Rostyslav Bubnov

Chronic sympathoexcitation (sympathetic overdrive syndrome) is defined as the sustained dominance of sympathetic over parasympathetic tone, measurable at the organ, vascular, and neural levels, and differs fundamentally from brief, adaptive “fight-or-flight” responses. Persistent vasoconstrictor drive perturbs cellular metabolism and reshapes host–tumor interfaces. Although this state is well characterized in cardiometabolic medicine, its oncologic implications remain comparatively underexplored, despite converging evidence that adrenergic inputs modulate tumor and stromal behavior. One of the main reasons for presenting this conceptual innovation study is that the sympathetic overdrive phenotype (SOP) carriers, by far, are not rare in the population. Robust statistics towards SOP incidence and prevalence are still missing, despite the urgency of plausible healthcare solutions. Currently, the best described SOP-relevant subpopulation are the Flammer Syndrome phenotype (FSP) carriers who, for instance, are highly prevalent in the academic career-making professional groups. Certain genetic predispositions play a role, however, the key pathways involved into the health-to-disease transition are epigenetically regulated and, to a large extent, represent systemic modifiable phenotype-associated risk factors which are, therefore, a promising target for holistic proactive medical approaches with a high potential to save lives and financial resources. Graphical Abstract The alternative text for this image may have been generated using AI.

Cancer drug resistance poses a significant challenge in oncology, primarily driven by cancer cell plasticity, which promotes tumor initiation, progression, metastasis, and therapeutic evasion in many different cancers. Breast cancers (BCs) are a prominent example of that, with an estimated 2.3 million new cases and 670,000 BC-related deaths registered worldwide annually. Triple-negative BC is especially challenging for treatments demonstrating particularly aggressive disease course, an early manifestation of metastatic disease, frequent drug-resistant cancer types, and poor individual outcomes. Although chemosensitizing agents have been developed, their clinical utility in oncology remains unproven. The mitogen-activated protein kinase (MAPK) pathway is considered a critical regulator of intracellular and extracellular signaling highly relevant for both — genetic and epigenetic modifications. Dysregulation of the MAPK signaling pathways plays a significant role in conferring chemoresistance in BC. Contextually, targeting the MAPK pathway represents a promising strategy for overcoming drug resistance and enhancing the therapeutic efficacy of anticancer agents in BC treatment. On the other hand, flavonoids, a prominent class of phytochemicals, are key modulators of MAPK signaling. Flavonoids interact with the ERK, JNK, p38, and ERK5 pathways of the MAPK signaling cascade and present a promising avenue for developing novel anti-cancer therapies and re-sensitizing agents for the treatment of BC. Compounds such as quercetin, kaempferol, genistein, luteolin, myricetin, EGCG, baicalein, baicalin, nobiletin, morin, delphinidin, acacetin, isorhamnetin, apigenin, silymarin, among others, have been identified as specific modulators of MAPK signaling, exerting complex downstream effects in BC cells increasing therewith drug efficacy and suppressing tumor growth and aggressivity. These properties reflect mechanisms of great clinical relevance to overcome therapeutic resistance in overall BC management. This article highlights corresponding mechanisms and provides clinically relevant illustrations in the framework of 3P medicine for primary (protection of individuals at high risk against health-to-disease transition) and secondary care (protection against metastatic BC progression). 3PM novelty makes good use of patient phenotyping and stratification, predictive multi-level diagnostics, and application of Artificial Intelligence (AI) tools to the individualized interpretation of big data — all proposed for cost-effective treatments tailored to individualized patient profiles with clear benefits to patients and advanced BC management.

Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM), impacting the kidneys. Ultrasound serves as a valuable tool for evaluating manifestations of metabolic syndrome and nephropathy [1-3]. This study aims to investigate the efficacy of ultrasound (US) as a predictive diagnostic tool for identifying specific variants of nephropathy in patients with DM. Methods: Thirty individuals with diabetes (age 38-76, 18 females) requiring medication for glucose control were compared with 30 age-matched controls (equal gender distribution). All participants underwent general clinical and laboratory tests. Abdominal US with convex 2-10 MHz probes was performed, including multiparameter US of the kidneys, utilizing Doppler, shear wave elastography (SWE), and measurement of fat accumulations, including visceral fat (VF) and subcutaneous fat (SF) thickness and areas [1]. Results: The resistive index (RI) in segmental renal arteries exhibited a significant increase (PP<0.05). Conclusion: Multiparameter ultrasound is effective in detecting and distinguishing kidney disease patterns in DM. It provides valuable information for differentiation, modifying treatment approaches, and targeted prevention. The study underscores the significance of US in assessing diabetic nephropathy, offering additional insights into its manifestations. References: 1. Bubnov R, Kalika L, Spivak M. Ultrasound evaluation of visceral fat and posture: relevance for diagnosing metabolic syndrome and obesity. Ultrasound in Medicine and Biology, 2019, 45: S83-S84. DOI: 10.1016/j.ultrasmedbio.2019. 07.283 2. Bubnov R. Shear wave elastography effective in ultrasound diagnosis of chronic kidney disease in patients with hyperuricaemia and gout. Nephrol Dial Transplant. 2022; 37(Supplement_3):gfac096.004. DOI: 10.1093/ndt/gfac096. 004 3. Bubnov R. Ultrasound imaging patterns of kidney disease in patients with metabolic syndrome. Nephrol Dial Transplant, 2023; 38(Supplement_1):gfad 063c_4869. DOI: 10.1093/ndt/gfad063c_4869

Introduction: The Gut-Brain Axis (GBA) is implicated in various conditions, including migraine, headache disorders, Irritable Bowel Syndrome (IBS), hypertension, and vascular dysregulation. While ophthalmic artery Doppler shows promise in conditions like migraine and stroke prevention [2], effective treatments targeting these mechanisms are still under exploration. Probiotic therapy, as a potential molecular and cellular modulator, may balance regulatory systems leading to pathological conditions. Aim: To explore the relevance of ophthalmic artery Doppler as a test for the efficacy of probiotic therapy in potentially modulating the gut-brain axis. Methods: A cohort of 10 patients diagnosed with migraine, headache disorders, seasonal dizziness, nausea, IBS, and hypertension underwent general clinical, lab tests, and radiology tests for a metabolic biomarker panel. Probiotic strains, including Lactobacillus and Bifidobacterium genera, were administered at a dose of 10^9 CFU per day for ten days was based on symptoms [3-5]. Ophthalmic artery Doppler analysis was conducted before and after interventions to assess changes in blood flow parameters. Standardized scales evaluated improvements in eye symptoms. Kidney Doppler, blood flow resistive index in segmental arteries, and parameters like visceral fat were also tested. Results: Analysis revealed significant changes in ophthalmic artery Doppler parameters post-interventions. Peak systolic velocity increased from 25 cm/sec to 35 cm/sec (PP<0.01), suggesting reduced vascular resistance. Similar trends were noted in ciliary and other ophthalmic parameters. Effective outcomes were observed in kidney blood flow, with decreased IR. Low and normal BMI patients experiencing treatment effects exhibited increased visceral fat. Other symptoms related to GBA, including IBS, asthma, and hypertension, showed alleviation. Conclusion: Microbiome modification via probiotic therapy may impact certain diseases in both short-term and long-term scales. The Gut-Brain Axis emerges as a potential mechanism, urging further exploration and clinical consideration. Future research should delve into mycobiome, neuromodulators, interleukins (IL-6), cortisol levels, metabolites, Short-Chain Fatty Acids (SCFA), serotonergic agents, CGRP-signaling, hypoxic signaling, and the modulation of calcitonin gene-related peptide (CGRP) within the trigeminal system [1-3]. References : 1. Bubnov R. Effects of us-guided trigger point interventions on ophthalmic artery doppler parameters and their predictive value for stroke prevention in patients with migraine and headache disorders. International Journal of Stroke. 2023;18(3_suppl):439. https://doi.org/10.1177/17474930231201072#sec-462. Bubnov R, Spivak M. Individualized Short-term Probiotic Therapy of Metabolic Syndrome According to the Host’s Phenotype. Journal of Clinical Gastroenterology. 2020; 54:25–26.