tumour malignancy in breast cancer with fractal dimension.

R Soc Open Sci. 2016 Dec;3(12):160558

Authors: Chan A, Tuszynski JA

Abstract
Breast cancer is one of the most prevalent types of cancer today in women. The main avenue of diagnosis is through manual examination of histopathology tissue slides. Such a process is often subjective and error-ridden, suffering from both inter- and intraobserver variability. Our objective is to develop an automatic algorithm for analysing histopathology slides free of human subjectivity. Here, we calculate the fractal dimension of images of numerous breast cancer slides, at magnifications of 40×, 100×, 200× and 400×. Using machine learning, specifically, the support vector machine (SVM) method, the F1 score for classification accuracy of the 40× slides was found to be 0.979. Multiclass classification on the 40× slides yielded an accuracy of 0.556. A reduction of the size and scope of the SVM training set gave an average F1 score of 0.964. Taken together, these results show great promise in the use of fractal dimension to predict tumour malignancy.

PMID: 28083100 [PubMed]

Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics.

1 year 2 months ago
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Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics.

Biol Direct. 2017 Jan 19;12(1):2

Authors: Grasso G, Tuszynski JA, Morbiducci U, Licandro G, Danani A, Deriu MA

Abstract
BACKGROUND: Molecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 (SCA3) where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain (JD), play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure. In this connection, computational modeling has demonstrated to be helpful in exploring the protein molecular dynamics and mechanism of action.
RESULTS: Conformational dynamics of the JD is here finely investigated by replica exchange molecular dynamics simulations able to sample the microsecond time scale and to provide both a thermodynamic and kinetic description of the protein conformational changes. Accessible structural conformations of the JD have been identified in: open, intermediate and closed like arrangement. Data indicated the closed JD arrangement as the most likely protein arrangement. The protein transition from closed toward intermediate/open states was characterized by a rate constant higher than 700 ns. This result also explains the inability of classical molecular dynamics to explore transitions from closed to open JD configuration on a time scale of hundreds of nanoseconds.
CONCLUSION: This work provides the first kinetic estimation of the JD transition pathway from open-like to closed-like arrangement and vice-versa, indicating the closed-like arrangement as the most likely configuration for a JD in water environment. More widely, the importance of our results is also underscored considering that the ability to provide a kinetic description of the protein conformational changes is a scientific challenge for both experimental and theoretical approaches to date.
REVIEWERS: This article was reviewed by Oliviero Carugo, Bojan Zagrovic.

PMID: 28103906 [PubMed - indexed for MEDLINE]

Search for Magnetic Monopoles with the MoEDAL Forward Trapping Detector in 13 TeV Proton-Proton Collisions at the LHC.

1 year 2 months ago
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Search for Magnetic Monopoles with the MoEDAL Forward Trapping Detector in 13 TeV Proton-Proton Collisions at the LHC.

Phys Rev Lett. 2017 Feb 10;118(6):061801

Authors: Acharya B, Alexandre J, Baines S, Benes P, Bergmann B, Bernabéu J, Branzas H, Campbell M, Caramete L, Cecchini S, de Montigny M, De Roeck A, Ellis JR, Fairbairn M, Felea D, Flores J, Frank M, Frekers D, Garcia C, Hirt AM, Janecek J, Kalliokoski M, Katre A, Kim DW, Kinoshita K, Korzenev A, Lacarrère DH, Lee SC, Leroy C, Lionti A, Mamuzic J, Margiotta A, Mauri N, Mavromatos NE, Mermod P, Mitsou VA, Orava R, Parker B, Pasqualini L, Patrizii L, Păvălaş GE, Pinfold JL, Popa V, Pozzato M, Pospisil S, Rajantie A, Ruiz de Austri R, Sahnoun Z, Sakellariadou M, Sarkar S, Semenoff G, Shaa A, Sirri G, Sliwa K, Soluk R, Spurio M, Srivastava YN, Suk M, Swain J, Tenti M, Togo V, Tuszyński JA, Vento V, Vives O, Vykydal Z, Whyntie T, Widom A, Willems G, Yoon JH, Zgura IS, MoEDAL Collaboration

Abstract
MoEDAL is designed to identify new physics in the form of long-lived highly ionizing particles produced in high-energy LHC collisions. Its arrays of plastic nuclear-track detectors and aluminium trapping volumes provide two independent passive detection techniques. We present here the results of a first search for magnetic monopole production in 13 TeV proton-proton collisions using the trapping technique, extending a previous publication with 8 TeV data during LHC Run 1. A total of 222 kg of MoEDAL trapping detector samples was exposed in the forward region and analyzed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges exceeding half the Dirac charge are excluded in all samples and limits are placed for the first time on the production of magnetic monopoles in 13 TeV pp collisions. The search probes mass ranges previously inaccessible to collider experiments for up to five times the Dirac charge.

PMID: 28234515 [PubMed - in process]

Stream of consciousness: Quantum and biochemical assumptions regarding psychopathology.

1 year 2 months ago
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Stream of consciousness: Quantum and biochemical assumptions regarding psychopathology.

Med Hypotheses. 2017 Apr;101:78-84

Authors: Tonello L, Cocchi M, Gabrielli F, Tuszynski JA

Abstract
The accepted paradigms of mainstream neuropsychiatry appear to be incompletely adequate and in various cases offer equivocal analyses. However, a growing number of new approaches are being proposed that suggest the emergence of paradigm shifts in this area. In particular, quantum theories of mind, brain and consciousness seem to offer a profound change to the current approaches. Unfortunately these quantum paradigms harbor at least two serious problems. First, they are simply models, theories, and assumptions, with no convincing experiments supporting their claims. Second, they deviate from contemporary mainstream views of psychiatric illness and do so in revolutionary ways. We suggest a possible way to integrate experimental neuroscience with quantum models in order to address outstanding issues in psychopathology. A key role is played by the phenomenon called the "stream of consciousness", which can be linked to the so-called "Gamma Synchrony" (GS), which is clearly demonstrated by EEG data. In our novel proposal, a unipolar depressed patient could be seen as a subject with an altered stream of consciousness. In particular, some clues suggest that depression is linked to an "increased power" stream of consciousness. It is additionally suggested that such an approach to depression might be extended to psychopathology in general with potential benefits to diagnostics and therapeutics in neuropsychiatry.

PMID: 28351500 [PubMed - indexed for MEDLINE]

Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma.

1 year 2 months ago
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Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma.

Oncotarget. 2017 May 30;8(22):35639-35655

Authors: Velpula KK, Guda MR, Sahu K, Tuszynski J, Asuthkar S, Bach SE, Lathia JD, Tsung AJ

Abstract
Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (TMZ), acquired chemoresistance is a universal feature of recurrent GBMs. To mimic the GBM resistant state, we generated an in vitro TMZ resistant model and demonstrated that dichloroacetate (DCA), a metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1), reverses the Warburg effect. Microarray analysis conducted on the TMZ resistant cells with their subsequent treatment with DCA revealed PDK1 as its sole target. DCA treatment also induced mitochondrial membrane potential change and apoptosis as evidenced by JC-1 staining and electron microscopic studies. Computational homology modeling and docking studies confirmed DCA binding to EGFR, EGFRvIII and PDK1 with high affinity. In addition, expression of EGFRvIII was comparable to PDK1 when compared to EGFR in GBM surgical specimens supporting our in silico prediction data. Collectively our current study provides the first in vitro proof of concept that DCA reverses the Warburg effect in the setting of EGFRvIII positivity and TMZ resistance leading to GBM cytotoxicity, implicating cellular tyrosine kinase signaling in cancer cell metabolism.

PMID: 28410193 [PubMed - indexed for MEDLINE]

Linoleic acid: Is this the key that unlocks the quantum brain? Insights linking broken symmetries in molecular biology, mood disorders and personalistic emergentism.

1 year 2 months ago
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Linoleic acid: Is this the key that unlocks the quantum brain? Insights linking broken symmetries in molecular biology, mood disorders and personalistic emergentism.

BMC Neurosci. 2017 Apr 19;18(1):38

Authors: Cocchi M, Minuto C, Tonello L, Gabrielli F, Bernroider G, Tuszynski JA, Cappello F, Rasenick M

Abstract
In this paper we present a mechanistic model that integrates subneuronal structures, namely ion channels, membrane fatty acids, lipid rafts, G proteins and the cytoskeleton in a dynamic system that is finely tuned in a healthy brain. We also argue that subtle changes in the composition of the membrane's fatty acids may lead to down-stream effects causing dysregulation of the membrane, cytoskeleton and their interface. Such exquisite sensitivity to minor changes is known to occur in physical systems undergoing phase transitions, the simplest and most studied of them is the so-called Ising model, which exhibits a phase transition at a finite temperature between an ordered and disordered state in 2- or 3-dimensional space. We propose this model in the context of neuronal dynamics and further hypothesize that it may involve quantum degrees of freedom dependent upon variation in membrane domains associated with ion channels or microtubules. Finally, we provide a link between these physical characteristics of the dynamical mechanism to psychiatric disorders such as major depression and antidepressant action.

PMID: 28420346 [PubMed - indexed for MEDLINE]

Software for molecular docking: a review.

1 year 2 months ago
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Software for molecular docking: a review.

Biophys Rev. 2017 Apr;9(2):91-102

Authors: Pagadala NS, Syed K, Tuszynski J

Abstract
Molecular docking methodology explores the behavior of small molecules in the binding site of a target protein. As more protein structures are determined experimentally using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, molecular docking is increasingly used as a tool in drug discovery. Docking against homology-modeled targets also becomes possible for proteins whose structures are not known. With the docking strategies, the druggability of the compounds and their specificity against a particular target can be calculated for further lead optimization processes. Molecular docking programs perform a search algorithm in which the conformation of the ligand is evaluated recursively until the convergence to the minimum energy is reached. Finally, an affinity scoring function, ΔG [U total in kcal/mol], is employed to rank the candidate poses as the sum of the electrostatic and van der Waals energies. The driving forces for these specific interactions in biological systems aim toward complementarities between the shape and electrostatics of the binding site surfaces and the ligand or substrate.

PMID: 28510083 [PubMed]

Ion channel and neurotransmitter modulators as electroceutical approaches to the control of cancer.

1 year 2 months ago
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Ion channel and neurotransmitter modulators as electroceutical approaches to the control of cancer.

Curr Pharm Des. 2017 May 29;:

Authors: Tuszynski J, Tilli TM, Levin M

Abstract
The activities of individual cells must be tightly coordinated in order to build and maintain complex 3-dimensional body structures during embryogenesis and regeneration. Thus, one way to view cancer is within systems biology as a network disorder affecting the ability of cells to properly interact with a morphodynamic field of instructive signals that keeps proliferation and migration orchestrated toward the anatomical needs of the host organism. One layer of this set of instructive microenvironmental cues is bioelectrical. Voltage gradients among all somatic cells (not just excitable nerve and muscle) control cell behavior, and the ionic coupling of cells into networks via electrochemical synapses allows them to implement tissue-level patterning decisions. These gradients have been increasingly implicated in the induction and suppression of tumorigenesis and metastasis, in the emerging links between developmental bioelectricity to the cancer problem. Consistent with the well-known role of neurotransmitter molecules in transducing electrical activity to downstream cascades in the brain, serotonergic signaling has likewise been implicated in cancer. Here, we review these recent data and propose new approaches for manipulating bioelectric and neurotransmitter pathways in cancer biology based on a bioelectric view of cancer. To support this methodology, we present new data on the effects of the SSRI Prozac and its analog (ZINC ID = ZINC06811610) on survival of both cancer (MCF7) and normal (MCF10A) breast cells exposed to these compounds. We found an IC50 concentration (25 M for Prozac and 100 M for the Prozac analog) at which these compounds inhibited tumor cell survival and proliferation. Additionally, at these concentrations, we did not observe alterations in a non-tumoral cell line. This constitutes a proof-of-concept demonstration for our hypothesis that the use of both existing and novel drugs as electroceuticals could serve as an alternative to highly toxic chemotherapy strategies replacing or augmenting them with less toxic alternatives. We believe this new approach forms an exciting roadmap for future biomedical advances.

PMID: 28554310 [PubMed - as supplied by publisher]

A computational method for selecting short peptide sequences for inorganic material binding.

1 year 2 months ago
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A computational method for selecting short peptide sequences for inorganic material binding.

Proteins. 2017 Nov;85(11):2024-2035

Authors: Nayebi N, Cetinel S, Omar SI, Tuszynski JA, Montemagno C

Abstract
Discovering or designing biofunctionalized materials with improved quality highly depends on the ability to manipulate and control the peptide-inorganic interaction. Various peptides can be used as assemblers, synthesizers, and linkers in the material syntheses. In another context, specific and selective material-binding peptides can be used as recognition blocks in mining applications. In this study, we propose a new in silico method to select short 4-mer peptides with high affinity and selectivity for a given target material. This method is illustrated with the calcite (104) surface as an example, which has been experimentally validated. A calcite binding peptide can play an important role in our understanding of biomineralization. A practical aspect of calcite is a need for it to be selectively depressed in mining sites.

PMID: 28734030 [PubMed - indexed for MEDLINE]

Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin.

1 year 2 months ago
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Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin.

Int J Mol Sci. 2017 Aug 02;18(8):

Authors: Spasevska I, Ayoub AT, Winter P, Preto J, Wong GK, Dumontet C, Tuszynski JA

Abstract
Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by Colchicum autumnale. While C. autumnale produces a potent cytotoxin, colchicine, and expresses its target protein, it is immune to colchicine's cytotoxic action and the mechanism of this resistance is hitherto unknown. In the present paper, the molecular mechanisms responsible for colchicine resistance in C. autumnale are investigated and compared to human tubulin. To this end, homology models for C. autumnale α-β tubulin heterodimer are created and molecular dynamics (MD) simulations together with molecular mechanics Poisson-Boltzmann calculations (MM/PBSA) are performed to determine colchicine's binding affinity for tubulin. Using our molecular approach, it is shown that the colchicine-binding site in C. autumnale tubulin contains a small number of amino acid substitutions compared to human tubulin. However, these substitutions induce significant reduction in the binding affinity for tubulin, and subsequently fewer conformational changes in its structure result. It is suggested that such small conformational changes are insufficient to profoundly disrupt microtubule dynamics, which explains the high resistance to colchicine by C. autumnale.

PMID: 28767055 [PubMed - indexed for MEDLINE]

Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.

1 year 2 months ago
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Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.

PLoS One. 2017;12(8):e0182400

Authors: Wang RC, Chen X, Parissenti AM, Joy AA, Tuszynski J, Brindley DN, Wang Z

Abstract
INTRODUCTION: One of the main reasons for disease recurrence in the curative breast cancer treatment setting is the development of drug resistance. Microtubule targeted agents (MTAs) are among the most commonly used drugs for the treatment of breaset cancer and therefore overcoming taxane resistance is of primary clinical importance. Our group has previously demonstrated that the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitivity to docetaxel due to the distinct expression profiles of β-tubulin isotypes in addition to the high expression of p-glycoprotein (ABCB1). In the present investigation we examined whether taxane-resistant breast cancer cells are more sensitive to microtubule destabilizing agents including vinca alkaloids and colchicine-site binding agents (CSBAs) than the non-resistant cells.
METHODS: Two isogenic MCF-7 breast cancer cell lines were selected for resistance to docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to examine if taxane-resistant breast cancer cells are sensitive to microtubule-destabilizing agents including vinca alkaloids and CSBAs. Cytotoxicity assays, immunoblotting, indirect immunofluorescence and live imaging were used to study drug resistance, apoptosis, mitotic arrest, microtubule formation, and microtubule dynamics.
RESULTS: MCF-7TXT cells were demonstrated to be cross resistant to vinca alkaloids, but were more sensitive to treatment with colchicine compared to parental non-resistant MCF-7CC cells. Cytotoxicity assays indicated that the IC50 of MCF-7TXT cell to vinorelbine and vinblastine was more than 6 and 3 times higher, respectively, than that of MCF-7CC cells. By contrast, the IC50 of MCF-7TXT cell for colchincine was 4 times lower than that of MCF-7CC cells. Indirect immunofluorescence showed that all MTAs induced the disorganization of microtubules and the chromatin morphology and interestingly each with a unique pattern. In terms of microtubule and chromain morphology, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, but more sensitive to colchicine compared to MCF-7CC cells. PARP cleavage assay further demonstrated that all of the MTAs induced apoptosis of the MCF-7 cells. However, again, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, and more sensitive to colchicine compared to MCF-7CC cells. Live imaging demonstrated that the microtubule dynamics of MCF-7TXT cells were less sensitive to vinca alkaloids, and more sensitive to colchicine. MCF-7TXT cells were also noted to be more sensitive to other CSBAs including 2MeOE2, ABT-751 and phosphorylated combretastatin A-4 (CA-4P).
CONCLUSION: Docetaxel-resistant MCF-7TXT cells have demonstrated cross-resistance to vinca alkaloids, but appear to be more sensitive to CSBAs (colchicine, 2MeOE2, ABT-751 and CA-4P) compared to non-resistant MCF-7CC cells. Taken together these results suggest that CSBAs should be evaluated further in the treatment of taxane resistant breast cancer.

PMID: 28787019 [PubMed - indexed for MEDLINE]