Mossakowski Medical Research Centre

Background: Oncological treatment of breast cancer may be associated with adverse effects on myocardial function. Objectives: The objective of this study was to compare the influence of three oncological treatment methods of intervention on the echocardiographic (ECHO) parameters of left ventricular function. Materials and Methods: One hundred and fifty-five women with breast cancer were divided into three groups depending on the type of therapy used: group I (AC)-anthracyclines; group II (AC + TZ)-anthracyclines + trastuzumab; and group III (RTls+)-anthracyclines with or without trastuzumab + left-sided radiotherapy. Prospective ECHO examinations were performed at baseline and every 3 months, up to 12 months from the start of the therapy. Patients with a history of chemotherapy or who were diagnosed with heart disease were not included in the study. Results: Out of 155 patients, 3 died due to cancer as the primary cause, and 12 withdrew their consent for further observation. Baseline systolic and diastolic ECHO parameters did not differ between the analyzed groups. Cardiotoxicity, according to the LVEF criteria, occurred during follow-up in 20 patients (14.3%), irrespective of the treatment method used. Diastolic echocardiographic parameters did not change significantly after 12 months in each group, except for the left atrial volume index (LAVi), which was significantly higher in the AC + TZ compared to the values in the RTls+ group. Conclusions: All three oncologic therapeutic modalities in women with breast cancer showed no significant differences in relation to the incidence of echocardiographic cardiotoxicity criterion; however, transient systolic decrease in LVEF was most frequently observed in the AC + TZ therapeutic regimen. Left-sided radiotherapy was not associated with excess left ventricular systolic and diastolic dysfunction during a 12-month follow-up period. The predictors of negative changes in diastolic parameters included age and combined anthracycline and trastuzumab therapy.

Vitiligo is a chronic pigmentary disease with complex etiology, the signs of which are caused by the destruction of melanocytes in the epidermis, leading to the lack of melanin pigment responsible for skin coloration. The treatment of vitiligo, which aims at repigmentation, depends both on the clinical characteristics of the disease as well as on molecular markers that may predict the response to treatment. The aim of this review is to provide an overview of the clinical evidence for vitiligo cell-based therapies taking into account the required procedures and equipment necessary to carry them out as well as their effectiveness in repigmentation, assessed using the percentage of repigmentation of the treated area. This review was conducted by assessing 55 primary clinical studies published in PubMed and ClinicalTrails.gov between 2000 and 2022. This review concludes that the extent of repigmentation, regardless of the treatment method, is highest in stable localized vitiligo patients. Moreover, therapies that combine more than one cell type, such as melanocytes and keratinocytes, or more than one method of treatment, such as the addition of NV-UVB to another treatment, increase the chances of >90% repigmentation. Lastly, this review concludes that various body parts respond differently to all treatments.

Objective: Evaluation of the effects of endothelin type A (ETA) receptor blockade on the echocardiography, hemodynamic cardiac and renal parameters, and the course of high-output heart failure (HF) in rats with angiotensin II-dependent hypertension. Design and Methods: Eight-week-old male Ren-2 transgenic rats (TGR) were used as a model of angiotensin II-dependent hypertension. HF was induced by creating an aorto-caval fistula (ACF). Two weeks later, rats were divided into four groups: placebo (water) or three therapeutic groups (initial n minimum of 31 rats), and the treatment was initiated: in the first group, selective ETA receptor blockade was achieved by atrasentan, the second group received trandolapril, an angiotensin-converting enzyme inhibitor (ACEi), and the third was treated by combinational therapy (atrasentan + trandolapril), all in drinking water. The follow-up period was twenty weeks, then echocardiography, renal hemodynamics and albuminuria, invasive pressure-volume (P-V) analysis of left ventricle (LV), and organ weight measurement were done. Results: Eighteen days after creating ACF, untreated TGR began to die, and none was alive by day 79. Both atrasentan and trandolapril treatment improved the survival rate, ultimately to 56% (18 of 31 animals) and 69% (22 of 32 animals), respectively. Combined ACE and ETA receptor blockade improved the final survival rate to 52% (17 of 33 animals). The effects of the three treatment regimens on the survival rate did not significantly differ (Log-rank (Mantel-Cox) p = 0.345) (Figure 1, A). Untreated ACF TGR displayed marked renal dysfunction, cardiac hypertrophy, lung congestion, and impairment of LV contractility. None of the treatment regimens affected the progress of renal dysfunction, but they suppressed the albuminuria (Figure 1, B), development of cardiac hypertrophy and lung congestion and improved LV systolic function. Conclusion: The treatment with ETA receptor antagonist delays the onset of decompensation of volume-overload HF and improves the survival rate in hypertensive TGR similar to ACE inhibition.

BackgroundAssociation of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient’s prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. MethodsCKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. ResultsThe final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. ConclusionsOur results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions.

Abstract In the last few years, rare-earth-doped upconverting nanoparticles (UCNPs) have been widely used in different life sciences due to their unique properties. Nanoparticles have become a multifunctional and promising new approach to neurobiological disorders and have shown extraordinary application potential to overcome problems related to conventional treatment strategies. This study evaluated the internalization mechanisms, bio-distribution, and neurotoxicity of NaYF4:20%Yb3+,2%Er3+ UCNPs in rat organotypic hippocampal slices. TEM results showed that UCNPs were easily internalized by hippocampal cells and co-localized with selected organelles inside neurons and astrocytes. Moreover, we found that UCNPs were taken into the neurons via clathrin- and caveolae-mediated endocytosis. Propidium iodide staining and TEM analysis did not confirm the adverse effects of UCNPs on hippocampal slice viability and morphology. Therefore, UCNPs may be a potent tool for bio-imaging and testing new therapeutic strategies for brain diseases in the future.

White matter damage (WMD), one of the research hotspots of subarachnoid hemorrhage (SAH), mainly manifests itself as myelin injury and oligodendrocyte differentiation disorder after SAH, although the specific mechanism remains unclear. Dexamethasone-induced Ras-related protein 1(Dexras1) has been reported to be involved in nervous system damage in autoimmune encephalitis and multiple sclerosis. However, whether Dexras1 participates in dysdifferentiation of oligodendrocytes and myelin injury after SAH has yet to be examined, which is the reason for creating the research content of this article. Here, intracerebroventricular lentiviral administration was used to modulate Dexras1 levels in order to determine its functional influence on neurological injury after SAH. Immunofluorescence, transmission electron microscopy, and Western blotting methods, were used to investigate the effects of Dexras1 on demyelination, glial cell activation, and differentiation of oligodendrocyte progenitor cells (OPCs) after SAH. Primary rat brain neurons were treated with oxyhemoglobin to verify the association between Dexras1 and cAMP-CREB. The results showed that Dexras1 levels were significantly increased upon in vivo SAH model, accompanied by OPC differentiation disturbances and myelin injury. Dexras1 overexpression significantly worsened OPC dysdifferentiation and myelin injury after SAH. In contrast, Dexras1 knockdown ameliorated myelin injury, OPC dysdifferentiation, and glial cell activation. Further research of the underlying mechanism discovered that the cAMP-CREB pathway was inhibited after Dexras1 overexpression in the in vitro model of SAH. This study is the first to confirm that Dexras1 induced oligodendrocyte dysdifferentiation and myelin injury after SAH by inhibiting the cAMP-CREB pathway. This present research may reveal novel therapeutic targets for the amelioration of brain injury and neurological dysfunction after SAH.

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

Abstract Although Slavic populations account for over 3.5% of world inhabitants, no centralized, open source reference database of genetic variation of any Slavic population exists to date. Such data are crucial for either biomedical research and genetic counseling and are essential for archeological and historical studies. Polish population, homogenous and sedentary in its nature but influenced by many migrations of the past, is unique and could serve as a good genetic reference for middle European Slavic nations.The aim of the present study was to describe first results of analyses of a newly created national database of Polish genomic variant allele frequencies. Never before has any study on the whole genomes of Polish population been conducted on such a large number of individuals (1,079).A wide spectrum of genomic variation was identified and genotyped, such as small and structural variants, runs of homozygosity, mitochondrial haplogroups and Mendelian inconsistencies. The allele frequencies were calculated for 943 unrelated individuals and released publicly as The Thousand Polish Genomes database. A precise detection and characterisation of rare variants enriched in the Polish population allowed to confirm the allele frequencies for known pathogenic variants in diseases, such as Smith-Lemli-Opitz syndrome (SLOS) or Nijmegen breakage syndrome (NBS). Additionally, the analysis of OMIM AR genes led to the identification of 22 genes with significantly different cumulative allele frequencies in the Polish (POL) vs European NFE population. We hope that The Thousand Polish Genomes database will contribute to the worldwide genomic data resources for researchers and clinicians.

Abstract Preclinical and clinical studies have shown that stem cells can promote the regeneration of damaged tissues, but therapeutic protocols need better quality control to confirm the location and number of transplanted cells. This study describes in vivo imaging while assessing reporter gene expression by its binding to a radiolabelled molecule to the respective receptor expressed in target cells. Five mice underwent human skeletal-derived stem/progenitor cell (huSkMDS/PC EF1-HSV-TK) intracardial transplantation after induction of myocardial infarction (MI). The metabolic parameters of control and post-infarction stem progenitor cell-implanted mice were monitored using 2-deoxy-18F-fluorodeoxyglucose ([18F]-FDG) before and after double promotor/reporter probe imaging with 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]-FHBG) using positron emission tomography (PET) combined with computed tomography (CT). Standardized uptake values (SUVs) were then calculated based on set regions of interest (ROIs). Experimental animals were euthanized after magnetic resonance imaging (MRI). Molecular [18F]-FHBG imaging of myogenic stem/progenitor cells in control and post-infarction mice confirmed the survival and proliferation of transplanted cells, as shown by an increased or stable signal from the PET apparatus throughout the 5 weeks of monitoring. huSkMDS/PC EF1-HSV-TK transplantation improved cardiac metabolic ([18F]-FDG with PET) and haemodynamic (MRI) parameters. In vivo PET/CT and MRI revealed that the precise use of a promotor/reporter probe incorporated into stem/progenitor cells may improve non-invasive monitoring of targeted cellular therapy in the cardiovascular system.