Back
 OJBIPHY  Vol.12 No.2 , April 2022
Stimulation and Control of Homeostasis
Abstract: Healthy homeostasis is a principal driving force of the dynamic equilibrium of living organisms. The dynamical basis of homeostasis is the complex and interconnected feedback mechanisms, which are fundamentally governed by the nervous system, mainly the balance of the sympathetic and parasympathetic controlling actions. The balancing regulation is well presented in the heart’s sinus node and can be measured by the time-domain heart-rate variation (HRV) of its frequency domain to analyze the constitutional frequencies of the variation. This last is a fluctuation that shows 1/f time fractal arrangement (f is the composing frequency). The time-fractal arrangement could depend on the structural fractal of the His-Purkinje system of the heart and personally modify the HRV. The cancers gradually destroy the homeostatic harmony, starting locally and finishing systemically. The controlling activity of vagus-nerve changes the HRV or the power density spectrum of the signal fluctuations in malignant development, presenting an appropriate control of the cancerous processes. The modified spectrum by a non-invasive radiofrequency treatment could arrest the tumor growth. An appropriate modulation could support the homeostatic control and force reconstructing of the broken complexity.
Cite this paper: Szasz, A. (2022) Stimulation and Control of Homeostasis. Open Journal of Biophysics, 12, 89-131. doi: 10.4236/ojbiphy.2022.122004.
References

[1]   Dvorak, H.F. (2015) Tumors: Wounds That Do Not Heal—Redux. Cancer Immunology Research, 3, 1-11.
https://doi.org/10.1158/2326-6066.CIR-14-0209

[2]   Trigos, A.S., Pearson, R.B., Papenfuss, A.T., et al. (2016) Altered Interactions between Unicellular and Multicellular Genes Drive Hallmarks of Transformation in a Diverse Range of Solid Tumors. PNAS, 114, 6406-6411.
https://doi.org/10.1073/pnas.1617743114

[3]   Davidson, C.D., Wang, W.Y., Zaimi, I., et al. (2019) Cell Force-Mediated Matrix Reorganization Underlies Multicellular Network Assembly. Scientific Reports, 9, Article No. 12.
https://doi.org/10.1038/s41598-018-37044-1

[4]   Balmain, A., Gray, J. and Ponder, B. (2014) The Genetics and Genomics of Cancer. Nature Genetics, 33, 238-244.
https://doi.org/10.1038/ng1107

[5]   Szigeti, G.P., Szasz, O. and Hegyi, G. (2017) Connections between Warburg’s and Szentgyorgyi’s Approach about the Causes of Cancer. Journal of Neoplasm, 1, 1-13.

[6]   Hanahan, D. and Weinberg, R.A. (2000) The Hallmarks of Cancer. Cell, 100, 57-70.
https://doi.org/10.1016/S0092-8674(00)81683-9

[7]   Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: The Next Generation. Cell, 144, 646-674.
https://doi.org/10.1016/j.cell.2011.02.013

[8]   Dyas, F.G. (1928) Chronic Irritation as a Cause of Cancer. JAMA, 90, 457.
https://doi.org/10.1001/jama.1928.92690330003008c

[9]   Dvorak, H.F. (1986) Tumors: Wounds That Do Not Heal, Similarities between Tumor Stroma Generation and Wound Healing. The New England Journal of Medicine, 315, 1650-1659.
https://doi.org/10.1056/NEJM198612253152606

[10]   Platz, E.A. and De, Marzo, A.M. (2004) Epidemiology of Inflammation and Prostate Cancer. The Journal of Urology, 171, S36-S40.
https://doi.org/10.1097/01.ju.0000108131.43160.77

[11]   Punyiczki, M. and Fesus, L. (1998) Heat Shock and Apoptosis: The Two Defense Systems of the Organisms May Have Overlapping Molecular Elements. Annals of the New York Academy of Sciences, 951, 67-74.
https://doi.org/10.1111/j.1749-6632.1998.tb08978.x

[12]   Aktipis, C.A., Bobby, A.M., Jansen, G., et al. (2015) Cancer across the Tree of Life: Cooperation and Cheating in Multicellularity. Philosophical Transactions of the Royal Society B, 370, Article ID: 20140219.
https://doi.org/10.1098/rstb.2014.0219

[13]   Szasz, A. (2020) Preface. In: Szasz, A., Ed., Challenges and Solutions of Oncological Hyperthermia, Cambridge Scholars Publishing, Newcastle upon Tyne, 8-13.
https://www.cambridgescholars.com/challenges-and-solutions-of-oncological-hyperthermia

[14]   Szasz, A. (2021) Time-Fractal Modulation—Possible Modulation Effects in Human Therapy. Open Journal of Biophysics, 12, 38-87.
https://doi.org/10.4236/ojbiphy.2022.121003

[15]   Conley, B. (2019) Microbial Extracellular Electron Transfer Is a Far-Out Metabolism. The American Society for Microbiology, Washington DC.
https://asm.org/Articles/2019/November/Microbial-Extracellular-Electron-Transfer-is-a-Far

[16]   Szasz, A., van Noort, D., Scheller, A., et al. (1994) Water States in Living Systems. I. Structural Aspects. Physiological Chemistry and Physics, 26, 299-322.

[17]   Agmon, N. (1995) The Grotthuss Mechanism. Chemical Physics Letters, 244, 456-462.
https://doi.org/10.1016/0009-2614(95)00905-J

[18]   Markovitch, O. and Agmon, N. (2007) Structure and Energetics of the Hydronium Hydration Shells. The Journal of Physical Chemistry A, 111, 2253-2256.
https://doi.org/10.1021/jp068960g

[19]   Tuckerman, M.E., Laasonen, K., Sprik, M., et al. (1995) Ab Initio Molecular Dynamics Simulation of the Solvation and Transport of Hydronium and Hydroxyl Ions in Water. The Journal of Chemical Physics, 103, 150-161.
https://doi.org/10.1063/1.469654

[20]   Tuckerman, M.E., Laasonen, K., Sprik, M. and Parrinello, M. (1995) Ab Initio Molecular Dynamics Simulation of the Solvation and Transport of H3O+ and OH- Ions in Water. The Journal of Physical Chemistry, 99, 5749-5752.
https://doi.org/10.1021/j100016a003

[21]   Marx, D., Tuckerman, M.E., Hutter, J., et al. (1999) The Nature of the Hydrated Excess Proton in Water. Nature, 397, 601-604.
https://doi.org/10.1038/17579

[22]   Csermely, P. (2009) Weak Links: A Universal Key of Network Diversity and Stability. Springer, Berlin.
https://doi.org/10.1007/978-3-540-31157-7_3

[23]   Szendro, P., Vincze, G. and Szasz, A. (2001) Pink-Noise Behaviour of Biosystems. European Biophysics Journal, 30, 227-231.
https://doi.org/10.1007/s002490100143

[24]   Lakhtakia, A. (1995) Physical Fractals: Self-Similarity and Square-Integrability. Speculation in Science and Technology, 18, 153-156.

[25]   Zbilut, J.P. and Marwan, N. (2008) The Wiener-Khinchin Theorem and Recurrence Quantification. Physics Letters A, 372, 6622-6626.
https://doi.org/10.1016/j.physleta.2008.09.027

[26]   Lin, Y.K. (1967) Probabilistic Theory of Structural Dynamics. McGraw-Hill, New York.

[27]   Aselli, G.B., Porta, A., Montano, N., Gnecchi-Ruscone, T., Lombardi, F. and Cerutti, S. (1992) Linear and Non-Linear Effects in the Beat-by-Beat Variability of Sympathetic Discharge in Decerebrate Cats. 14th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Vol. 7, 482-483.
https://doi.org/10.1109/IEMBS.1992.5761070

[28]   Strimbu, K. and Tavel, J.A. (2010) What Are Biomarkers? Current Opinion in HIV and AIDS, 5, 463-466.
https://doi.org/10.1097/COH.0b013e32833ed177

[29]   Dash, P.K., Zhao, J., Hergenroeder, G. and Noore, A.N. (2010) Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury. Neurotherapeutics, 7, 100-114.
https://doi.org/10.1016/j.nurt.2009.10.019

[30]   Henry, N.L. and Hayes, D.F. (2012) Cancer Biomarkers. Molecular Oncology, 6, 140-146.
https://doi.org/10.1016/j.molonc.2012.01.010

[31]   Byrnes, S.A. and Weigl, B.H. (2018) Selecting Analytical Biomarkers for Diagnostic Applications: A First Principles Approach. Expert Review of Molecular Diagnostics, 18, 19-26.
https://doi.org/10.1080/14737159.2018.1412258

[32]   Boessen, R., Heerspink, H.J.L., De Zeeuw, D.D., Grobbee, D.E., Groenwold, R.H.H. and Roes, K. (2014) Improving Clinical Trial Efficiency by Biomarker-Guided Patient Selection. Trials, 15, 103. http://www.trialsjournal.com/content/15/1/103
https://doi.org/10.1186/1745-6215-15-103


[33]   Ru, Y., Dancik, G.M. and Theodorescu, D. (2011) Biomarkers for Prognosis and Treatment Selection in Advanced Bladder Cancer Patients. Current Opinion in Urology, 21, 420-427.
https://doi.org/10.1097/MOU.0b013e32834956d6

[34]   Sindo, Y., Hazama, S., Suzuki, N., Iguchi, H., Uesugi, K., et al. (2017) Predictive Biomarkers for the Efficacy of Peptide Vaccine Treatment: Based on the Results of a Phase II Study on Advanced Pancreatic Cancer. Journal of Experimental and Clinical Cancer Research, 36, 36.
https://doi.org/10.1186/s13046-017-0509-1

[35]   Luckett, T., King, M.T., Butow, P.N., Oguchi, M., et al. (2011) Choosing between the EORTC QLQ-C30 and FACT-G for Measuring Health-Related Quality of Life in Cancer Clinical Research: Issues, Evidence and Recommendations. Annals of Oncology, 22, 2179-2190.
https://doi.org/10.1093/annonc/mdq721

[36]   Evelyne (2018) Heart Rate Variability as a Prognostic Factor for Cancer Survival—A Systematic Review. Frontiers in Physiology, 9, Article No. 623.
https://doi.org/10.3389/fphys.2018.00623

[37]   Lee, S.Y., Fiorentini, G., Szasz, A.M., Szigeti, Gy., Szasz, A. and Minnaar, C.A. (2020) Quo Vadis Oncological Hyperthermia (2020)? Frontiers in Oncology, 10, Article No. 1690.
https://doi.org/10.3389/fonc.2020.01690

[38]   Lu, Y.M., et al. (2013) Deep Regional Hyperthermia Combined with Traditional Chinese Medicine in Treating Benign Diseases in Clifford Hospital. Oncothermia Journal, 7, 157-165.

[39]   Casadei, V., Sarti, D., Milandri, C., Dentico, P., Guadagni, S. and Fiorentini, C. (2020) Comparing the Effectiveness of Pain Therapy (PT) and Modulated Electro-Hyperthermia (mEHT) versus Pain Therapy Alone in Treating Patients with Painful Bony Metastases: An Observational Trial. In: Szasz, A., Ed., Challenges and Solutions of Oncological Hyperthermia, Cambridge Scholars, Washington DC, Ch. 15, 337-345.

[40]   Hegyi, G., Molnar, I., Mate, A. and Petrovics, G. (2017) Targeted Radiofrequency Treatment—Oncothermia Application in Non-Oncological Diseases as Special Physiotherapy to Delay the Progressive Development. Clinics and Practice, 14, 73-77.
https://doi.org/10.4172/clinical-practice.100098

[41]   Zais, O. (2013) Lyme Disease and Oncothermia. Conference Papers in Medicine, 2013, Article ID: 275013.
https://doi.org/10.1155/2013/275013

[42]   Theodor, W.H. (2003) Transcranial Magnetic Stimulation in Epilepsy. Epylepsy Currents, 3, 191-197.
https://doi.org/10.1046/j.1535-7597.2003.03607.x

[43]   Nussbaum, E.L., Houghton, P., Anthony, J., Rennie, S., et al. (2017) Neuromuscular Electrical Stimulation for Treatment of Muscle Impairment: Critical Review and Recommendations for Clinical Practice. Physiotherapy Canada, 69, 1-76.
https://doi.org/10.3138/ptc.2015-88

[44]   Liu, A., Voroslakos, M., Kronberg, G., Henin, S., et al. (2018) Immediate Neurophysiological Effects of Transcranial Electrical Stimulation. Nature Communications, 9, Article No. 2092.
https://doi.org/10.1038/s41467-018-07233-7

[45]   Gershon, A.A., Dannon, P.N. and Grunhaus, L. (2003) Transcranial Magnetic Stimulation in the Treatment of Depression. American Journal of Psychiatry, 160, 835-845.
http://ajp.psychiatryonline.org
https://doi.org/10.1176/appi.ajp.160.5.835


[46]   Zygmunt, A. and Stanczyk, J. (2010) Methods of Evaluation of Autonomic Nervous System. Archives of Medical Science, 6, 11-18.
https://doi.org/10.5114/aoms.2010.13500

[47]   Andersson, U. and Tracy, K.J. (2012) Neural Reflexes in Inflammation and Immunity. Journal of Experimental Medicine, 209, 1057-1068.
https://doi.org/10.1084/jem.20120571

[48]   Berthoud, H.R. and Neuhuber, W.L. (2000) Functional and Chemical Anatomy of the Afferent Vagal System. Autonomic Neuroscience, 85, 1-17.
https://doi.org/10.1016/S1566-0702(00)00215-0

[49]   Howland, R.H. (2014) Vagus Nerve Stimulation. Current Behavioral Neuroscience Reports, 1, 64-73.
https://doi.org/10.1007/s40473-014-0010-5

[50]   Yap, J.Y.Y., Keatch, C., Lambert, E., Woods, W., et al. (2020) Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Frontiers in Neuroscience, 14, Article No. 284.
https://doi.org/10.3389/fnins.2020.00284

[51]   Koopman, F.A., Chavan, S.S., Miljko, S., Grazio, S., et al. (2016) Vagus Nerve Stimulation Inhibits Cytokine Production and Attenuates Disease Severity in Rheumatoid Arthritis. PNAS, 113, 8284-8289.
https://doi.org/10.1073/pnas.1605635113

[52]   Guo, Y., Koshy, S., Hui, D., Palmer, J.L., Shin, K., Bozkurt, M. and Yusuf, S.W. (2015) Prognostic Value of Heart Rate Variability in Patients with Cancer. Journal of Clinical Neurophysiology, 32, 516-520.
https://doi.org/10.1097/WNP.0000000000000210

[53]   Teff, K.L. (2008) Visceral Nerves: Vagal and Sympathetic Innervation. Journal of Parenteral and Enteral Nutrition, 32, 569-571.
https://doi.org/10.1177/0148607108321705

[54]   Mancino, M., Ametler, E., Gascon, P. and Almendro, V. (2011) The Neuronal Influence on Tumor Progression. Biochimica et Biophysica Acta (BBA)—Reviews on Cancer, 1816, 105-118.
https://doi.org/10.1016/j.bbcan.2011.04.005

[55]   Wang, L., Xu, J., Xiai, Y., Yin, K., Li, Z., Li, B., Wand, W., Xu, H., Yang, L. and Xu, Z. (2018) Muscarinic Acetylcholine Receptor 3 Mediates Vagus Nerve-Induced Gastric Cancer. Oncogenesis, 7, 88.
https://doi.org/10.1038/s41389-018-0099-6

[56]   Faulkner, S., Jobling, P., March, B. and Jiang, C.C. (2019) Tumor Neurobiology and the War of Nerves in Cancer. Cancer Discovery, 9, 702-710.
https://doi.org/10.1158/2159-8290.CD-18-1398

[57]   Gidron, Y., Perry, H. and Glennie, M. (2005) Does the Vagus Nerve Inform the Brain about Pre-Clinical Tumours and Modulate Them? The Lancet Oncology, 6, 245-248.
https://doi.org/10.1016/S1470-2045(05)70096-6

[58]   Reijmen, E., Vannucci, L., De, Couck, M., De, Greve, J. and Gidron, Y. (2018) Therapeutic Potential of the Vagus Nerve in Cancer. Immunology Letters, 202, 38-43.
https://doi.org/10.1016/j.imlet.2018.07.006

[59]   De, Visser, K.E. and Coussens, L.M. (2006) The Inflammatory Tumor Microenvironment and Its Impact on Cancer Development. Contributions to Microbiology, 13, 118-137.
https://doi.org/10.1159/000092969

[60]   Pages, F., Galon, J., Dieu, Nosjean, M.C., Tartour, E., Sautes, Fridman, C. and Fridman, W.H. (2010) Immune Infiltration in Human Tumors: A Prognostic Factor That Should Not Be Ignored. Oncogene, 29, 1093-1102.
https://doi.org/10.1038/onc.2009.416

[61]   Qian, B.Z. and Pollard, J.W. (2010) Macrophage Diversity Enhances Tumor Progression and Metastasis. Cell, 141, 39-51.
https://doi.org/10.1016/j.cell.2010.03.014

[62]   Gidron, Y., De Couck, M., Schallier, D., De Greve, J., Van Laethem, J.L. and Marechal, R. (2018) The Relationship between a New Biomarker of Vagal Neuroimmunomodulation and Survival in Two Fatal Cancers. Journal of Immunology Research, 2018, Article ID: 4874193.
https://doi.org/10.1155/2018/4874193

[63]   De Couck, M. and Caers, R. (2018) Why We Should Stimulate the Vagus Nerve in Cancer. Clinical Oncology, 3, 1515. https://doi.org/10.1155/2018/1236787

[64]   Balasubramanian, K., Harikumar, K., Nagaraj, N. and Pati, S. (2017) Vagus Nerve Stimulation Modulated Complexity of Heart Rate Variability Differently during Sleep and Wakefulness. Annals of Indian Academy of Neurology, 20, 403-407.
https://doi.org/10.4103/aian.AIAN_148_17

[65]   Goldberger, A.L. and West, B.J. (1987) Chaos in Physiology: Hearth or Disease? In: Degn, H., et al., Eds., Chaos in Biological Systems, Springer Science + Business Media, New York, 1-4.
https://doi.org/10.1007/978-1-4757-9631-5_1

[66]   Mandell, A.J., Knapp, S., Ehlers, C.L. and Russo, P.V. (1983) The Stability of Constrained Randomness: Lithium Prophylaxis at Several Neurobiological Levels. In: Post, R.M. and Ballenger, J.C., Eds., Neurobiology of the Mood Disorders, Williams & Wilkins, Baltimore, 744-776.

[67]   Kobayashi, M. and Musha, T. (1982) 1/f Fluctuation of Heartbeat Period. IEEE Transactions on Biomedical Engineering, 29, 456-457.
https://doi.org/10.1109/TBME.1982.324972

[68]   Trimmel, K., Sacha, J. and Huikuri, H.V. (2015) Heart Rate Variability: Clinical Applications and Interaction between HRV and Heart Rate. Frontiers Media, Lausanne.
https://doi.org/10.3389/978-2-88919-652-4

[69]   Kleiger, R.E., Stein, D.S. and Bigger, M.D. (2005) Heart Rate Variability: Measurement and Clinical Utility. Annals of Noninvasive Electrocardiology, 10, 88-101.
https://doi.org/10.1111/j.1542-474X.2005.10101.x

[70]   Malik, M. (1996) Heart Rate Variability. Standards of Measurement, Physiological Interpretation, and Clinical Use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. European Heart Journal, 17, 354-381.
https://doi.org/10.1093/oxfordjournals.eurheartj.a014868

[71]   Benichous, T., Pereira, B., Mermillod, M., Tauveron, I., et al. (2018) Heart Rate Variability in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. PLoS ONE, 13, e0195166. https://doi.org/10.1371/journal.pone.0195166

[72]   Chou, Y.H., Huang, W.L., Chang, C.H., Yang, C.C.H., Kuo, T.B.J., et al. (2019) Heart Rate Variability as a Predictor of Rapid Renal Function Deterioration in Chronic Kidney Disease Patients. Nephrology (Carlton), 24, 806-813.
https://doi.org/10.1111/nep.13514

[73]   Da, Silva, V.P., Oliveira, B.R.R., Mello, R.G.T., Moraes, H., et al. (2018) Heart Rate Variability Indexes in Dementia: A Systematic Review with a Quantitative Analysis. Current Alzheimer Research, 15, 80-88.
https://doi.org/10.2174/1567205014666170531082352

[74]   Jung, W., Jang, K.I. and Lee, S.H. (2018) Heart and Brain Interaction of Psychiatric Illness: A Review Focused on Heart Rate Variability, Cognitive Function, and Quantitative Electrocephalography. Clinical Psychopharmacology and Neuroscience, 17, 459-474.
https://doi.org/10.9758/cpn.2019.17.4.459

[75]   Sajjadieh, A., Shahsavari, A., Safaei, A., Penzel, T., Schoebel, C., et al. (2020) The Association of Sleep Duration and Quality with Heart Rate Variability and Blood Pressure. Tanaffos, 19, 135-143.

[76]   Kopp, W.J., Synowski, S.J., Newel, M.E., Schmidt, L.A., et al. (2011) Autonomic Nervous System Reactivity to Positive and Negative Mood Induction: The Role of Acute Psychological Responses and Frontal Electrocortical Activity. Biological Psychology, 86, 230-238.
https://doi.org/10.1016/j.biopsycho.2010.12.003

[77]   Sarlis, N.V., Skordas, E.S. and Varotsos, P.A. (2009) Heart Rate Variability in Natural Time and 1/f “Noise”. EPL, 87, 18003.
https://doi.org/10.1209/0295-5075/87/18003

[78]   De Couck, M. and Gidron, Y. (2013) Norms of Vagal Nerve Activity, Indexed by Heart Rate Variability in Cancer Patients. Cancer Epidemiology, 37, 737-741.
https://doi.org/10.1016/j.canep.2013.04.016

[79]   Arab, C., Dias, D.P.M., Barbosa, R.T., de Almeida, de Carvalho, T.D., et al. (2016) Heart Rate Variability Measure in Breast Cancer Patients and Survivors: A Systematic Review. Psychoneuroendocrinology, 68, 57-68.
https://doi.org/10.1016/j.psyneuen.2016.02.018

[80]   Lombardi, F., Montano, N., Finocchiaro, M.L., Gnecchi, Ruscone, T., Baselli, G., Cerutti, S. and Malliani, A. (1990) Spectral Analysis of Sympathetic Discharge in Decerebrate Cats. Journal of the Autonomic Nervous System, 30, S97-S99.
https://doi.org/10.1016/0165-1838(90)90109-V

[81]   Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology (1996) Heart Rate Variability: Standards of Measurement, Physiological Interpretation, and Clinical Use. Circulation, 93, 1043-1065.

[82]   Tulppo, M.P., Makikallio, T.H., Takala, T.E.S., Seppanen, T. and Huikuri, H.V. (1996) Quantitative Beat-to-Beat Analysis of Heart Rate Dynamics during Exercise. American Journal of Physiology, 271, H244-H252.
https://doi.org/10.1152/ajpheart.1996.271.1.H244

[83]   Acharya, R.U., Sing, O.W., Ping, L.Y. and Chua, T.L. (2004) Heart Rate Analysis in Normal Subjects of Various Age Groups. BioMedical Engineering OnLine, 3, 24.
https://doi.org/10.1186/1475-925X-3-24

[84]   Kamen, P.W., Krum, H. and Tonkin, A.M. (1996) Poincare Plot of Heart Rate Variability Allows Quantitative Display of Parasympathetic Nervous Activity. Clinical Science, 91, 201-208.
https://doi.org/10.1042/cs0910201

[85]   Roth, Y. (2018) Homeostasis Processes Expressed as Flashes in a Poincaré Sections. Journal of Modern Physics, 9, 2135-2140.
https://doi.org/10.4236/jmp.2018.912134

[86]   Woo, M.A., Stevenson, W.G., Moser, D.K., Trelease, R.B. and Harper, R.H. (1992) Patterns of Beat-to-Beat Heart Rate Variability in Advanced Heart Failure. American Heart Journal, 123, 704-707.
https://doi.org/10.1016/0002-8703(92)90510-3

[87]   Brennan, M., Palaniswami, M. and Kamen, P. (2001) Do Existing Measures of Poincare Plot Geometry Reflect Nonlinear Features of Heart Rate Variability? IEEE Transactions on Biomedical Engineering, 48, 1342-1347.
https://doi.org/10.1109/10.959330

[88]   Thu, T.N.P., Hernandez, A.I., Costet, N., Patural, H., Pichot, V., et al. (2019) Improving Methodology in Heart Rate Variability Analysis for the Premature Infants: Impact of the Time Length. PLoS ONE, 14, e0220692.
https://doi.org/10.1371/journal.pone.0220692

[89]   Peng, C.K., Havlin, S., Stanley, H.E. and Goldberger, A.L. (1995) Quantification of Scaling Exponents and Crossover Phenomena in Nonstationary Heartbeat Time Series. Chaos, 5, 82-87.
https://doi.org/10.1063/1.166141

[90]   Goldberger, A.L., Amaral, L.A.N., Hausdorff, J.M., Ivanov, P.C., Peng, C.K. and Stanley, H.E. (2002) Fractal Dynamics in Physiology: Alterations with Disease and Aging. PNAS, 99, 2466-2472.
https://doi.org/10.1073/pnas.012579499

[91]   Ho, K.K.L., Moody, G.B., Peng, C.K., et al. (1997) Predicting Survival in Heart Failure Case and Control Subjects by Use of Fully Automated Methods for Deriving Nonlinear and Conventional Indices of Heart Rate Dynamis. Circulation, 96, 842-848.
https://doi.org/10.1161/01.CIR.96.3.842

[92]   Goldberger, A.L., Bhargava, V., West, B. and Mandell, A.J. (1985) Some Observations on the Question: Is Ventricular Fibrillation “Chaos”? Physica D, 19, 282-289.
https://doi.org/10.1016/0167-2789(86)90024-2

[93]   Goldberger, A.L., Bhargava, V. and West, B.J. (1985) Nonlinear Dynamics of Heartbeat, II. Subharmonic Bifurcations of the Cardiac Interbeat Interval in Sinus Node Disease. Physica D, 17, 207-214.
https://doi.org/10.1016/0167-2789(85)90005-3

[94]   Goldberger, A.L. and West, B.J. (1987) Applications of Nonlinear Dynamics to Clinical Cardiology. Annals of the New York Academy of Sciences, 504, 195-213.
https://doi.org/10.1111/j.1749-6632.1987.tb48733.x

[95]   Goldberger, A.L. (2006) Complex Systems. Proceedings of the American Thoracic Society, 3, 467-472.
https://doi.org/10.1513/pats.200603-028MS

[96]   Turner, J.D. (1988) Frequency Domain Analysis. In: Instrumentation for Engineers, Palgrave, London, Ch. 7, 159-179.
https://doi.org/10.1007/978-1-4684-6300-2_7

[97]   Li, K., Rudiger, H. and Ziemssen, T. (2019) Spectral Analysis of Heart Rate Variability: Time Window Matters. Frontiers in Neurology, 10, Article No. 545.
https://doi.org/10.3389/fneur.2019.00545

[98]   Shaffer, F. and Ginsberg, J.P. (2017) An Overview of Heart Rate Variability Metrics and Norms. Frontiers in Public Health, 5, Article No. 258.
https://doi.org/10.3389/fpubh.2017.00258

[99]   Owens, A.P. (2020) The Role of Heart Rate Variability in the Future of Remote Digital Diomarkers. Frontiers in Neuroscience, 14, Article ID: 582145.
https://doi.org/10.3389/fnins.2020.582145

[100]   Fossion, R., Rivera, A.L. and Estanol, B. (2018) A Physicist’s View of Homeostasis: How Time Series of Continuous Monitoring Reflect the Function of Physiological Variabilities in Regulatory Mechanisms. Physiological Measurement, 39, Article ID: 084007.
https://doi.org/10.1088/1361-6579/aad8db

[101]   Riganello, F., Garbarino, S. and Sannita, W.G. (2012) Heart Rate Variability, Homeostasis, and Brain Function: A Tutorial and Review of Application. Journal of Psychophysiology, 26, 178-203.
https://doi.org/10.1027/0269-8803/a000080

[102]   De Couck, M., Caers, R., Spiegel, D. and Gidron, Y. (2018) The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review. Journal of Oncology, 2018, Article ID: 1236787.
https://doi.org/10.1155/2018/1236787

[103]   Cooper, T.M., McKinley, P.S., Seeman, T.E., Choo, T.H., Lee, S. and Sloan, R.P. (2015) Heart Rate Variability Predicts Levels of Inflammatory Markers: Evidence for the Vagal Anti-Inflammatory Pathway. Brain, Behavior, and Immunity, 49, 94-100.
https://doi.org/10.1016/j.bbi.2014.12.017

[104]   Ohira, H., Matsunaga, M., Osumi, T., Fukuyama, S., Shinoda, J., Yamada, J. and Gidron, Y. (2013) Vagal Nerve Activity as a Moderator of Brain-Immune Relationships. Journal of Neuroimmunology, 260, 28-36.
https://doi.org/10.1016/j.jneuroim.2013.04.011

[105]   Young, H.A. and Benton, D. (2018) Heart-Rate Variabiity: A Biomarker to Study the Influence of Nutrition on Physiological and Psychological Health? Behavioural Pharmacology, 29, 140-151.
https://doi.org/10.1097/FBP.0000000000000383

[106]   Hayano, J. and Yuda, E. (2019) Pitfalls of Assessment of Autonomic Function by Heart Rate Variability. Journal of Physiological Anthropology, 38, Article No. 3.
https://doi.org/10.1186/s40101-019-0193-2

[107]   Quintana, D.S. and Heathers, A.J. (2014) Considerations in the Assessment of Heart Rate Variability in Biobehavioral Research. Frontiers in Psychology, 5, Article No. 805.
https://doi.org/10.3389/fpsyg.2014.00805

[108]   Szasz, A. and Szasz, O. (2020) Time-Fractal Modulation of Modulated Electro-Hyperthermia (mEHT). In: Szasz, A., Ed., Challenges and Solutions of Oncological Hyperthermia, Cambridge Scholars, Washington DC, Ch. 17, 377-415.

[109]   Szasz, A.M., Minnaar, C.A., Szentmartoni, Gy., et al. (2019) Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist. Frontiers in Oncology, 9, Article No. 1012.
https://doi.org/10.3389/fonc.2019.01012

[110]   Szasz, O. (2020) Local Treatment with Systemic Effect: Abscopal Outcome. In: Szasz, A., Ed., Challenges and Solutions of Oncological Hyperthermia, Cambridge Scholars, Washington DC, Ch. 11, 192-205.

[111]   Minnaar, C.A., Kotzen, J.A., Ayeni, O.A., et al. (2020) Potentiation of the Abscopal Effect by Modulated Electro-Hyperthermia in Locally Advanced Cervical Cancer Patients. Frontiers in Oncology, 10, Article No. 376.
https://doi.org/10.3389/fonc.2020.00376

[112]   Andocs, G., Szasz, O. and Szasz, A. (2009) Oncothermia Treatment of Cancer: From the Laboratory to Clinic. Electromagnetic Biology and Medicine, 28, 148-165.
https://doi.org/10.1080/15368370902724633

[113]   Yang, K.L., Huang, C.C., Chi, M.S., Chiang, H.C., Wang, Y.S. andocs, G., et al. (2016) In Vitro Comparison of Conventional Hyperthermia and Modulated Electro-Hyperthermia. Oncotarget, 7, 84082-84092.
https://doi.org/10.18632/oncotarget.11444

[114]   Wust, P., Ghadjar, P., Nadobny, J., et al. (2019) Physical Analysis of Temperature-Dependent Effects of Amplitude-Modulated Electromagnetic Hyperthermia. International Journal of Hypertension, 36, 1246-1254.
https://doi.org/10.1080/02656736.2019.1692376

[115]   Wust, P., Kortum, B., Strauss, U., Nadobny, J., Zschaeck, S., Beck, M., et al. (2020) Non-Thermal Effects of Radiofrequency Electromagnetic Fields. Scientific Reports, 10, Article No. 13488.
https://doi.org/10.1038/s41598-020-69561-3

[116]   Wust, P., Nadobny, J., Zschaeck, S. and Ghadjar, P. (2020) Physics of Hyperthermia—Is Physics Really against Us? In: Szasz, A., Ed., Challenges and Solutions of Oncological Hyperthermia, Cambridge Scholars, Washington DC, Ch. 16, 346-376.

[117]   Chang, R.B. (2019) Body Thermal Responses and the Vagus Nerve. Neuroscience Letters, 698, 209-216.
https://doi.org/10.1016/j.neulet.2019.01.013

[118]   Andocs, G., Rehman, M.U., Zhao, Q.L., Tabuchi, Y., Kanamori, M. and Kondo, T. (2016) Comparison of Biological Effects of Modulated Electro-Hyperthermia and Conventional Heat Treatment in Human Lymphoma U937 Cell. Cell Death Discovery, 2, 16039.
https://doi.org/10.1038/cddiscovery.2016.39

[119]   Andocs, G., Rehman, M.U., Zhao, Q.L., Papp, E., Kondo, T. and Szasz, A. (2015) Nanoheating without Artificial Nanoparticles Part II. Experimental Support of the Nanoheating Concept of the Modulated Electro-Hyperthermia Method, Using U937 Cell Suspension Model. Biology and Medicine, 7, 1-9.
https://doi.org/10.4172/0974-8369.1000247

[120]   Szasz, A. (2019) Thermal and Nonthermal Effects of Radiofrequency on Living State and Applications as an Adjuvant with Radiation Therapy. Journal of Radiation and Cancer Research, 10, 1-17.
https://doi.org/10.4103/jrcr.jrcr_25_18

[121]   Danics, L., Schvarcz, Cs., Viana, P., et al. (2020) Exhaustion of Protective Heat Shock Response Induces Significant Tumor Damage by Apoptosis after Modulated Electro-Hyperthermia Treatment of Triple Negative Breast Cancer Isografts in Mice. Cancers, 12, 2581.
https://doi.org/10.3390/cancers12092581

[122]   Forika, G., Balogh, A., Vancsik, T., Zalatnai, A., et al. (2020) Modulated Electro-Hyperthermia Resolves Radioresistance of Panc1 Pancreas Adenocarcinoma and Promotes DNA Damage and Apoptosis in Vitro. International Journal of Molecular Sciences, 21, 5100.
https://doi.org/10.3390/ijms21145100

[123]   Krenacs, T., Meggyeshazi, N., Forika, G., et al. (2020) Modulated Electro-Hyper-thermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models. International Journal of Molecular Sciences, 21, 6270.
https://doi.org/10.3390/ijms21176270

[124]   Scheff, J.D., Griffel, B., Corbett, S.A., Calvano, S.E., et al. (2014) On Heart Rate Variability and Autonomic Activity in Homeostasis and in Systemic Inflammation. Mathematical Biosciences, 252, 36-44.
https://doi.org/10.1016/j.mbs.2014.03.010

[125]   Goldberger, A.L., Bhargava, V., West, B.J. and Mandell, A.J. (1985) On a Mechanism of Cardiac Electrical Stability, the Fractal Hypothesis. Biophysics Journal, 48, 525-528.
https://doi.org/10.1016/S0006-3495(85)83808-X

[126]   Kauffman, S.A. and Johnsen, S. (1991) Coevolution to the Edge of Chaos: Coupled Fitness Landscapes, Poised States, and Coevolutionary Avalanches. Journal of Theoretical Biology, 149, 467-505.
https://doi.org/10.1016/S0022-5193(05)80094-3

[127]   Bak, P., Tang, C. and Wiesenfeld, K. (1988) Self-Organized Criticality. Physical Review A, 38, 364-374.
https://doi.org/10.1103/PhysRevA.38.364

[128]   Lewin, R. (1992) Complexity, Life at the Edge of Chaos. University of Chicago Press, Chicago.

[129]   Ito, K. and Gunji, Y.P. (1994) Self-Organisation of Living Systems towards Criticality at the Edge of Chaos. Biosystems, 33, 17-24.
https://doi.org/10.1016/0303-2647(94)90057-4

[130]   Prigogine, I. and Stengers, I. (1985) Order out of Chaos. Flamingo, London.
https://doi.org/10.1063/1.2813716

[131]   Calaprice A. (2000) The Expanded Quotable Einstein. Princeton University Press, Princeton, 456.

[132]   Bernardes, A.T. and dos Santos, R.M. (1997) Immune Network at the Edge of Chaos. Journal of Theoretical Biology, 186, 173-187.
https://doi.org/10.1006/jtbi.1996.0316

[133]   Bertschinger, N. and Natschlager, T. (2004) Real-Time Computation at the Edge of Chaos in Recurrent Neural Networks. Neural Computation, 16, 1413-1436.
https://doi.org/10.1162/089976604323057443

[134]   Stokic, D., Hanel, R. and Thurner, S. (2008) Inflation of the Edge of Chaos in a Simple Model of Gene Interaction Networks. Physical Review E, 77, Article ID: 061917.
https://doi.org/10.1103/PhysRevE.77.061917

[135]   Kauffman, S., Hill, C., Hood, L. and Huang, S. (2014) Transforming Medicine: A Manifesto, Scientific American-World View.
https://web.archive.org/web/20140713110927/http://www.saworldview.com/special-report-cancer/transforming-medicine-a-manifesto

[136]   Eke, A., Hermán, P., Bassingthwaighte, J.B., Raymond, G.M., Percival, D.B., Cannon, M., Balla, I. and Ikrényi, C. (2000) Physiological Time Series: Distinguishing Fractal Noises from Motions. Pflügers Archiv—European Journal of Physiology, 439, 403-415.
https://doi.org/10.1007/s004249900135

[137]   Barunik, J. and Kristoufek, L. (2010) On Hurst Exponent Estimation under Heavy-Tailed Distributions. Physica A: Statistical Mechanics and Its Applications, 389, 3844-3855.
https://doi.org/10.1016/j.physa.2010.05.025

[138]   Beran, J. (1994) Statistics for Long-Memory Processes. Taylor & Francis, London.

[139]   Arneodo, A., Audit, B., Kestener, P. and Roux, S. (2008) Wavelet-Based Multifractal Analysis. Scholarpedia, 3, 4103.
https://doi.org/10.4249/scholarpedia.4103

[140]   Ivanov, P.Ch., Amaral, L.A.N., Goldberger, A.L., Havlin, S., Rosenblum, M.G., et al. (2001) From 1/f Noise to Multifractal Cascades in Heartbeat Dynamics. Chaos, 11, 641-652.
https://doi.org/10.1063/1.1395631

[141]   Ivanov, P.Ch., Amaral, L.A.N., Goldberger, A.L., Havlin, S., Rosenblum, M.G., Struzik, Z.R. and Stanley, H.E. (1999) Multifractality in Human Heartbeat Dynamics. Nature, 399, 461-465.
https://doi.org/10.1038/20924

[142]   Kravitz, R.L., Duan, N. and Braslow, J. (2004) Evidence-Based Medicine, Heterogeneity, and the Trouble with Averages. The Milbank Quarterly, 82, 661-687.
https://doi.org/10.1111/j.0887-378X.2004.00327.x

[143]   Imai, J. (2021) Regulation of Adaptive Cell Proliferation by Vagal Nerve Signals for Maintenance of Whole-Body Homeostasis: Potential Therapeutic Target for Insulin-Deficient Diabetes. Tohoku Journal of Experimental Medicine, 254, 245-252.
https://doi.org/10.1620/tjem.254.245

[144]   Matteoli, G. and Boeckxstaens, G.E. (2013) The Vagal Innervation of the Gut and Immune Homeostasis. Gut, 62, 1214-1222.
https://doi.org/10.1136/gutjnl-2012-302550

[145]   Szigeti, Gy.P., Szasz, O. and Hegyi, G. (2020) Experiment with Personalised Dosing of Hyperthermia. In: Ito, S., Ed., Current Topics in Medicine and Medical Research, Chapter 15, Vol. 3, Book Publisher International, New York, 140-157.

[146]   Szasz, A. (2013) Challenges and Solutions in Oncological Hyperthermia. Thermal Medicine, 29, 1-23.
https://doi.org/10.3191/thermalmed.29.1

[147]   Ferenczy, G.L. and Szasz, A. (2020) Technical Challenges and Proposals in Oncological Hyperthermia. In: Szasz, A., Ed., Challenges and Solutions of Oncological Hyperthermia, Ch. 3, Cambridge Scholars, Cambridge, 72-90.

[148]   Szasz, A. (2014) Oncothermia: Complex Therapy by EM and Fractal Physiology. 31th URSI General Assembly and Scientific Symposium (URSI GASS), Beijing, 20 October 2014, 1-4.
https://doi.org/10.1109/URSIGASS.2014.6930100

[149]   Szasz, A. (2015) Bioelectromagnetic Paradigm of Cancer Treatment Oncothermia. In: Rosch, P.J., Ed., Bioelectromagnetic and Subtle Energy Medicine, CRC Press, Boca Raton, 323-336.

[150]   Zhao, H., Raines, L.N. and Huang, S. (2020) Molecular Chaperones: Molecular Assembly Line Brings Metabolism and Immunity in Shape. Metabolites, 10, 394.
https://doi.org/10.3390/metabo10100394

[151]   Prohaszka, Z. (2007) Chaperones as Part of Immune Networks. In: Csermely, P. and Vigh, L., Eds., Molecular Aspects of the Stress Response: Chaperones, Membranes and Networks, Landes Bioscience and Springer Science + Business Media, Ch. 14, Berlin, 159-166.
https://doi.org/10.1007/978-0-387-39975-1_14

[152]   Chavan, S.S., Pavlov, V.A. and Tracey, K.J. (2017) Mechanisms and Therapeutic Relevance of Neuro-Immune Communication. Immunity, 46, 927-942.
https://doi.org/10.1016/j.immuni.2017.06.008

[153]   Kuwabara, S., Goggins, E. and Tanaka, S. (2021) Neuroimmune Circuits Activated by Vagus Nerve Stimulation. Nephron, 1-5.
https://doi.org/10.1159/000518176

[154]   Parent, R. (2019) The Potential Implication of the Autonomic Nervous System in Hepatocellular Carcinoma. Cellular and Molecular Gastroenterology and Hepatology, 8, 145-148.
https://doi.org/10.1016/j.jcmgh.2019.03.002

[155]   Szasz, A. (2020) Towards the Immunogenic Hyperthermic Action: Modulated Electro-Hyperthermia, Clinical Oncology and Research. Science Repository, 3, 5-6.
https://doi.org/10.31487/j.COR.2020.09.07

[156]   Tsang, Y.W., Huang, C.C., Yang, K.L., Chi, M.S., Chiang, H.C., Wang, Y.S., Andocs, G., Szasz, A., Li, W.T. and Chi, K.H. (2015) Improving Immunological Tumor Microenvironment Using Electro-Hyperthermia Followed by Dendritic Cell Immunotherapy. Oncothermia Journal, 15, 55-66.
https://doi.org/10.1186/s12885-015-1690-2

[157]   Qin, W., Akutsu, Y., Andocs, G., et al. (2014) Modulated Electro-Hyperthermia Enhances Dendritic Cell Therapy through an Abscopal Effect in Mice. Oncology Reports, 32, 2373-2379.
https://doi.org/10.3892/or.2014.3500

[158]   Van, Gool, S.W., Makalowski, J., Feyen, O., Prix, L., Schirrmacher, V. and Stuecker, W. (2018) The Induction of Immunogenic Cell Death (ICD) during Maintenance Chemotherapy and Subsequent Multimodal Immunotherapy for Glioblastoma (GBM). Austin Oncology Case Reports, 3, 1-8.

[159]   Mantovani, A., Allavena, P., Sica, A. and Balkwill, F. (2008) Cancer-Related Inflammation. Nature, 454, 436-444.
https://doi.org/10.1038/nature07205

[160]   De Couck, M., Marechal, R., Moorthamers, S., Van, Laethem, J.L. and Gidron, Y. (2016) Vagal Nerve Activity Predicts Overall Survival in Metastatic Pancreatic Cancer, Mediated by Inflammation. Cancer Epidemiology, 40, 47-51.
https://doi.org/10.1016/j.canep.2015.11.007

[161]   Kim, K., Chae, J. and Lee, S. (2015) The Role of Heart Rate Variability in Advanced Non-Small-Cell Lung Cancer Patients. Journal of Palliative Care, 31, 103-108.
https://doi.org/10.1177/082585971503100206

[162]   Zhou, X., Ma, Z., Zhan, L., Zhu, S., Wang, J., Wang, B. and Fu, W. (2016) Heart Rate Variability in the Prediction of Survival in Patients with Cancer: A Systematic Review and Meta-Analysis. Journal of Psychosomatic Research, 89, 20-25.
https://doi.org/10.1016/j.jpsychores.2016.08.004

[163]   Kim, D.H., Kim, J.A., Choi, Y.S., Kim, S.H., Lee, J.Y. and Kim, Y.E. (2010) Heart Rate Variability and Length of Survival in Hospice Cancer Patients. Journal of Korean Medical Science, 25, 1140-1145.
https://doi.org/10.3346/jkms.2010.25.8.1140

[164]   Kloter, E., Barrueto, K., Klein, S.D., Scholkmann, F. and Wolf, U. (2018) Heart Rate Variability as a Prognostic Factor for Cancer Survival—A Systematic Review. Frontiers in Physiology, 9, Article No. 623.
https://doi.org/10.3389/fphys.2018.00623

[165]   Hu, S., Lou, J., Zhang, Y. and Chen, P. (2018) Low Heart Rate Variability Relates to the Progression of Gastric Cancer. World Journal of Surgical Oncology, 16, 49.
https://doi.org/10.1186/s12957-018-1348-z

[166]   Mouton, C., Ronson, A., Racavi, D., Delhaye, F., Kupper, N., Paesmans, M., Moreau, M., Nogaret, J.M., Hendisz, A. and Gidron, Y. (2012) The Relationship between Heart Rate Variability and Time-Course of Carcinoembryonic Antigen in Colorectal Cancer. Autonomic Neuroscience: Basic and Clinical, 166, 96-99.
https://doi.org/10.1016/j.autneu.2011.10.002

[167]   Chiang, J.K., Moo, M., Kuo, T.B.J. and Fu, C.H. (2010) Association between Cardiovascular Autonomic Functions and Time to Death in Patients with Terminal Hepatocellular Carcinoma. Journal of Pain and Symptom Management, 39, 673-679.
https://doi.org/10.1016/j.jpainsymman.2009.09.014

[168]   De Couck, M., Van Brummelen, D., Schallier, D., De Greve, J. and Gidron, Y. (2013) The Relationship between Vagal Nerve Activity and Clinical Outcomes in Prostate and Non-Small Cell Lung Cancer Patients. Oncology Reports, 30, 2435-2441.
https://doi.org/10.3892/or.2013.2725

[169]   Giese-Davis, J., Wilhelm, F.H., Tamagawa, R., Palesh, O., Neri, E., Taylor, C.B., Kraemer, H.C. and Spiegel, D. (2015) Higher Vagal Activity as Related to Survival in Patients with Advanced Breast Cancer: An Analysis of Autonomic Dysregulation. Psychosomatic Medicine, 77, 346-355.
https://doi.org/10.1097/PSY.0000000000000167

[170]   Wang, Y.M., Wu, H.T., Huang, E.Y., Kou, Y.R. and H, S.S. (2013) Heart Rate Variability Is Associated with Survival in Patients with Brain Metastasis: A Preliminary Report. BioMedResearch International, 2013, Article ID: 503421.
https://doi.org/10.1155/2013/503421

[171]   De Couck, M., Mravec, B. and Gidron, Y. (2012) You May Need the Vagus Nerve to Understand Pathophysiology and to Treat Diseases. Clinical Science, 122, 323-328.
https://doi.org/10.1042/CS20110299

[172]   Kaniuysas, E., Kampusch, S., Tittgemeyer, M., Panetsos, F., Gines, R.F., et al. (2019) Currentdirections in the Auricular Vagus Nerve Stimulation I—A Physiological Perspective. Frontiers in Neuroscinece, 13, Article No. 854.
https://doi.org/10.3389/fnins.2019.00854

 
 
Top