INTL. SYMP. ON TECHNOLOGICAL INNOVATIONS IN MEDICINE FOR SUSTAINABLE DEVELOPMENT
Editors: F. Kongoli, F. Murad, T. Yoshikawa, S. Waldman, J. Ribas, S. Hirano, D. Joseph, R. Guerrant, W. Petri, H. Inufusa, H. Yedoyan, S. Heysell.

Despite therapeutic advances that improve longevity and quality of life, chronic heart failure has kept its progressive nature associated with poor prognosis.
We have developed an original Direct Cardiac Compression cardiac assist device dedicated to the assistance of patients suffering from end-stage chronic heart failure (CHF). This type of assistance allows treatment of heart failure without direct contact with the patient's blood (unlike circulatory assistance where blood contact is a problem) and without requiring major surgery. Introduced into the thorax by small thoracotomy, this device is totally implantable, i.e. all the elements of the device (prosthesis but also the control, power supply and motorization systems) can be surgically implanted in the patient. Advantageously attached to the apex of the heart, it is able to exert localized pressure at specific locations on the outer wall of the heart in order to improve cardiac circulatory function. This device can operate synchronously with the native heart rhythm of the patient via a pacemaker control unit.
The device is now under preclinical investigation in porcine model to be proved as an effective alternative strategy to treat end-stage heart failure.

On the nm scale, cellular constituents are highly heterogeneous: the dielectric constant boundaries, the uneven dispersion of fixed and mobile charges, partial ordering of water molecules create an environment where the local chemical and physical properties differ from one site to another. The study of this ‘ensemble” requires a methodology that can discriminate among nm size sites, where a “gauging” particle will remain for not more than few ns. This requirement is readily met by proton pule experiments (1).
The photo-excited state of certain aromatic compound are very acidic (pK*< 2) and by illumination ejects a proton to the solvent. The released proton diffuses within the immediate vicinity and may recombine with the excited anion (ϕO-*) in response to its electric field reforming the ϕOH* state. Altogether, the observation time is few ns and the distance the proton can disperse, before the molecule relaxes to its ground state, is ~2-4 nm, thus assuring a localized observation (2). Judicious insertion of the photo-acids, like pyranine, into a well-defined environment (3) enables quantitative evaluation of the physical-chemical properties of the immediate vicinity of the site. The various studies were spread over a large biological domains; like active site of proteins (Apomyiglobin, lac permease), or the water filled space of a Large-Pore Channel protein (PhoE) or the interface between solvent and carbohydrate molecule (cyclodextrine), the aquose phase between lipid bilayer (multilamentar) and the reverse micelles of different radiuses. The micro loci are characterized by a lower chemical activity of the water, modulated diffusion coefficient, enhanced electrostatic field and highly affected by the geometry of the local space.

Metabolic pathways are summation of many simultaneous parallel reactions with numerous interactions between the reactants. Here, a general mode capable of treating a large number of linked processes as a set of coupled kinetic equations is described, where all forward and backward reactions are expressed. The analysis is capable of considering multi component processes with high precision; determining the rate constants of partial reactions without neglecting any event, providing an insight into parameters like the local viscosity, the energy barrier, the diffusivity of the reactants in the reaction space and identify redundant pathways that are not essential for the process. The input for the analysis are time resolved signals generated by brief perturbation of the system; the analysis is carried out by integration of the differential rate equations that reconstruct the observed signals. The analysis was first implemented for experiments, where acid-base equilibria were perturbed by sub-nanosecond increments of the H+ concentration (1). The analysis was extended to study biological multi-equilibria systems like the interaction of Calmodulin with bio-membranes (2), the quality control of protein synthesis (3), proton-ion exchange between aqueous phases separated by a bio-membrane impregnated by a diffusing carrier (4), the sequential reactions involving the release of signaling small molecules by the pre-synaptic membrane, or the evaluation of the heterogeneous reactivity of the Syntaxin molecules on the inner leaflet of the plasma membrane (5). This chapter will discuss both the theoretical framework and as well as the methodology in order to make it applicable for diverged biochemical and chemical processes.

Obesity is a worldwide health crisis, with >1 billion adults who are overweight (BMI >25 kg/m2), and 500 million who are obese (BMI >30 kg/m2). Annual US medical costs in the U.S. reflecting obesity are in excess of $150 billion, and by 2030 will increase 120%. Obesity reflects excess nutrition, in which calories consumed exceed those expended metabolically, in part due to abnormal satiety responses regulating appetite. Beyond cardiovascular and metabolic consequences producing morbidity and mortality in obesity, there is a linkage between body weight and cancer risk, including colorectal cancer. Obese patients have up to a 60% greater risk of, and ~200% greater death rate from, colorectal cancer. While the epidemiology of this relationship is known, mechanisms linking obesity and colorectal cancer have not been defined. GUCY2C is the receptor for the hormones uroguanylin in small intestine and guanylin in the colorectum. A novel mechanistic paradigm suggests that guanylin loss silencing GUCY2C signaling, and epithelial cell homeostasis, is an essential step initiating colorectal cancer.[1] Further, small intestine secretion of uroguanylin into the circulation forms an intestine-brain axis controlling hypothalamic GUCY2C regulating satiety, body weight, and metabolic balance.[2-4] In the present studies, we reveal that hyperphagia, and the consumption of excess calories, suppresses the expression guanylin and uroguanylin by the colorectum and small intestine, respectively, disrupting GUCY2C paracrine and endocrine signaling axes at the intersection of colorectal cancer and obesity.5 Expression of those hormones, but not GUCY2C, is reduced in across the rostral-caudal axis of the intestine, by diet-induced obesity in mice and humans. Expression of hormones are reversibly suppressed by consumed calories by a mechanism involving endoplasmic reticulum stress. Indeed, transgenic supplementation of guanylin in intestine eliminates tumorigenesis induced by obesity. Additionally, transgenic uroguanylin in brain improves satiety responses in diet-induced obesity. Together, these data suggest a pathophysiological model in which caloric suppression of hormone expression silencing GUCY2C is at the nexus of mechanisms underlying obesity and the risk of colorectal cancer.[5] Beyond this mechanism, these studies offer a therapeutic paradigm which exploits the preservation of GUCY2C expression in hyper-nutrition, in which hormone supplementation restores endocrine and paracrine axes to reconstitute appetite control opposing obesity and intestinal homeostasis preventing transformation.[5]

Lyophilization/Freeze-drying is an essential technology for the production of stable dried pharmaceuticals with longer shelf life. Lyophilization produces porous product with a large surface area and high hygroscopicity. Although most current industrial pharmaceutical lyophilization are carried out in vial with rubber cap, moisture sorption remains a major problem during long-term storage in the range of year [1]. Moisture sorption is governed by the glass-rubber transition of the lyophilized matrix. Since this transition relates to the temperature and moisture content, the onset of transition is influenced by the balance between the fluidity of the matrix and the sorption rate. Therefore, a model strategy that relates the glass transition and moisture sorption kinetics to the humidity-induced-collapse is fundamental for quantitative prediction of the shelf-life of the lyophilized products [2], but such a model has not yet been reported. This study is to develop a new mathematical model of sorption kinetics applicable to glassy lyophilized matrices. By incorporating experimentally obtained moisture sorption isotherms and glass transition lines into the model development, it is shown that the time until the humidity-induced-collapse occurs can be predicted with higher accuracy. Results were visually summarized in stability maps as a function of the storage conditions, such as relative humidity and temperature. The location of the limit line, the border to induce humidity-induced-collapse, was observed to depend on the sorption rate constant, moisture sorption isotherm, and glass transition temperature of the selected material. As expected, matrices with relatively high transition temperatures exhibited a wider stability zone. The mathematical model proposed in this study could be a robust tool for quantitatively predicting product stability against storage conditions that reflect the properties of materials.

Tauopathies are neurodegenerative disorders characterized by the intracellular accumulation of filamentous aggregates composed of tau protein, with Alzheimer’s disease (AD) being the most prevalent example [1]. Recent cryo-electron microscopy (CryoEM) reports have revealed the polymorphic nature of these filaments, where tau protomers adopt disease-specific folds within the amyloid cores of each conformer [2]. Despite this conformational heterogeneity, each polymorph core consists of the microtubule repeat region of tau and contains at least one hexapeptide motif (i.e., PHF6 and PHF6* motifs) essential for initiating aggregation through a nucleation-dependent mechanism [3]. In addition to tau, the majority of disease-derived conformers copurify with undefined non-proteinaceous substances [2]. These interact with specific amino acids side chains, especially Lys, implying they have poly-anionic character. Whether non-proteinaceous materials influence tau nucleation and polymorphism or are merely trapped during aggregation is unknown.
To clarify how anionic substances foster tau aggregation, full-length recombinant human 2N4R tau was fibrillized in the presence of Geranine G, a small-molecule dye. Resulting aggregates were then subjected to sedimentation, spectrophotometic and CryoEM analyses. The role of Lys residues in Geranine G-mediated induction was interrogated by Lys-to-Ala mutagenesis and in vitro aggregation assay.
Sedimentation and spectrophotometric analysis showed that Geranine G remained stably associated with tau aggregates after induction (8.7 ± 0.6 mol/mol stoichiometry). Upon CryoEM analysis, 2D classification revealed the presence of multiple polymorphs. One species corresponding to a tau protofilment was solved at 3.3 Å resolution. The core region of this tau aggregate was not a perfect replica of any known polymorph but most closely resembled the heparin-induced synthetic protofilament and the kernal of three-layer tau aggregates isolated from human brain (e.g., globular glial tauopathy). The density map also captured densities for seven GG molecules in complex with it. Interactions were primarily through Lys residues via solvent separated ion pairing. Lys-to-Ala mutagenesis identified the binding pose associated with Lys317/Lys321 as making the greatest contribution to Geranine-G induced tau aggregation propensity.
We propose two mechanisms for Geranine G-mediated induction of 2N4R tau aggregation. First, GG neutralizes the net positive charge of tau protein. This effect is likely nonspecific for individual Lys residues. Second, GG specifically stabilizes the heterosteric zipper formed by the PHF6* motif through bridging Lys residues within its interacting segment. This segment frequently associates with nonproteinaceous substances in tauopathy polymorphs (i.e., in AD and all three-layer polymorphs) consistent with a potential role in promoting aggregation and modulating formation of disease conformers.

Over the past decade, cancer treatment has made remarkable progress. The standard treatments-surgery, radiotherapy, and systemic chemotherapy have played a significant role. Nevertheless, standard treatments continue to cause side effects for a growing number of patients. Further complicating matters, cancer treatment is becoming increasingly expensive. The solutions to these problems require the application of some new concepts and newly developed medical technologies[1]. Cancer treatment with less damage to patients, enabling patients to carry on with their work as well as normal family lives even after treatment should never be defined as a miracle cure but as a practical treatment. Nowadays, with the help of the latest medical imaging technology, it is feasible to identify the exact location of cancer and find the best approach to treatment[2]. Then a microcatheter with a diameter as small as 0.7 mm can be inserted into a patient’s body and travel anywhere in the body[3]. Additionally, the spherical embolic microspheres deliver drugs for an extended period while keeping the drugs remaining inside the targeted lesion[4]. With these technologies, we continue to develop new methods of cancer treatment. Moreover, if cancer treatment were aimed at living with cancer in a non-life-threatening situation rather than eradicating it, cancer treatment would be significantly changed.
There are very few cancer patients who have benefited from "arterial embolization," which is only known to a small number of medical experts. Our team has been working on this treatment for 20 years, and we are still trying to find ways to achieve better treatment outcomes while also reducing medical costs, and allowing more people to live cancer-free. The purpose of this presentation is to demonstrate how this treatment is applied to patients and what kind of therapeutic effect it has. This medical technology will play a crucial role in the effective delivery of new drugs to the targeted lesion, as well as in the fields of immunotherapy and regenerative medicine.

Aminoglycosides inhibit bacterial growth by binding to the A-site decoding region of the bacterial 16s ribosomal RNA (rRNA) within the 30S ribosomal subunit. Previous work has shown that there is approximately a five-fold difference in the affinity of neomycin for the human A-site model and the E. coli model. The methodology for synthesizing, screening for both ribosomal binding/selectivity and bacterial growth inhibition, and rapid analysis of the data provides a systematic method for identification of bacterial ribosome specific antibacterials that can evade bacterial resistance pathways. We have developed rapid synthetic and screening methods that rapidly identify compounds that discriminate between the two model rRNA structures.
Novel potent aminoglycosides that show high selectivity for the bacterial ribosome over mammalian ribosome were identified. Our approach, coupled with a rapid solid phase synthesis of peptidic aminosugars, has identified active aminoglycosides that show large differences in binding affinity for the E. coli A-site vs. the human A-site. Synergistic applications with clinical antibiotics have allowed us to develop novel antimicrobials that can inhibit the growth of multidrug resistant bacteria.

Anti-cancer immunotherapy has become popular after immune-checkpoint inhibitors (ICI) proved effective in some cancer patients compared to conventional chemotherapies. However, the effectiveness of ICI has been reported to be around 20% and is not far from satisfactory. One of the reasons should be an inadequate understanding of the relationship between cancer cells and tumor immunity. As a result, conventional treatments have not aggressively approached the tumorigenesis side of the immune response.
We have developed new anti-cancer immunotherapy with the following vital procedures.
1. Controlling innate immune system and cancer microenvironment (CME)
2. Low dose radiation
3. Intra-tumoral injection of immune cells
With these steps in order, we have confirmed that cancer-specific cytotoxic T cells were effectively induced and could kill cancer cells rapidly in clinical practice.
This lecture will focus on the relationship between cancer cells and immune response and how our new treatment works well for patients with such advanced cancer.

This work contributes to the chemistry of chromones. Chromone is a privileged scaffold for drug discovery.[1] Variety of useful properties of naturally occurring chromones encourage to expect interesting types of biological activity in newly synthetized chromone derivatives.[2] However, structural modification of chromone scaffold is not a trivial task because of the instability of their γ-pyrone cycle. Which methods could be applied to modify the chromone moiety? We answer this question by presentation of rapid and effective three-step domino reaction, which delivers a wide library of novel substituted chromenopyrrolones.[3,4]
Application of a chemiluminescent assay demonstrates ability of isolated chromenopyrrolones to inhibit mammalian tissue nonspecific alkaline phosphatase in micromolar range of concentrations.[4] This kind of biological activity was not reported for chromone derivatives to date. Elevated levels of the given enzyme causes pathological hypercalcification disorders in soft tissues in the body. Potently chromenopyrrolone inhibitors of alkaline phosphatase can find application as therapeutic agents in treatment of atherosclerotic lesions.

Quantum theory is often displayed in nature, and understanding the application of quantum mechanics to it, is the first step in applying it to medicine. In nature, applications of quantum mechanics often deals with superposition, entanglement and tunneling. Energy-converting biological processes such as chemical reactions, light absorption that are instantaneous or extremely efficient can be explained through quantum mechanics. These include and are not limited to photosynthesis, cellular respiration, vision, and DNA mutations and repair. While much more research needs to be done on quantum biology, we still have the obligation of designing and implementing medical devices and treatment protocols based on our understandings of what we have learned and observed over the last 100 years in the field of quantum mechanics and their profound healing affects on human & animal biology. We will review a number of medical devices, protocols, and technologies which are utilized by doctors practicing advanced integrative medicine to treat the root cause of disease; with the common denominator being that the mechanism of action for all of these treatment modalities is solidly based on the principals of quantum mechanics.There’s one industry that is especially poised for massive changes on many levels from quantum technology: health care. Quantum technology is set to revolutionize the way we think about health care, medical data, and even our own biology. In this lecture, we shall also explore the possible medical role of Einstein's "completion" of quantum mechanics into hadronic mechanics, with particular reference to R. M. Santilli' conception of cells and, therefore, human bodies, as a collection of extended wavepackets in one single, total, mutual entanglement.

Multiple lines of evidence suggest that a substantial segment of published research yields results that are not reproducible. In the last decade, we have had the ability to examine large segments of the scientific corpus, using methods that can provide bird’s eye views of the status and evolution of scientific disciplines in terms of reproducibility, transparency, and bias indicators. The lecture will assess the scope of this evidence and will discuss solutions that have been proposed to enhance the credibility of research efforts. Many of these solutions are already effective and have improved the performance of multiple scientific fields while others are more speculative and they require careful testing before their adoption.

About 100 years ago, Chiyozo Makino, a director of Makino Iodine Research Institute (Japan) wrote in the book entitled "Epidemic Influenza" as follows; subcutaneous injection of iodide ion was effective in prevention and healing of Spanish flu, and that patients of tuberculosis (correctly pneumonia) were healed [1]. We now report on the basis of computational theory verification, i.e. density functional theory based molecular modeling (DFT/MM) [2][3] that all living cells become active by antioxidative action of iodide ions on mitochondria(mt) as power plants of living cells, and the patient's respiratory epithelial cells are regenerated by pluripotent stem cells full with activated mt, which means disappearance of the virus propagated in lung epithelial cells.
Influenza virus and mt are both endoplasmic reticulum in living cells, and viral growth in living cells must impair mitochondrial metabolic function. DFT/MM verifies that mt’s energy production by consuming superoxide radical anion (O2.-) stops and the overproduced O2.- reduces hydrogen peroxide (HOOH), which is accumulated in mt of aged cells, into hydroxyl radical (HO.) [4]. Reductive production of HO. and the attack on virus causes oxidative degradation of virus membranes as is validated for oxidative degradation of mt membranes. The theory verification well explains that influenza patients will recover gradually as far as the mt in respiratory cell systems are working with breathing.
I will discuss why iodine therapy works as antiviral agent as ethanol, quaternary ammonium chloride, and hypochlorous acid work as antibacterial agents in the medical field.

The advent of novel engineering technologies affords unprecedented advances toward long-elusive objectives of medical research. Individualized medicine responds to the basic but generally unattainable question of identifying the right therapy, reaching the right therapeutic target in the body at the right time, and securing immediate feedback as for its efficacy and undesired collateral effect. Finally, individualized medicine appears to be a credible general objective in many pathologies, owing to the integration of classical disciplines of clinical medicine, methods of molecular biology, and novel technology platforms.
Nanotechnologies are of great interest in the context of the drive toward individualized medicine, and may prove to be the necessary catalyst for its large-scale implementation. In this talk I will focus on nanoporous-silicon-based approaches for the individualization of medical intervention: multistage vectors for the preferential localization of therapeutic agents; injectable nano-particle generators for the therapy and prevention of metastatic cancer.
While these novel platforms engender direct clinical applications, at the same time they afford the formulation of novel frameworks and hypotheses for the basic understanding of pathological processes. In particular, multistage particulates are the probes that afford the exploration of a new perspective of cancer, that is, that the unifying aspect of the canonical ‘hallmarks of cancers’ all relate to dys-regulation of mass transport at scales including the molecular, cellular, microenvironmental, and systemic. These considerations are the starting point for “Transport OncoPhysics”.

It is demonstrated that according to the first law of thermodynamics the equality of entropic and negentropic components is the condition of resonance stationary state of systems. The initial nomograms of entropic and negentropic characteristics for many processes and phenomena in nature, engineering and physical chemistry are given. The entopic technique for forming fractal systems is presented. The coronavirus scenario in Russia is analyzed. The accuracy of forecast regarding the maximum number of diseases at the given moment and plateau duration is 96.5 % and 98.5%, respectively.
Keywords: coronavirus, entropy, negentropy, nomograms, stationary state, forecasts, fractals

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