Rostyslav V Bubnov

Medicine in the early twenty-first century: paradigm and anticipation - EPMA position paper 2016.

Background Challenges of “standardisation” and “individualisation” have always been characteristic for medical services. In terms of individualisation, the best possible individual care is the ethical imperative of medicine, and it is a good right of any patient to receive it. However, in terms of standardisation, all the available treatments are based on guideline recommendations derived from large multicentre trials with many thousands of patients involved. In the most optimal way, the standardisation and individualisation should go hand-in-hand, in order to identify the right patient treating him/her with the right medication and the right dose at the right time point! Further, in paradigm and anticipation, there is a big discrepancy between “disease care” and “health care” which dramatically impacts ethical and economical aspects of medical services. Several approaches have been suggested in ancient and modern medicine to conduct medical services in a possibly optimal way. What is the difference amongst all of them and how big is the potential beyond corresponding approach to satisfy the needs of the individual, the patient, professional groups involved and society at large? On behalf of the “European Association for Predictive, Preventive and Personalised Medicine,” the dedicated EPMA working group provides a deep analysis in the issue followed by the expert recommendations considering the multifaceted aspects of both “disease care” and “health care” practices including ethics and economy, life quality of individuals and patients, interests of professional groups involved, benefits of subpopulations, health care system(s) and society as a whole.

EPMA position paper in cancer: Current overview and future perspectives

At present, a radical shift in cancer treatment is occurring in terms of predictive, preventive, and personalized medicine (PPPM). Individual patients will participate in more aspects of their healthcare. During the development of PPPM, many rapid, specific, and sensitive new methods for earlier detection of cancer will result in more efficient management of the patient and hence a better quality of life. Coordination of the various activities among different healthcare professionals in primary, secondary, and tertiary care requires well-defined competencies, implementation of training and educational programs, sharing of data, and harmonized guidelines. In this position paper, the current knowledge to understand cancer predisposition and risk factors, the cellular biology of cancer, predictive markers and treatment outcome, the improvement in technologies in screening and diagnosis, and provision of better drug development solutions are discussed in the context of a better implementation of personalized medicine. Recognition of the major risk factors for cancer initiation is the key for preventive strategies (EPMA J. 4(1):6, 2013). Of interest, cancer predisposing syndromes in particular the monogenic subtypes that lead to cancer progression are well defined and one should focus on implementation strategies to identify individuals at risk to allow preventive measures and early screening/diagnosis. Implementation of such measures is disturbed by improper use of the data, with breach of data protection as one of the risks to be heavily controlled. Population screening requires in depth cost-benefit analysis to justify healthcare costs, and the parameters screened should provide information that allow an actionable and deliverable solution, for better healthcare provision.

Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: a theranostic potential for PPP cardiology

IntroductionNanoscale gold particles (AuNPs) have wide perspectives for biomedical applications because of their unique biological properties, as antioxidative activity and potentials for drug delivery.Aims and objectivesThe aim was to test effects of AuNPs using suggested heart failure rat model to compare with proved medication Simdax, to test gold nanoparticle for drug delivery, and to test sonoporation effect to increase nanoparticles delivery into myocardial cells.Material and methodsWe performed biosafety and biocompatibility tests for AuNPs and conjugate with Simdax. For in vivo tests, we included Wistar rats weighing 180–200 g (n = 54), received doxorubicin in cumulative dose of 12.0 mg/kg to model advance heart failure, registered by ultrasonography. We formed six groups: the first three groups of animals received, respectively, 0.06 ml Simdax, AuNPs, and conjugate (AuNPs-Simdax), intrapleurally, and the second three received them intravenously. The seventh group was control (saline). We performed dynamic assessment of heart failure regression in vivo measuring hydrothorax. Sonoporation of gold nanoparticles to cardiomyocytes was tested.ResultsWe designed and constructed colloidal, spherical gold nanoparticles, AuNPs-Simdax conjugate, both founded biosafety (in cytotoxicity, genotoxicity, and immunoreactivity). In all animals of the six groups after the third day post-medication injection, no ascites and liver enlargement were registered (P < 0.001 vs controls). Conjugate injection showed significantly higher hydrothorax reduction than Simdax injection only (P < 0.01); gold nanoparticle injection showed significantly higher results than Simdax injection (P < 0.05). AuNPs and conjugate showed no significant difference for rat recovery. Difference in rat life continuity was significant between Simdax vs AuNPs (P < 0.05) and Simdax vs conjugate (P < 0.05). Sonoporation enhances AuNP transfer into the cell and mitochondria that were highly localized, superior to controls (P < 0.01 for both).ConclusionsGold nanoparticles of 30 nm and its AuNPs-Simdax conjugate gave positive results in biosafety and biocompatibility in vitro and in vivo. AuNPs-Simdax and AuNPs have similar significant cardioprotective effects in rats with doxorubicin-induced heart failure, higher than that of Simdax. Intrapleural (local) delivery is preferred over intravenous (systemic) delivery according to all tested parameters. Sonoporation is able to enhance gold nanoparticle delivery to myocardial cells in vivo.

Gold nanoparticles - the theranostic challenge for PPPM: nanocardiology application

The article overviews the potential biomedical applications of nanoscale gold particles for predictive, preventive and personalised nanomedicine in cardiology. The review demonstrates the wide opportunities for gold nanoparticles due to their unique biological properties. The use of gold nanoparticles in cardiology is promising to develop fundamentally new methods of diagnosis and treatment. The nanotheranostics in cardiovascular diseases allows the non-invasive imaging associated with simultaneous therapeutic intervention and predicting treatment outcomes. Imaging may reflect the effectiveness of treatment and has become a fundamental optimisation setting for therapeutic protocol. Combining the application of biomolecular and cellular therapies with nanotechnologies foresees the development of complex integrated nanodevices. Nanocardiology may challenge existing healthcare system and economic benefits as cardiovascular diseases are the leading cause of morbidity and mortality at present.

Evidence-based pain management: is the concept of integrative medicine applicable?

This article is dedicated to the concept of predictive, preventive, and personalized (integrative) medicine beneficial and applicable to advance pain management, overviews recent insights, and discusses novel minimally invasive tools, performed under ultrasound guidance, enhanced by model-guided approach in the field of musculoskeletal pain and neuromuscular diseases. The complexity of pain emergence and regression demands intellectual-, image-guided techniques personally specified to the patient. For personalized approach, the combination of the modalities of ultrasound, EMG, MRI, PET, and SPECT gives new opportunities to experimental and clinical studies. Neuromuscular imaging should be crucial for emergence of studies concerning advanced neuroimaging technologies to predict movement disorders, postural imbalance with integrated application of imaging, and functional modalities for rehabilitation and pain management. Scientific results should initiate evidence-based preventive movement programs in sport medicine rehabilitation. Traditional medicine and mathematical analytical approaches and education challenges are discussed in this review. The physiological management of exactly assessed pathological condition, particularly in movement disorders, requires participative medical approach to gain harmonized and sustainable effect.

“Pre-metastatic niches” in breast cancer: are they created by or prior to the tumour onset? “Flammer Syndrome” relevance to address the question

Breast cancer (BC) epidemic in the twenty-first century is characterised by around half a million deaths and 1.7 million new cases registered annually worldwide. Metastatic disease is the major cause of death in BC patient cohorts. Current statistics are much alarming from the viewpoint of the early mortality amongst BC patients with de novo metastatic disease. A new paradigm of so-called “pre-metastatic niches” may sufficiently promote our knowledge regarding potential pathomechanisms, individual predisposition and prognosis in development and progression of the metastatic disease. However, the crucial question remains unaddressed, whether hypoxic pre-metastatic niches in BC are created by or prior to the tumour onset. So far, the current interpretation of the “Seed and Soil” theory of metastasis proposing that the pre-metastatic niches are formed by primary tumours which “induce and guide” the process is incomplete, since it does not provide satisfactory explanations towards several facts overviewed in the article. The overall results of this study clearly support the working hypothesis presented by the authors proposing that the epi/genetic predisposition of individuals at risk to form the systemic hypoxic pre-metastatic niches can be established a long time before breast malignancy is clinically manifested. “Flammer Syndrome” (FS) phenotype may strongly contribute to particularly poor outcomes of metastatic breast cancer. Significance and relevance of individual FS symptoms for breast cancer metastatic disease are discussed in extenso.

Probiotics and immunity: provisional role for personalized diets and disease prevention

There is great interest in the interaction between diet and immune system and concomitantly in the potential of probiotic bacteria, especially given recent advances in understanding of gut microbiota effects on health in the context of microbiome research. Following our recent study on bacterial wall elasticity as a predictive measure of phagocytic cellular reactions and related outcomes, a question was raised regarding the scope of the application of these findings in various medical conditions in the context of predictive, preventive, and personalized medicine (PPPM). This summarizing review of the data describes the contributions, both observed and potential, of probiotics to the gut-brain axis and various medical conditions, including immune and atopic states, metabolic and inflammatory diseases—including liver disease and diabetes mellitus—cancer, and more. It also suggests novel insights for a number of beneficial applications of probiotics and advances in development of novel probiotic-based treatments and personalized diets, as well as application of sophisticated imaging techniques and nanobiotechnologies that can be adopted in the near future by innovative medical experts, warranting further research and practical translation.

The role of beneficial bacteria wall elasticity in regulating innate immune response.

BackgroundProbiotics have great potential to contribute to development of healthy dietary regimes, preventive care, and an integrated approach to immunity-related disease management. The bacterial wall is a dynamic entity, depending on many components and playing an essential role in modulating immune response. The impact of cell wall elasticity on the beneficial effects of probiotic strains has not been sufficiently studied.The aim was to investigate the effect of lactic acid bacteria (LAB) and bifidobacteria strains on phagocytic system cells (macrophages) as related to bacterial wall elasticity, estimated using atomic force microscopy (AFM).MethodsWe conducted studies on Balb/c line mice 18–20 g in weight using lyophilized strains of LAB—Lactobacillus acidophilus IMV B-7279, Lactobacillus casei IMV B-7280, Lactobacillus delbrueckii subsp. bulgaricus IMV B-7281, and bifidobacteria—Bifidobacterium animalis VKL and Bifidobacterium animalis VKB. We cultivated the macrophages obtained from the peritoneal cavity of mice individually with the strains of LAB and bifidobacteria and evaluated their effect on macrophages, oxygen-dependent bactericidal activity, nitric oxide production, and immunoregulatory cytokines. We used AFM scanning to estimate bacterial cell wall elasticity.ResultsAll strains had a stimulating effect on the functional activity of macrophages and ability to produce NO/NO2 in vitro. Lactobacilli strains increased the production of IL-12 and IFN-γ in vitro. The AFM demonstrated different cell wall elasticity levels in various strains of LAB and bifidobacteria. The rigidity of the cell walls among lactobacilli was distributed as follows: Lactobacillus acidophilus IMV B-7279 > Lactobacillus casei IMV B-7280 > Lactobacillus delbrueckii subsp. bulgaricus IMV B-7281; among the strains of bifidobacteria: B. animalis VKB > B. animalis VKL. Probiotic strain survival in the macrophages depended on the bacterial cell wall elasticity and on the time of their joint cultivation.ConclusionLAB and bifidobacteria strains stimulate immune-modulatory cytokines and active oxygen and nitrogen oxide compound production in macrophages. Strains with a more elastic cell wall according to AFM data demonstrated higher resistance to intracellular digestion in macrophages and higher level of their activation.AFM might be considered as a fast and accurate method to assess parameters of probiotic strain cell wall to predict their immune-modulatory properties.

Development of biomarker panel to predict, prevent and create treatments tailored to the persons with human papillomavirus-induced cervical precancerous lesions

IntroductionHuman papillomavirus (HPV) induce many cancer conditions and cause cervical cancer, second in frequency of malignant disease in women.The aim was to develop biomarker panel for HPV-induced cervical precancerous diseases in patients infected with herpes simplex virus (HSV).Material and methodsThe study involved 71 women with cervical precancerous diseases (mean age 26 ± 5 years) revealed by colposcopic, cytomorphological, and ultrasound signs which were assessed according to the following: first group, 44 patients infected with HPV; second group, 27 HPV-negative patients; and third group, 30 healthy patients (controls). In cervical specimen, we identified HPV DNA of different oncogenic risk types by polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) kits (JSC SPC ‘DiaprofMed’) were used for detecting antibodies to HSV1 and/or HSV2 and for determining the avidity index. The production of pro-inflammatory cytokines, interferon-γ (IFN-γ), IFN-α, TNF-α, and interleukin-1β (IL-1β), and anti-inflammatory cytokines, IL-4, IL-10, and transforming growth factor-β1 (TGF-β1), were studied by ELISA.ResultsIn HPV-induced cervix precancerous diseases, we identified low-avidity IgG antibodies to HSV serum of 20 patients; in the serum of 17 patients, we identified average-avidity antibodies, and high-avidity antibodies were found in 2 patients only. In 14 HPV-negative patients, we found low-avidity IgG antibodies to HSV; in 10 patients, medium avidity. Patients with low-avidity IgG antibodies to herpes virus showed high and medium oncogenic risk HPV types and a decrease of IFN-γ compared to patients with medium-avidity IgG antibodies. Production of IFN-γ was suppressed also in HPV-negative patients with cervical precancers, but we found low- and medium-avidity IgG antibodies to herpes virus. In patients with low-avidity antibodies, we observed increased level of IL-10. Level of IFN-α, IL-1β, IL-2, and IL-4 did not change in patients of all groups, but TGF-β1 increased.ConclusionsIn HPV-positive patients, those with low-avidity IgG antibodies to HSV had immunosuppression, confirmed by increased TGF-β1 and violation of IFN-γ production. Therefore, in pro- and anti-inflammatory cytokines and IgG antibodies to HSV, their avidity is an important diagnostic biomarker of HPV-induced precancerous cervical diseases. Low-avidity IgG antibodies may be an indication for treatment with immunomodulators and antiviral drugs.

The perspectives of biomedical application of the nanoceria

The scientific information on biological activity of ceria dioxide nanoparticles (CeO2, nanoceria) is still very fragmentary. It is known, that nanoceria interaction with biological systems is based on two principal properties of this substance: low toxicity and high reducibility [1]. These factors determines activity of nanoceria in biological redox processes, especially in inactivation of reactive oxygen species, including free radicals that are formed inside living cells.