Priming Human Mesenchymal Stromal Cells to Enhance their Regenerative Potential

MSCs show promise for cell therapy due to their immune-suppressive and regenerative properties. Consequently, MSCs have been widely used in an increasing number of clinical trials to treat a variety of pathological conditions including cardiovascular diseases and disorders with dysregulated immune function. The outcome of prospective MSC therapy trials however, has shown marginal benefit warranting further investigation to develop strategies to enhance their therapeutic potential. The latter requires better understanding of the mechanisms by which MSCs exert their effects, and studying MSCs under conditions resembling the in vivo microenvironment will help to develop such understanding. The focus of this thesis is to explore the effect of a collagen-based matrix (successfully used in bioengineering approaches for tissue regeneration including for cardiac repair) and Toll-like receptor (TLR) stimulation (providing an in vitro model of an inflammatory environment and widely used for priming MSCs in vitro) on the regenerative properties of MSCs. The first aim of this study (discussed in Chapter 3) involves a comparative analysis of the regenerative properties of MSCs cultivated as a monolayer or on collagen scaffolds, or activated with TLR3 or TL4 agonists. I found that MSCs developed a more cardioprotective phenotype on scaffolds, although no functional changes were detectable when analyzing MSCs in a bioengineered model of heart tissue. The findings of this chapter provide a mechanistic explanation for the potential contribution of MSCs primed with cardiomyogenic cues or TLR agonists. In the second aim (discussed in Chapter 4), signaling through TLR3 was dissected and the effects on MSC phenotype were investigated. The knowledge created in this aim provide some insight into the dynamics of TLR3 signaling, which can be further used to develop preconditioning strategies. In Aim 3 (discussed in Chapter 5), the effects of TLR3 and TLR4 activation on immunomodulatory function of MSCs were further explored. I discovered that activation of either TLR3 or TLR4 enhanced the capacity of MSCs to generate regulatory T lymphocytes. The findings in this aim are applicable to a variety of settings, including tissue regeneration, organ transplantation and autoimmune disorders in which boosting immune suppression can prevent disease development and/or progression.Ph.D.2018-11-17 00:00:0

Targeting of solid tumors and blood malignancies by antibody-based therapies - EGFR-pathway as an example

A well-coordinated interaction between extracellular signals and intracellular response forms the basis of life within multicellular organisms, with growth factors playing a crucial role in these interactions. Discoveries in recent years have shown that components of the Epidermal Growth Factor (EGF) signaling system have frequently been used by cancer cells to autonomously provide survival and proliferation signals. The main focus of this review is the ErbB epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4 as therapeutic targets. Since the ErbB receptor family regulates cell proliferation through the Ras-mitogen-activated protein kinase (RAS/MAPK) pathway, and cell survival and transformation through the phosphatidylinositol 3-kinase (PI3K/AKT) pathway, pharmacological targeting of these pathways is also discussed. We will also address the clinical studies that have been conducted to evaluate antibody-based therapies mostly on solid tumors and hematologic malignancies. (c) Versita Warsaw and Springer-Verlag Berlin Heidelberg. All rights reserved

Targeting of solid tumors and blood malignancies by antibody-based therapies - EGFR-pathway as an example

A well-coordinated interaction between extracellular signals and intracellular response forms the basis of life within multicellular organisms, with growth factors playing a crucial role in these interactions. Discoveries in recent years have shown that components of the Epidermal Growth Factor (EGF) signaling system have frequently been used by cancer cells to autonomously provide survival and proliferation signals. The main focus of this review is the ErbB epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4 as therapeutic targets. Since the ErbB receptor family regulates cell proliferation through the Ras-mitogen-activated protein kinase (RAS/MAPK) pathway, and cell survival and transformation through the phosphatidylinositol 3-kinase (PI3K/AKT) pathway, pharmacological targeting of these pathways is also discussed. We will also address the clinical studies that have been conducted to evaluate antibody-based therapies mostly on solid tumors and hematologic malignancies. (c) Versita Warsaw and Springer-Verlag Berlin Heidelberg. All rights reserved

Autoimmunity and apoptosis - Therapeutic implications

Acquisition of a complex immune system during evolution provided organisms with the most effective defense mechanism against "foreign" or "non-self" invaders. This efficient protection against pathogens, however, has been achieved at the expense of a higher risk for "self"-directed reaction or autoimmunity. Establishment of self-tolerance and homeostasis in the immune system is regulated at different physiological stages of immune cells development. The breakdown in discrimination between "self" and "non-self" causes an aberrant immune response against autoantigens that promote damage to the "self" cells and tissue(s), resulting in various autoimmune phenotypes. Whereas activation and clonal proliferation of autoreactive T- and B-lymphocytes underlies the pathogenesis of autoimmune diseases, the mechanism by which self-tolerance is lost and autoimmune responses are induced is not clear yet. Autoimmunity is a multi-step process that occurs as a consequence of complex interaction between genetic susceptibility and non-genetic factors. Programmed cell death, as a key mechanism to regulate immune system function, has a crucial influence on both the selection process of immune cells and the maintenance of this immune tolerance in peripheral repertoire. Thus, defects in apoptotic death pathways may contribute to the development of autoimmune response in susceptible individuals in certain conditions

Ltd. „Tendo Management” competitiveness and perspectives in Kuldiga

Acquisition of a complex immune system during evolution provided organisms with the most effective defense mechanism against "foreign" or "non-self" invaders. This efficient protection against pathogens, however, has been achieved at the expense of a higher risk for "self"-directed reaction or autoimmunity. Establishment of self-tolerance and homeostasis in the immune system is regulated at different physiological stages of immune cells development. The breakdown in discrimination between "self" and "non-self" causes an aberrant immune response against autoantigens that promote damage to the "self" cells and tissue(s), resulting in various autoimmune phenotypes. Whereas activation and clonal proliferation of autoreactive T- and B-lymphocytes underlies the pathogenesis of autoimmune diseases, the mechanism by which self-tolerance is lost and autoimmune responses are induced is not clear yet. Autoimmunity is a multi-step process that occurs as a consequence of complex interaction between genetic susceptibility and non-genetic factors. Programmed cell death, as a key mechanism to regulate immune system function, has a crucial influence on both the selection process of immune cells and the maintenance of this immune tolerance in peripheral repertoire. Thus, defects in apoptotic death pathways may contribute to the development of autoimmune response in susceptible individuals in certain conditions

Apoptin, a tumor-selective killer

Apoptin, a small protein from chicken anemia virus, has attracted great attention, because it specifically kills tumor cells while leaving normal cells unharmed. The subcellular localization of apoptin appears to be crucial for this tumor-selective activity. In normal cells, apoptin resides in the cytoplasm, whereas in cancerous cells it translocates into the nucleus. The nuclear translocation of apoptin is largely controlled by its phosphorylation. In tumor cells, apoptin causes the nuclear accumulation of survival kinases including Akt and is phosphorylated by CDK2. Thereby, apoptin redirects survival signals into cell death responses. Apoptin also binds as a multimeric complex to DNA and interacts with several nuclear targets, such as the anaphase-promoting complex, resulting in a G2/M phase arrest. The proapoptotic signal of apoptin is then transduced from the nucleus to cytoplasm by Nur77, which triggers a p53-independent mitochondrial death pathway. In this review, we summarize recent discoveries of apoptin's mechanism of action that might provide intriguing insights for the development of novel tumor-selective anticancer drugs.Invited Review</p

Sister Experience Trophic Ulcers in Patient Care

Bakalaura darba tēma „Māsu pieredze trofisko čūlu pacientu aprūpē”. Darba izstrādei tika izvirzīts mērķis – noskaidrot māsu pieredzi, trofisko čūlu pacientu aprūpē. Pētījums ir balstīts uz aptaujas rezultātiem un zinātniski teorētiskās literatūras analīzi. Pētniecības teorētiskajā daļā tiek aprakstīta trofisko čūlu klasifikācija, klīniskā aina, raksturīgākās īpašības, komplikācijas, ārstēšana un profilakses pasākumi. Pētniecības darbā izmantota K. Rojas māszinību teorija, kas ir orientēta uz cilvēka mijiedarbību ar mainīgo apkārtējo vidi, kas stimulē adaptācijas reakciju veidošanos. Pētniecības darba praktiskajā daļā iekļauts aptaujas anketu apkopojums, rezultātu analīze, secinājumi un priekšlikumi. Tika analizēti un apkopoti 28 literatūras avoti. Pētījumā tika izmantota kvantitatīvā pētniecības metode – anketēšana, kas sastāvēja no 13 jautājumiem. Praktiskajā daļā uzrādīti pētījuma rezultāti, kas attēloti diagrammās, ir veikta šo rezultātu analīze un izdarīti secinājumi. Analizējot pētījumu var secināt, ka medicīnas māsai ir ļoti daudz darba sakarā ar tiem pacientiem, kuriem ļoti sīki ir jāpaskaidro trofisko čūlu aprūpi, gan stacionārā, gan mājās. Medicīnas māsas zināšanas ir minimālas ja tā strādā nodaļā, kura ar trofisko čūlu pacientiem saskare ir ierobežota. Tomēr, tai ir ļoti liela loma aprūpes izskaidrošanai, palīdzības sniegšanai, un atbalstīšanai. Māsu pieredze trofisko čūlu pacientu aprūpē ir pietiekoša, jo ņemot kopumā to, ka māsām vēl ir daudz visdažādāka darba, viņas ar to aprūpi tiek gala. Pētījuma dati apstiprina izvirzīto hipotēzi.The theme of the „Sister experience trophic ulcers in patient care”. The development was the aim – to clarify her experience trophic ulcers in patient care. The study is based on the results of the survey and the theoretical literature and analysis. The theoretical part of the research is described in the trophic ulcers classification, clinical picture characteristic properties, complications, treatments and preventive measures. Research work used K. Rojas nursing theory that is focused on the human interaction with the environment that stimulates the formation of adaptation responses. Research work included in the summary, the analysis of the results of the questionnaire, the conclusions and proposals. Was analysed and collected 28 literary sources. The study used a quantitative research method – surveys, which consisted of 13 questions. In the practice session at the presentation of the results of the study, which displayed charts is performed analysis of those results and conclusions. The analysis of the study may be concluded as a nurse is a lot of work in connection with those which need to be clarified very detailed trophic ulcers care, both in hospital and at home. The nurse's knowledge is minimal if it is working with the department, which trophic ulcers in patients contact is limited. However, it has a very large role in the health-care world, assistance and support. Her experience is sufficient trophic ulcers in patient care since, in general, the sisters still has a lot of work they take with their care is final. The study data support the hypothesis