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The Role of Nonmainstream Approach in Science Discoveries

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 59099

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Prof. Dr. Stefano Fais

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Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Interests: translational research in medicine; experimental oncology; health; exosomes; regulation of pH in health and diseases; cell-in-cell phenomena
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Dear Colleagues,

As a scientist, I do not want to ascribe great significance to, inasmuch as nonmainstream does not simply mean NONCONVENTIONAL or ATYPICAL or UNCOMMON. To me, in science, it should mean an approach to experimental procedure that is so open that what appears to be a mistake may suddenly become a discovery if viewed from a different angle. We know from past experience that what is called “serendipity” has a pivotal role in drug discovery. The definition of serendipity implies the finding of one thing while looking for something else. The most known example of this is the discovery of penicillin. Fleming was studying ‘‘Staphylococcus influenzae’’ when one of his culture plates became contaminated and developed a mold that created a bacteria-free circle. Then, he found within the mold a substance that was very active against the vast majority of the bacteria infecting human beings. A provocative article was published in Financial Times in 2008 re-proposing a role for serendipity in the future of medicine. In reality, serendipity has had a key role in the discovery of a wide panel of psychotropic drugs as well, including aniline purple, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine. I would like to first recall and emphasize that to notice something that others did not realize before you, and, therefore, to get to a serendipity-mediated discovery, you need to pay a high level of attention on what is occurring with a 360° view around you. However, this is not entirely enough, since, and properly talking about scientific discoveries, you should keep a mind that is sufficiently unbiased from mainstream infrastructures, which normally make one extremely focused on a particular endpoint and prevent them from paying attention to potential ‘‘unexpected discoveries’’. A researcher in medicine should look at things with the curious and innocent eyes of a child. Perhaps, research in medicine should come back to the age of innocence, which should cancel the age of mainstream reports, definitively not contributing to real advances in the cure of human diseases. Max Planck said ‘‘Science progresses not because scientists change their minds, but rather because scientists attached to erroneous views die, and are replaced’’ and Otto Warburg used the same words when he realized the lack of acceptance of his ideas.

In any event, with this Special Issue that the International Journal of Molecular Science is hosting and proposing, I would like to collect as many as reviews and original articles that will show better than my words above the topics I have discussed.

One last issue that should drive this Issue is that there is a recent field of pharmacology that recognizes the off-target of drugs through their side effects, meaning that it is hard to imagine a future where our body will always respond to even targeted or personalized drugs without reasonable off-targeting.

All in all, this Special Issue calls for papers that support a real role for a nonmainstream approach in science discoveries. This includes scientific papers, reviews, and perspectives that will comment on either past but neglected discoveries, or recent evidence supported by a nonmainstream approach as well. It is mandatory that we not be limited to research in medicine but instead focus on all fields of science, including biology, chemistry and bio-chemistry, molecular biology, plant and marine biology, mathematics, and physics. However, articles supporting what is called PNEI (psico/neuro/endocrine/immunology), which is probably the new frontier in the way the body of the higher animals, including the human beings, actually works, are also welcome.

Prof. Dr. Stefano Fais
Guest Editor

References:

Shaywitz, D.; Taleb, N. Drug research needs serendipity. Financial Times July 30, 2008.
Fais, S. A nonmainstream approach against cancer. J. Enzyme Inhib. Med. Chem. 2016, 31, 882–889.
Ban, T.A. The role of serendipity in drug discovery. Dialog. Clin. Neurosci. 2006, 8, 335–344.
Benjamin, D.J. The efficacy of surgical treatment of cancer—20 years later. Med. Hypoth. 2014, 82, 412–420.
Campillos, M.; Kuhn, M.; Gavin, A.C.; et al. Drug target identification using side-effect similarity. Science 2008, 321, 263–266.

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Keywords

Nonmainstream science
Serendipity
Natural products
Antioxidants
Antiacidic molecules
Proton pumps
Exosomes
Toxicology

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Published Papers (11 papers)

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Editorial

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10 pages, 225 KiB

Open AccessEditorial

Unexpected Discoveries Should Be Reconsidered in Science—A Look to the Past?

by Alberto Foletti and Stefano Fais

Int. J. Mol. Sci. 2019, 20(16), 3973; https://doi.org/10.3390/ijms20163973 - 15 Aug 2019

Cited by 8 | Viewed by 3247

Abstract

From the past, we know how much “serendipity” has played a pivotal role in scientific discoveries. The definition of serendipity implies the finding of one thing while looking for something else. The most known example of this is the discovery of penicillin. Fleming was studying “Staphylococcus influenzae” when one of his culture plates became contaminated and developed a mold that created a bacteria-free circle. Then he found within the mold, a substance that proved to be very active against the vast majority of bacteria infecting human beings. Serendipity had a key role in the discovery of a wide panel of psychotropic drugs as well, including aniline purple, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine. Actually, many recent studies support a step back in current strategies that could lead to new discoveries in science. This change should seriously consider the idea that to further focus research project milestones that are already too focused could be a mistake. How can you observe something that others did not realize before you? Probably, one pivotal requirement is that you pay a high level of attention on what is occurring all around you. But this is not entirely enough, since, specifically talking about scientific discoveries, you should have your mind sufficiently unbiased from mainstream infrastructures, which normally make you extremely focused on a particular endpoint without paying attention to potential “unexpected discoveries”. Research in medicine should probably come back to the age of innocence and avoid the age of mainstream reports that do not contribute to real advances in the curing of human diseases. Max Planck said “Science progresses not because scientists change their minds, but rather because scientists attached to erroneous views die, and are replaced”, and Otto Warburg used the same words when he realized the lack of acceptance of his ideas. This editorial proposes a series of examples showing, in a practical way, how unfocused research may contribute to very important discoveries in science. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

Research

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11 pages, 635 KiB

Open AccessArticle

Pilot Study on the Effect of Biophysical Therapy on Salivary Alpha-Amylase as a Surrogate Measure of Anxiety/Stress: In Search of a Novel Noninvasive Molecular Approach for the Management of Stress

by Ida Ferrara, Colin Gerard Egan and Alberto Foletti

Int. J. Mol. Sci. 2020, 21(2), 415; https://doi.org/10.3390/ijms21020415 - 9 Jan 2020

Cited by 2 | Viewed by 3750

Abstract

Anxiety and depression impact dramatically on public health, underlying the importance of alternative cost-effective treatments. Previous studies have shown that biophysical treatment can significantly reduce anxiety symptoms and recently, salivary alpha-amylase (SAA) has been identified as an objective correlate of the sympathetic-parasympathetic imbalance related to increased stress burden, defined as allostatic load. The aim of this study was to evaluate the effect of biophysical therapy on SAA levels, in addition to the Depression Anxiety Stress Scale (DASS)-21 questionnaire. Twenty-four workers (sales representatives) presenting with mild anxiety/stress symptoms (Generalized Anxiety Disorder 7-item scale of > 5) were randomized to biophysical treatment (N = 12) or placebo control (N = 12). The biophysical group underwent electromagnetic information transfer through an aqueous system procedure, with daily self-administration for one month. SAA collection and the DASS-21 questionnaire were undertaken at baseline and after one month in all patients. Clinical characteristics and baseline DASS-21 subscale scores were similar between placebo and biophysical group at baseline. After one month, patients receiving biophysical therapy had significantly reduced SAA levels compared to the placebo group (27.8 ± 39.4 vs. 116.8 ± 114.9 U/mL, p = 0.019). All three DASS-21 subscales, depression (9.3 ± 5.1 vs. 5.7 ± 5.5, p = 0.1), anxiety (6.7 ± 25 vs. 3.7 ± 2.2, p = 0.0049) and stress (10.8 ± 4.2 vs. 7.3 ± 3.7, p = 0.041) were also decreased after biophysical treatment compared to placebo after one month. Our findings suggest that biophysical therapy can benefit workers with mild (subclinical) anxiety/stress. These results were also validated by the concomitant reduction of SAA levels and an improvement in DASS-21 subscales. The underlying molecular mechanisms of this therapy remain to be characterized. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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Review

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32 pages, 901 KiB

Open AccessReview

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer Based upon Its Hydrogen Ion Dynamics

by Salvador Harguindey, Khalid Alfarouk, Julián Polo Orozco, Kévin Hardonnière, Daniel Stanciu, Stefano Fais and Jesús Devesa

Int. J. Mol. Sci. 2020, 21(3), 1110; https://doi.org/10.3390/ijms21031110 - 7 Feb 2020

Cited by 12 | Viewed by 6764

Abstract

Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success story. The advances in surgery, chemotherapy and radiotherapy have not been sufficient at all. Indeed, the accumulated experience clearly indicates that new perspectives and non-main stream approaches are needed to better characterize the etiopathogenesis and treatment of this disease. This contribution deals with how the new pH-centric anticancer paradigm plays a fundamental role in reaching a more integral understanding of the etiology, pathogenesis, and treatment of this multifactorial disease. For the first time, the armamentarium available for the treatment of the different types and phases of BC is approached here from a Unitarian perspective-based upon the hydrogen ion dynamics of cancer. The wide-ranged pH-related molecular, biochemical and metabolic model is able to embrace most of the fields and subfields of breast cancer etiopathogenesis and treatment. This single and integrated approach allows advancing towards a unidirectional, concerted and synergistic program of treatment. Further efforts in this line are likely to first improve the therapeutics of each subtype of this tumor and every individual patient in every phase of the disease. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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15 pages, 661 KiB

Open AccessReview

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics

by Jekaterina Erenpreisa and Alessandro Giuliani

Int. J. Mol. Sci. 2020, 21(1), 240; https://doi.org/10.3390/ijms21010240 - 29 Dec 2019

Cited by 23 | Viewed by 3559

Abstract

The apparent lack of success in curing cancer that was evidenced in the last four decades of molecular medicine indicates the need for a global re-thinking both its nature and the biological approaches that we are taking in its solution. The reductionist, one gene/one protein method that has served us well until now, and that still dominates in biomedicine, requires complementation with a more systemic/holistic approach, to address the huge problem of cross-talk between more than 20,000 protein-coding genes, about 100,000 protein types, and the multiple layers of biological organization. In this perspective, the relationship between the chromatin network organization and gene expression regulation plays a fundamental role. The elucidation of such a relationship requires a non-linear thermodynamics approach to these biological systems. This change of perspective is a necessary step for developing successful ‘tumour-reversion’ therapeutic strategies. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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23 pages, 2392 KiB

Open AccessReview

Synergy Between Low Dose Metronomic Chemotherapy and the pH-Centered Approach Against Cancer

by Tomas Koltai, Rosa A. Cardone and Stephan J. Reshkin

Int. J. Mol. Sci. 2019, 20(21), 5438; https://doi.org/10.3390/ijms20215438 - 31 Oct 2019

Cited by 6 | Viewed by 3996

Abstract

Low dose metronomic chemotherapy (MC) is becoming a mainstream treatment for cancer in veterinary medicine. Its mechanism of action is anti-angiogenesis by lowering vascular endothelial growth factor (VEGF) and increasing trombospondin-1 (TSP1). It has also been adopted as a compassionate treatment in very advanced human cancer. However, one of the main limitations of this therapy is its short-term effectiveness: 6 to 12 months, after which resistance develops. pH-centered cancer treatment (pHT) has been proposed as a complementary therapy in cancer, but it has not been adopted or tested as a mainstream protocol, in spite of existing evidence of its advantages and benefits. Many of the factors directly or indirectly involved in MC and anti-angiogenic treatment resistance are appropriately antagonized by pHT. This led to the testing of an association between these two treatments. Preliminary evidence indicates that the association of MC and pHT has the ability to reduce anti-angiogenic treatment limitations and develop synergistic anti-cancer effects. This review will describe each of these treatments and will analyze the fundamentals of their synergy. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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12 pages, 1994 KiB

Open AccessReview

Probiotics Can Cure Oral Aphthous-Like Ulcers in Inflammatory Bowel Disease Patients: A Review of the Literature and a Working Hypothesis

by Francesco Cappello, Francesca Rappa, Federica Canepa, Francesco Carini, Margherita Mazzola, Giovanni Tomasello, Giuseppe Bonaventura, Giovanna Giuliana, Angelo Leone, Dario Saguto, Federica Scalia, Fabio Bucchieri, Alberto Fucarino and Giuseppina Campisi

Int. J. Mol. Sci. 2019, 20(20), 5026; https://doi.org/10.3390/ijms20205026 - 11 Oct 2019

Cited by 23 | Viewed by 13135

Abstract

Dysbiosis has been associated with the onset of several chronic autoimmune or inflammatory pathologies (e.g., inflammatory bowel diseases—IBD), because of its primary role in the establishment of a chronic inflammatory process leading to tissue damage. Inflammatory bowel diseases can even involve areas far away from the gut, such as the extraintestinal manifestations involving the oral cavity with the onset of aphthous-like ulcers (ALU). Studies carried out on animal models have shown that intestinal dysbiosis may be related to the development of autoimmune diseases, even if the mechanisms involved are not yet well known. The aim of this paper is to verify the hypothesis that in inflammatory bowel diseases patients, aphthous-like ulcers are the result of the concomitance of intestinal dysbiosis and other events, e.g., the microtraumas, occurring in the oral mucosa, and that ex adiuvantibus therapy with probiotics can be employed to modify the natural course of the aphthous-like ulcers. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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19 pages, 1752 KiB

Open AccessReview

Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies

by Salvador Harguindey, Julian Polo Orozco, Khalid O. Alfarouk and Jesús Devesa

Int. J. Mol. Sci. 2019, 20(17), 4278; https://doi.org/10.3390/ijms20174278 - 1 Sep 2019

Cited by 14 | Viewed by 4570

Abstract

The treatment of cancer has been slowly but steadily progressing during the last fifty years. Some tumors with a high mortality in the past are curable nowadays. However, there is one striking exception: glioblastoma multiforme. No real breakthrough has been hitherto achieved with this tumor with ominous prognosis and very short survival. Glioblastomas, being highly glycolytic malignancies are strongly pH-dependent and driven by the sodium hydrogen exchanger 1 (NHE1) and other proton (H⁺) transporters. Therefore, this is one of those pathologies where the lessons recently learnt from the new pH-centered anticancer paradigm may soon bring a promising change to treatment. This contribution will discuss how the pH-centric molecular, biochemical and metabolic perspective may introduce some urgently needed and integral novel treatments. Such a prospective therapeutic approach for malignant brain tumors is developed here, either to be used alone or in combination with more standard therapies. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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12 pages, 558 KiB

Open AccessReview

Dissecting the Proton Transport Pathway in Oral Squamous Cell Carcinoma: State of the Art and Theranostics Implications

by Alejandro I. Lorenzo-Pouso, Mario Pérez-Sayáns, Samuel Rodríguez-Zorrilla, Cintia Chamorro-Petronacci and Abel García-García

Int. J. Mol. Sci. 2019, 20(17), 4222; https://doi.org/10.3390/ijms20174222 - 29 Aug 2019

Cited by 7 | Viewed by 2930

Abstract

Cancer cells overexpress proton exchangers at the plasma membrane in order acidify the extracellular matrix and maintain the optimal pH for sustaining cancer growth. Among the families of proton exchangers implicated in carcinogenesis, carbonic anhydrases (CAs), monocarboxylate transporters (MCTs), Na⁺/H⁺ exchangers (NHEs), sodium bicarbonate cotransporters (NBCs), and vacuolar ATPases (V-ATPases) are highlighted. Considerable research has been carried out into the utility of the understanding of these machineries in the diagnosis and prognosis of several solid tumors. In addition, as therapeutic targets, the interference of their functions has contributed to the discovery or optimization of cancer therapies. According to recent reports, the study of these mechanisms seems promising in the particular case of oral squamous cell carcinoma (OSCC). In the present review, the latest advances in these fields are summarized, in particular, the usefulness of proton exchangers as potential prognostic biomarkers and therapeutic targets in OSCC. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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14 pages, 511 KiB

Open AccessReview

The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela

by Rosa Angela Cardone, Khalid Omer Alfarouk, Robert L. Elliott, Saad Saeed Alqahtani, Samrein B. M. Ahmed, Ahmed N. Aljarbou, Maria Raffaella Greco, Stefania Cannone and Stephan Joel Reshkin

Int. J. Mol. Sci. 2019, 20(15), 3694; https://doi.org/10.3390/ijms20153694 - 28 Jul 2019

Cited by 33 | Viewed by 5425

Abstract

Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pH_e) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pH_i to ∆pH_e) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs’ cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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13 pages, 2728 KiB

Open AccessReview

The Role of Cell Membrane Information Reception, Processing, and Communication in the Structure and Function of Multicellular Tissue

by Robert A. Gatenby

Int. J. Mol. Sci. 2019, 20(15), 3609; https://doi.org/10.3390/ijms20153609 - 24 Jul 2019

Cited by 35 | Viewed by 7217

Abstract

Investigations of information dynamics in eukaryotic cells focus almost exclusively on heritable information in the genome. Gene networks are modeled as “central processors” that receive, analyze, and respond to intracellular and extracellular signals with the nucleus described as a cell’s control center. Here, we present a model in which cellular information is a distributed system that includes non-genomic information processing in the cell membrane that may quantitatively exceed that of the genome. Within this model, the nucleus largely acts a source of macromolecules and processes information needed to synchronize their production with temporal variations in demand. However, the nucleus cannot produce microsecond responses to acute, life-threatening perturbations and cannot spatially resolve incoming signals or direct macromolecules to the cellular regions where they are needed. In contrast, the cell membrane, as the interface with its environment, can rapidly detect, process, and respond to external threats and opportunities through the large amounts of potential information encoded within the transmembrane ion gradient. Our model proposes environmental information is detected by specialized protein gates within ion-specific transmembrane channels. When the gate receives a specific environmental signal, the ion channel opens and the received information is communicated into the cell via flow of a specific ion species (i.e., K⁺, Na⁺, Cl⁻, Ca²⁺, Mg²⁺) along electrochemical gradients. The fluctuation of an ion concentration within the cytoplasm adjacent to the membrane channel can elicit an immediate, local response by altering the location and function of peripheral membrane proteins. Signals that affect a larger surface area of the cell membrane and/or persist over a prolonged time period will produce similarly cytoplasmic changes on larger spatial and time scales. We propose that as the amplitude, spatial extent, and duration of changes in cytoplasmic ion concentrations increase, the information can be communicated to the nucleus and other intracellular structure through ion flows along elements of the cytoskeleton to the centrosome (via microtubules) or proteins in the nuclear membrane (via microfilaments). These dynamics add spatial and temporal context to the more well-recognized information communication from the cell membrane to the nucleus following ligand binding to membrane receptors. Here, the signal is transmitted and amplified through transduction by the canonical molecular (e.g., Mitogen Activated Protein Kinases (MAPK) pathways. Cytoplasmic diffusion allows this information to be broadly distributed to intracellular organelles but at the cost of loss of spatial and temporal information also contained in ligand binding. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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Other

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8 pages, 688 KiB

Open AccessHypothesis

The Systemic–Evolutionary Theory of the Origin of Cancer (SETOC): A New Interpretative Model of Cancer as a Complex Biological System

by Antonio Mazzocca

Int. J. Mol. Sci. 2019, 20(19), 4885; https://doi.org/10.3390/ijms20194885 - 2 Oct 2019

Cited by 27 | Viewed by 3715

Abstract

The Systemic–Evolutionary Theory of Cancer (SETOC) is a recently proposed theory based on two important concepts: (i) Evolution, understood as a process of cooperation and symbiosis (Margulian-like), and (ii) The system, in terms of the integration of the various cellular components, so that the whole is greater than the sum of the parts, as in any complex system. The SETOC posits that cancer is generated by the de-emergence of the “eukaryotic cell system” and by the re-emergence of cellular subsystems such as archaea-like (genetic information) and/or prokaryotic-like (mitochondria) subsystems, featuring uncoordinated behaviors. One of the consequences is a sort of “cellular regression” towards ancestral or atavistic biological functions or behaviors similar to those of protists or unicellular organisms in general. This de-emergence is caused by the progressive breakdown of the endosymbiotic cellular subsystem integration (mainly, information = nucleus and energy = mitochondria) as a consequence of long-term injuries. Known cancer-promoting factors, including inflammation, chronic fibrosis, and chronic degenerative processes, cause prolonged damage that leads to the breakdown or failure of this form of integration/endosymbiosis. In normal cells, the cellular “subsystems” must be fully integrated in order to maintain the differentiated state, and this integration is ensured by a constant energy intake. In contrast, when organ or tissue damage occurs, the constant energy intake declines, leading, over time, to energy shortage, failure of endosymbiosis, and the de-differentiated state observed in dysplasia and cancer. Full article

(This article belongs to the Special Issue The Role of Nonmainstream Approach in Science Discoveries)

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