The exposure to extremely low frequency electromagnetic-fields inhibits the growth and potentiates the sensitivity to chemotherapy of bidimensional and tridimensional human osteosarcoma models.

We previously established a thermodynamical model to calculate the specific frequencies of extremely low frequency-electromagnetic field (ELF-EMF) able to arrest the growth of cancer cells. In the present study, for the first time, we investigated the efficacy of this technology on osteosarcoma, and we applied a precise frequency of the electromagnetic field on three human osteosarcoma cell lines, grown as adherent cells and spheroids. We evaluated the antitumour efficacy of irradiation in terms of response to chemotherapeutic treatments, which is usually poor in this type of cancer. Importantly, the results of this novel combinatorial approach revealed that the specific exposure can potentiate the efficacy of several chemotherapeutic drugs, both on bidimensional and tridimensional cancer models. The effectiveness of cisplatinum, methotrexate, ifosfamide and doxorubicin was greatly increased by the concomitant application of the specific ELF-EMF. Moreover, our experiments confirmed that ELF-EMF inhibited the proliferation and modulated the mitochondrial metabolism of all cancer models tested, whereas mesenchymal cells were not affected. The latter finding is extremely valuable, given the importance of preserving the cell reservoir necessary for tissue regeneration after chemotherapy. Altogether, this novel evidence opens new avenues to the clinical applications of ELF-EMF in oncology.

A Thermodynamic Perspective of Cancer Cells' Volume/Area Expansion Ratio.

The constructal law is used to improve the analysis of the resonant heat transfer in cancer cells. The result highlights the fundamental role of the volume/area ratio and its role in cancer growth and invasion. Cancer cells seek to increase their surface area to facilitate heat dissipation; as such, the tumour expansion ratio declines as malignant cells start to migrate and the cancer expands locally and systemically. Consequently, we deduce that effective anticancer therapy should be based on the control of some ion transport phenomena in an effort to increase the volume/area ratio. This emphasises restricting the local and systemic spatial expansion of the tumour system and thus gives further credence to the superior role of novel anti-migratory and anti-invasive treatment strategies over conventional anti-proliferative options only.

Irreversible and quantum thermodynamic considerations on the quantum zeno effect.

The quantum zeno effect slows down the quantum system's time evolution under frequent measurements. This paper aims to study this quantum effect by introducing the definition of time based on an irreversible thermodynamic analysis of quantum systems. Consequently, the quantum zeno effect requires (i) high values of the electromagnetic entropy generation rate related to the spontaneously down-converted light and (ii) a decrease in the quantum system's entropy value. So, the quantum zeno effect is a quantum process related to the interaction between a quantum system and the electromagnetic waves of the measurement device, causing a quantum thermodynamic stationary state. Last, the fundamental role of irreversibility emerges.

A Thermodynamic Approach to the Metaboloepigenetics of Cancer.

We present a novel thermodynamic approach to the epigenomics of cancer metabolism. Here, any change in a cancer cell's membrane electric potential is completely irreversible, and as such, cells must consume metabolites to reverse the potential whenever required to maintain cell activity, a process driven by ion fluxes. Moreover, the link between cell proliferation and the membrane's electric potential is for the first time analytically proven using a thermodynamic approach, highlighting how its control is related to inflow and outflow of ions; consequently, a close interaction between environment and cell activity emerges. Lastly, we illustrate the concept by evaluating the Fe2+-flux in the presence of carcinogenesis-promoting mutations of the TET1/2/3 gene family.

Thermomagnetic Resonance Effect of the Extremely Low Frequency Electromagnetic Field on Three-Dimensional Cancer Models.

In our recent studies, we have developed a thermodynamic biochemical model able to select the resonant frequency of an extremely low frequency electromagnetic field (ELF-EMF) specifically affecting different types of cancer, and we have demonstrated its effects in vitro. In this work, we investigate the cellular response to the ELF electromagnetic wave in three-dimensional (3D) culture models, which mimic the features of tumors in vivo. Cell membrane was modelled as a resistor-capacitor circuit and the specific thermal resonant frequency was calculated and tested on two-dimensional (2D) and three-dimensional (3D) cell cultures of human pancreatic cancer, glioblastoma and breast cancer. Cell proliferation and the transcription of respiratory chain and adenosine triphosphate synthase subunits, as well as uncoupling proteins, were assessed. For the first time, we demonstrate that an ELF-EMF hampers growth and potentiates both the coupled and uncoupled respiration of all analyzed models. Interestingly, the metabolic shift was evident even in the 3D aggregates, making this approach particularly valuable and promising for future application in vivo, in aggressive cancer tissues characterized by resistance to treatments.

Entropy estimation within in vitro neural-astrocyte networks as a measure of development instability.

The brain demands a significant fraction of the energy budget in an organism; in humans, it accounts for 2% of the body mass, but utilizes 20% of the total energy metabolized. This is due to the large load required for information processing; spiking demands from neurons are high but are a key component to understanding brain functioning. Astrocytic brain cells contribute to the healthy functioning of brain circuits by mediating neuronal network energy and facilitating the formation and stabilization of synaptic connectivity. During development, spontaneous activity influences synaptic formation, shaping brain circuit construction, and adverse astrocyte mutations can lead to pathological processes impacting cognitive impairment due to inefficiencies in network spiking activity. We have developed a measure that quantifies information stability within in vitro networks consisting of mixed neural-astrocyte cells. Brain cells were harvested from mice with mutations to a gene associated with the strongest known genetic risk factor for Alzheimer's disease, APOE. We calculate energy states of the networks and using these states, we present an entropy-based measure to assess changes in information stability over time. We show that during development, stability profiles of spontaneous network activity are modified by exogenous astrocytes and that network stability, in terms of the rate of change of entropy, is allele dependent.

Nonequilibrium Temperature: An Approach from Irreversibility.

Nonequilibrium temperature is a topic of research with continuously growing interest because of recent improvements in and applications of nonequilibrium thermodynamics, with particular regard to information theory, kinetic theory, nonequilibrium molecular dynamics, superfluids, radiative systems, etc. All studies on nonequilibrium temperature have pointed out that the definition of nonequilibrium temperature must be related to different aspects of the system, to the energy of the system, and to the energy fluxes between the system and its environment. In this paper, we introduce a definition of nonequilibrium temperature based on the Gouy-Stodola and Carnot theorems in order to satisfy all these theoretical requirements. The result obtained links nonequilibrium temperature to the electromagnetic outflow, generated by irreversibility during microscopic interaction in the system; to the environmental temperature; to the mean energy; and to the geometrical and physical characteristics of the system.

Thermal Resonance and Cell Behavior.

From a thermodynamic point of view, living cell life is no more than a cyclic process. It starts with the newly separated daughter cells and restarts when the next generations grow as free entities. During this cycle, the cell changes its entropy. In cancer, the growth control is damaged. In this paper, we analyze the role of the volume-area ratio in the cell in relation to the heat exchange between cell and its environment in order to point out its effect on cancer growth. The result holds to a possible control of the cancer growth based on the heat exchanged by the cancer toward its environment and the membrane potential variation, with the consequence of controlling the ions fluxes and the related biochemical reactions. This second law approach could represent a starting point for a possible future support for the anticancer therapies, in order to improve their effectiveness for the untreatable cancers.

Time, Irreversibility and Entropy Production in Nonequilibrium Systems.

The aim of this review is to shed light on time and irreversibility, in order to link macroscopic to microscopic approaches to these complicated problems. After a brief summary of the standard notions of thermodynamics, we introduce some considerations about certain fundamental aspects of temporal evolution of out-of-equilibrium systems. Our focus is on the notion of entropy generation as the marked characteristic of irreversible behaviour. The concept of time and the basic aspects of the thermalization of thermal radiation, due to the interaction of thermal radiation with matter, are explored concisely from complementary perspectives. The implications and relevance of time for the phenomenon of thermal radiation and irreversible thermophysics are carefully discussed. The concept of time is treated from a different viewpoint, in order to make it as clear as possible in relation to its different fundamental problems.

How Life Works-A Continuous Seebeck-Peltier Transition in Cell Membrane?

This paper develops a non-equilibrium thermodynamic approach to life, with particular regards to the membrane role. The Onsager phenomenological coefficients are introduced in order to point out the thermophysical properties of the cell systems. The fundamental role of the cell membrane electric potential is highlighted, in relation to ions and heat fluxes, pointing out the strictly relation between heat exchange and the membrane electric potential. A Seebeck-like and Peltier-like effects emerge in order to simplify the description of the heat and the ions fluxes. Life is described as a continuos transition between the Peltier-like effect to the Seebeck-like one, and viceversa.

The κ-statistics approach to epidemiology.

A great variety of complex physical, natural and artificial systems are governed by statistical distributions, which often follow a standard exponential function in the bulk, while their tail obeys the Pareto power law. The recently introduced [Formula: see text]-statistics framework predicts distribution functions with this feature. A growing number of applications in different fields of investigation are beginning to prove the relevance and effectiveness of [Formula: see text]-statistics in fitting empirical data. In this paper, we use [Formula: see text]-statistics to formulate a statistical approach for epidemiological analysis. We validate the theoretical results by fitting the derived [Formula: see text]-Weibull distributions with data from the plague pandemic of 1417 in Florence as well as data from the COVID-19 pandemic in China over the entire cycle that concludes in April 16, 2020. As further validation of the proposed approach we present a more systematic analysis of COVID-19 data from countries such as Germany, Italy, Spain and United Kingdom, obtaining very good agreement between theoretical predictions and empirical observations. For these countries we also study the entire first cycle of the pandemic which extends until the end of July 2020. The fact that both the data of the Florence plague and those of the Covid-19 pandemic are successfully described by the same theoretical model, even though the two events are caused by different diseases and they are separated by more than 600 years, is evidence that the [Formula: see text]-Weibull model has universal features.

Thermomagnetic resonance affects cancer growth and motility.

The fight against a multifaceted incurable disease such as cancer requires a multidisciplinary approach to overcome the multitude of molecular defects at its origin. Here, a new thermophysical biochemical approach has been suggested and associated with the use of electromagnetic fields to control the growth of cancer cells. In particular, thermodynamic analysis of the heat transfer is developed in correlation with cellular parameters such as the volume/area ratio. We propose that the electromagnetic wave, at the specific frequency calculated as the characteristic response time of any cell type to the external thermal perturbation, can affect resonant intracellular molecular oscillations. The biochemical model hypothesizes that microtubules are stabilized, and the impact is predicted on cell growth, migration and mitochondrial activity. Experimental validation of the theoretical results shows that the thermodynamic analysis allows the application of the specific electromagnetic field able to decrease cancer cell invasion and proliferation.

Time: a Constructal viewpoint & its consequences.

In the environment, there exists a continuous interaction between electromagnetic radiation and matter. So, atoms continuously interact with the photons of the environmental electromagnetic fields. This electromagnetic interaction is the consequence of the continuous and universal thermal non-equilibrium, that introduces an element of randomness to atomic and molecular motion. Consequently, a decreasing of path probability required for microscopic reversibility of evolution occurs. Recently, an energy footprint has been theoretically proven in the atomic electron-photon interaction, related to the well known spectroscopic phase shift effect, and the results on the irreversibility of the electromagnetic interaction with atoms and molecules, experimentally obtained in the late sixties. Here, we want to show how this quantum footprint is the "origin of time". Last, the result obtained represents also a response to the question introduced by Einstein on the analysis of the interaction between radiation and molecules when thermal radiation is considered; he highlighted that in general one restricts oneself to a discussion of the energy exchange, without taking the momentum exchange into account. Our result has been obtained just introducing the momentum into the quantum analysis.

The extremely low frequency electromagnetic stimulation selective for cancer cells elicits growth arrest through a metabolic shift.

The efficacy of the very low frequency electromagnetic field in cancer treatment remains elusive due to a lack of explanatory mechanisms for its effect. We developed a novel thermodynamic model that calculates for every cell type the frequency capable of inhibiting proliferation. When this frequency was applied to two human cancer cell lines, it reduced their growth while not affecting healthy cells. The effect was abolished by the inhibition of calcium fluxes. We found evidences of an enhanced respiratory activity due to the increased expression of the elements of the respiratory chain and oxidative phosphorylation, both at the mRNA and protein level. The respiratory burst potentiated the production of reactive oxygen species but was not associated to increased levels of ATP, leading to the conclusion that the energy was readily spent in the adaptive response to the electromagnetic field. Taken together, our data demonstrate that, regardless of individual molecular defects, it is possible to control cancer cells with a specific irradiation that imposes a mitochondrial metabolic switch, regulating calcium fluxes and deleterious to cancer growth. This approach lays the foundations for a personalized cancer medicine.

The importance of ion fluxes for cancer proliferation and metastasis: A thermodynamic analysis.

Following a thermodynamic approach, we develop a new theoretical analysis of ion transfer across cell membranes. Supported also by experimental data from the literature, we highlight that ion channels determine the typical features of cancer cells, i.e. independence from growth-regulatory signals, avoidance of apoptosis, indefinite proliferative potential, and the capability of inducing angiogenesis. Specifically, we analyse how ion transport, with particular regards to Ca2+ fluxes, modulates cancer cell proliferation, and regulates cell cycle checkpoints. Finally, our analysis also suggests that in malignant tumours aerobic glycolysis is the more efficient metabolic process when taking the required solvent capacity into account.

Constructal law analysis of Cl- transport in eyes aqueous humor.

Progressive loss-of-vision related to any intraocular disorder is known as glaucoma. Secretion of aqueous humor is physiologically important to provide nutrients and oxygen to the avascular anterior segment and ensuring normal visual function, even if, nowadays reducing the secretory rate to lower intraocular pressure is a major strategy in treating glaucomatous patients. Understanding the mechanisms and regulation of aqueous humor formation is very important to develop possible new approaches to lower intraocular pressure,but today there isn't any comprehensive model of the regulation of these component in forming aqueous humor. In this paper Construcal law is used to suggest how the Cl- fluxes can determine the water inflow and outflow, and, consequently, how the intraocular pressure is controlled by these fluxes.

An engineering thermodynamic approach to select the electromagnetic wave effective on cell growth.

To date, the choice of the characteristics of the extremely low-frequency electromagnetic field beneficial in proliferative disorders is still empirical. In order to make the ELF interaction selective, we applied the thermodynamic and biochemical principles to the analysis of the thermo-chemical output generated by the cell in the environment. The theoretical approach applied an engineering bio-thermodynamic approach recently developed in order to obtain a physical-mathematical model that calculated the frequency of the field able to maximize the mean entropy changes as a function of cellular parameters. The combined biochemical approach envisioned the changes of entropy as a metabolic shift leading to a reduction of cell growth. The proliferation of six human cancer cell lines was evaluated as the output signal able to confirm the correctness of the mathematical model. By considering the cell as a reactive system able to respond to the unbalancing external stimuli, for the first time we could calculate and validate the frequencies of the field specifically effective on distinct cells.

Second law efficiency for living cells.

The exergetic analysis of the biosystems is developed. It takes into account that cells are able to convert only part of the energy absorbed. The result is to highlight the fundamental role of the exergy as a quantity useful to develop considerations on the cells behavior in relation to normal or disease states.

Macroscopic irreversibility and microscopic paradox: A Constructal law analysis of atoms as open systems.

The relation between macroscopic irreversibility and microscopic reversibility is a present unsolved problem. Constructal law is introduced to develop analytically the Einstein's, Schrödinger's, and Gibbs' considerations on the interaction between particles and thermal radiation (photons). The result leads to consider the atoms and molecules as open systems in continuous interaction with flows of photons from their surroundings. The consequent result is that, in any atomic transition, the energy related to the microscopic irreversibility is negligible, while when a great number of atoms (of the order of Avogadro's number) is considered, this energy related to irreversibility becomes so large that its order of magnitude must be taken into account. Consequently, macroscopic irreversibility results related to microscopic irreversibility by flows of photons and amount of atoms involved in the processes.