Publications by authors named "M Infanger"

137 Publications

Changes in Exosome Release in Thyroid Cancer Cells after Prolonged Exposure to Real Microgravity in Space.

Int J Mol Sci 2021 Feb 21;22(4). Epub 2021 Feb 21.

Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Universitätsplatz 2, 39106 Magdeburg, Germany.

Space travel has always been the man's ultimate destination. With the ability of spaceflight though, came the realization that exposure to microgravity has lasting effects on the human body. To counteract these, many studies were and are undertaken, on multiple levels. Changes in cell growth, gene, and protein expression have been described in different models on Earth and in space. Extracellular vesicles, and in particular exosomes, are important cell-cell communicators, being secreted from almost all the cells and therefore, are a perfect target to further investigate the underlying reasons of the organism's adaptations to microgravity. Here, we studied supernatants harvested from the CellBox-1 experiment, which featured human thyroid cancer cells flown to the International Space Station during the SpaceX CRS-3 cargo mission. The initial results show differences in the number of secreted exosomes, as well as in the distribution of subpopulations in regards to their surface protein expression. Notably, alteration of their population regarding the tetraspanin surface expression was observed. This is a promising step into a new area of microgravity research and will potentially lead to the discovery of new biomarkers and pathways of cellular cross-talk.
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http://dx.doi.org/10.3390/ijms22042132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924847PMC
February 2021

The Effect of Continuous Positive Airway Pressure Therapy on Obstructive Sleep Apnea-Related Hypertension.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Department for Microgravity Research and Translational Regenerative Medicine, Otto-von-Guericke University, D-39106 Magdeburg, Germany.

Obstructive sleep apnea (OSA) is a common disease, with approximately 3-7% of men and 2-5% of women worldwide suffering from symptomatic OSA. If OSA is left untreated, hypoxia, microarousals and increased chemoreceptor stimulation can lead to complications like hypertension (HT). Continuous positive airway pressure (CPAP) is the most common treatment for OSA, and it works by generating airway patency, which will counteract the apnea or hypopnea. More than one billion people in the world suffer from HT, and the usual treatment is pharmacological with antihypertensive medication (AHM). The focus of this review will be to investigate whether the CPAP therapy for OSA affects HT.
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http://dx.doi.org/10.3390/ijms22052300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956605PMC
February 2021

Tissue Engineering of Cartilage Using a Random Positioning Machine.

Int J Mol Sci 2020 Dec 16;21(24). Epub 2020 Dec 16.

Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany.

Articular cartilage is a skeletal tissue of avascular nature and limited self-repair capacity. Cartilage-degenerative diseases, such as osteoarthritis (OA), are difficult to treat and often necessitate joint replacement surgery. Cartilage is a tough but flexible material and relatively easy to damage. It is, therefore, of high interest to develop methods allowing chondrocytes to recolonize, to rebuild the cartilage and to restore joint functionality. Here we studied the in vitro production of cartilage-like tissue using human articular chondrocytes exposed to the Random Positioning Machine (RPM), a device to simulate certain aspects of microgravity on Earth. To screen early adoption reactions of chondrocytes exposed to the RPM, we performed quantitative real-time PCR analyses after 24 h on chondrocytes cultured in DMEM/F-12. A significant up-regulation in the gene expression of , , , , , , and was detected, while the levels of , , , , , , , , , , , and mRNAs remained unchanged. The STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis demonstrated among others the importance of these differentially regulated genes for cartilage formation. Chondrocytes grown in DMEM/F-12 medium produced three-dimensional (3D) spheroids after five days without the addition of scaffolds. On day 28, the produced tissue constructs reached up to 2 mm in diameter. Using specific chondrocyte growth medium, similar results were achieved within 14 days. Spheroids from both types of culture media showed the typical cartilage morphology with aggrecan positivity. Intermediate filaments form clusters under RPM conditions as detected by vimentin staining after 7 d and 14 d. Larger meshes appear in the network in 28-day samples. Furthermore, they were able to form a confluent chondrocyte monolayer after being transferred back into cell culture flasks in 1 conditions showing their suitability for transplantation into joints. Our results demonstrate that the cultivation medium has a direct influence on the velocity of tissue formation and tissue composition. The spheroids show properties that make them interesting candidates for cellular cartilage regeneration approaches in trauma and OA therapy.
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http://dx.doi.org/10.3390/ijms21249596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765923PMC
December 2020

Influence of Microgravity on Apoptosis in Cells, Tissues, and Other Systems In Vivo and In Vitro.

Int J Mol Sci 2020 Dec 9;21(24). Epub 2020 Dec 9.

Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany.

All life forms have evolved under the constant force of gravity on Earth and developed ways to counterbalance acceleration load. In space, shear forces, buoyance-driven convection, and hydrostatic pressure are nullified or strongly reduced. When subjected to microgravity in space, the equilibrium between cell architecture and the external force is disturbed, resulting in changes at the cellular and sub-cellular levels (e.g., cytoskeleton, signal transduction, membrane permeability, etc.). Cosmic radiation also poses great health risks to astronauts because it has high linear energy transfer values that evoke complex DNA and other cellular damage. Space environmental conditions have been shown to influence apoptosis in various cell types. Apoptosis has important functions in morphogenesis, organ development, and wound healing. This review provides an overview of microgravity research platforms and apoptosis. The sections summarize the current knowledge of the impact of microgravity and cosmic radiation on cells with respect to apoptosis. Apoptosis-related microgravity experiments conducted with different mammalian model systems are presented. Recent findings in cells of the immune system, cardiovascular system, brain, eyes, cartilage, bone, gastrointestinal tract, liver, and pancreas, as well as cancer cells investigated under real and simulated microgravity conditions, are discussed. This comprehensive review indicates the potential of the space environment in biomedical research.
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http://dx.doi.org/10.3390/ijms21249373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764784PMC
December 2020

Breast Cancer Cells in Microgravity: New Aspects for Cancer Research.

Int J Mol Sci 2020 Oct 5;21(19). Epub 2020 Oct 5.

Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany.

Breast cancer is the leading cause of cancer death in females. The incidence has risen dramatically during recent decades. Dismissed as an "unsolved problem of the last century", breast cancer still represents a health burden with no effective solution identified so far. Microgravity (µg) research might be an unusual method to combat the disease, but cancer biologists decided to harness the power of µg as an exceptional method to increase efficacy and precision of future breast cancer therapies. Numerous studies have indicated that µg has a great impact on cancer cells; by influencing proliferation, survival, and migration, it shifts breast cancer cells toward a less aggressive phenotype. In addition, through the de novo generation of tumor spheroids, µg research provides a reliable in vitro 3D tumor model for preclinical cancer drug development and to study various processes of cancer progression. In summary, µg has become an important tool in understanding and influencing breast cancer biology.
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http://dx.doi.org/10.3390/ijms21197345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582256PMC
October 2020

[Registry Research Funding of the German Society of Plastic, Reconstructive and Aesthetic Surgeons (DGPRÄC) and Research Funding Report 2019/2020].

Handchir Mikrochir Plast Chir 2020 Sep 25. Epub 2020 Sep 25.

Abteilung für Hand-, Plastische und Ästhetische Chirurgie, Klinikum der Universität München, LMU München.

Background:  Since 2015/16 the DGPRÄC collects, evaluates and publishes the research activities of academic sections, departments and clinics for plastic surgery at university hospitals in Germany, in order to raise the awareness of plastic surgical research performance.

Materials And Methods:  The directors of plastic surgical academic institutions were contacted via the DGPRÄC and asked to report any requested/approved and rejected research applications to public, non-public and industrial funding organizations. Data was collected in our previously established online database: https://docs.google.com/forms/d/e/1FAIpQLSe6F5xmTyw-k7VKJx_2jkPA4LBXsA0sgBGMrC3rx_4bHj6uzQ/viewform?usp=sf_link. In addition, applications were identified via the DFG's public database GEPRIS.

Results:  A total of 41 funding applications to the public funding institutes DFG, BMBF, BMWi, BMG and EU were identified. 75.6 % (31/41) of the applications had already been approved at the time of data collection, of which 77.4 % (24/31) were DFG, 9.7 % (3/31) were BMWi, 6.5 % (2/31) were EU and 3.2 % (1/31) were BMBF or BMG applications. The average funding amounted to 358 301 Euro. In 50.0 % (12/24) of the cases, the approved DFG proposals were assigned to the subject review board 205-27 Orthopedics, Trauma Surgery, Reconstructive Surgery.

Conclusion:  The continuous publication of plastic surgical research funding reports submitted by the convention of university plastic surgeons of the DGPRÄC portraits the excellent, collaborative research activity in the field of plastic surgery.
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http://dx.doi.org/10.1055/a-1267-0388DOI Listing
September 2020

A case of upper lip necrosis after cosmetic injection of hyaluronic acid soft-tissue filler-Does capillary infarction play a role in the development of vascular compromise, and what are the implications?

J Cosmet Dermatol 2020 Jun 8;19(6):1316-1320. Epub 2020 Apr 8.

Department of Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke University, Magdeburg, Germany.

Facial rejuvenation with injectable filler substances is a frequently applied outpatient procedure. However, light, moderate, and even severe complications may occur. A case of tissue necrosis at the upper lip after injection of highly cross-linked hyaluronic acid together with the following salvage procedure is presented here. We discuss this complication with respect to relevant anatomy and physicochemical properties of the filler substance and review the recommendations given in literature for decreasing the likelihood of such an adverse event.
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http://dx.doi.org/10.1111/jocd.13391DOI Listing
June 2020

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy.

J Clin Med 2020 Mar 18;9(3). Epub 2020 Mar 18.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.

The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.
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http://dx.doi.org/10.3390/jcm9030824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141375PMC
March 2020

Insight in Adhesion Protein Sialylation and Microgravity Dependent Cell Adhesion-An Omics Network Approach.

Int J Mol Sci 2020 Mar 4;21(5). Epub 2020 Mar 4.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University Magdeburg, D-39120 Magdeburg, Germany.

The adhesion behavior of human tissue cells changes in vitro, when gravity forces affecting these cells are modified. To understand the mechanisms underlying these changes, proteins involved in cell-cell or cell-extracellular matrix adhesion, their expression, accumulation, localization, and posttranslational modification (PTM) regarding changes during exposure to microgravity were investigated. As the sialylation of adhesion proteins is influencing cell adhesion on Earth in vitro and in vivo, we analyzed the sialylation of cell adhesion molecules detected by omics studies on cells, which change their adhesion behavior when exposed to microgravity. Using a knowledge graph created from experimental omics data and semantic searches across several reference databases, we studied the sialylation of adhesion proteins glycosylated at their extracellular domains with regards to its sensitivity to microgravity. This way, experimental omics data networked with the current knowledge about the binding of sialic acids to cell adhesion proteins, its regulation, and interactions in between those proteins provided insights into the mechanisms behind our experimental findings, suggesting that balancing the sialylation against the de-sialylation of the terminal ends of the adhesion proteins' glycans influences their binding activity. This sheds light on the transition from two- to three-dimensional growth observed in microgravity, mirroring cell migration and cancer metastasis in vivo.
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http://dx.doi.org/10.3390/ijms21051749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084616PMC
March 2020

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells.

Int J Mol Sci 2020 Feb 13;21(4). Epub 2020 Feb 13.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.

Prostate cancer is one of the leading causes of cancer mortality in men worldwide. An unusual but unique environment for studying tumor cell processes is provided by microgravity, either in space or simulated by ground-based devices like a random positioning machine (RPM). In this study, prostate adenocarcinoma-derived PC-3 cells were cultivated on an RPM for time periods of 3 and 5 days. We investigated the genes associated with the cytoskeleton, focal adhesions, extracellular matrix, growth, survival, angiogenesis, and metastasis. The gene expression of signaling factors of the vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), and PI3K/AKT/mTOR (PAM) pathways was investigated using qPCR. We performed immunofluorescence to study the cytoskeleton, histological staining to examine the morphology, and a time-resolved immunofluorometric assay to analyze the cell culture supernatants. When PC-3 cells were exposed to simulated microgravity (s-µ), some cells remained growing as adherent cells (AD), while most cells detached from the cell culture flask bottom and formed multicellular spheroids (MCS). After 3-day RPM exposure, PC-3 cells revealed significant downregulation of the , , , , and gene expression in MCS, whereas , , , , , , , , and mRNAs were not significantly changed. and were elevated in AD, and , , , , , , and mRNAs were significantly upregulated in AD and MCS after 3 days. After a 5-day culture in s-µ, the PC-3 cells showed significant downregulations of mRNA in AD and MCS, and , , and in AD and in MCS. In addition, we measured significant upregulations in , , , , , , , and mRNAs in AD and MCS, and increases in , , and in MCS as well as , , , , , and mRNAs in AD. and were not altered by s-µ. In parallel, the secretion rate of VEGFA and NGAL proteins decreased. Cytoskeletal alterations (F-actin) were visible, as well as a deposition of collagen in the MCS. In conclusion, RPM-exposure of PC-3 cells induced changes in their morphology, cytoskeleton, and extracellular matrix protein synthesis, as well as in their focal adhesion complex and growth behavior. The significant upregulation of genes belonging to the PAM pathway indicated their involvement in the cellular changes occurring in microgravity.
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http://dx.doi.org/10.3390/ijms21041263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072928PMC
February 2020

Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity.

Cells 2020 02 5;9(2). Epub 2020 Feb 5.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.

Detachment and the formation of spheroids under microgravity conditions can be observed with various types of intrinsically adherent human cells. In particular, for cancer cells this process mimics metastasis and may provide insights into cancer biology and progression that can be used to identify new drug/target combinations for future therapies. By using the synthetic glucocorticoid dexamethasone (DEX), we were able to suppress spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells that were exposed to altered gravity conditions on a random positioning machine. DEX inhibited the growth of three-dimensional cell aggregates in a dose-dependent manner. In the first approach, we analyzed the expression of several factors that are known to be involved in key processes of cancer progression such as autocrine signaling, proliferation, epithelial-mesenchymal transition, and anoikis. Wnt/β-catenin signaling and expression patterns of important genes in cancer cell growth and survival, which were further suggested to play a role in three-dimensional aggregation, such as , , , (), or , were clearly affected by DEX. Our data suggest the presence of a more complex regulation network of tumor spheroid formation involving additional signal pathways or individual key players that are also influenced by DEX.
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http://dx.doi.org/10.3390/cells9020367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072698PMC
February 2020

The Vasoactive Mas Receptor in Essential Hypertension.

J Clin Med 2020 Jan 18;9(1). Epub 2020 Jan 18.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.

The renin-angiotensin-aldosterone system (RAAS) has been studied extensively, and with the inclusion of novel components, it has become evident that the system is much more complex than originally anticipated. According to current knowledge, there are two main axes of the RAAS, which counteract each other in terms of vascular control: The classical vasoconstrictive axis, renin/angiotensin-converting enzyme/angiotensin II/angiotensin II receptor type 1 (ATR), and the opposing vasorelaxant axis, angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor (MasR). An abnormal activity within the system constitutes a hallmark in hypertension, which is a global health problem that predisposes cardiovascular and renal morbidities. In particular, essential hypertension predominates in the hypertensive population of more than 1.3 billion humans worldwide, and yet, the pathophysiology behind this multifactorial condition needs clarification. While commonly applied pharmacological strategies target the classical axis of the RAAS, discovery of the vasoprotective effects of the opposing, vasorelaxant axis has presented encouraging experimental evidence for a new potential direction in RAAS-targeted therapy based on the G protein-coupled MasR. In addition, the endogenous MasR agonist angiotensin-(1-7), peptide analogues, and related molecules have become the subject of recent studies within this field. Nevertheless, the clinical potential of MasR remains unclear due to indications of physiological-biased activities of the RAAS and interacting signaling pathways.
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http://dx.doi.org/10.3390/jcm9010267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019597PMC
January 2020

Potential Beneficial Effects of Vitamin D in Coronary Artery Disease.

Nutrients 2019 Dec 30;12(1). Epub 2019 Dec 30.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.

Vitamin D plays a pivotal role in bone homeostasis and calcium metabolism. However, recent research has indicated additional beneficial effects of vitamin D on the cardiovascular system. This review aims to elucidate if vitamin D can be used as an add-on treatment in coronary artery disease (CAD). Large-scale epidemiological studies have found a significant inverse association between serum 25(OH)-vitamin D levels and the prevalence of essential hypertension. Likewise, epidemiological data have suggested plasma levels of vitamin D to be inversely correlated to cardiac injury after acute myocardial infarction (MI). Remarkably, in vitro trials have showed that vitamin D can actively suppress the intracellular NF-κB pathway to decrease CAD progression. This is suggested as a mechanistic link to explain how vitamin D may decrease vascular inflammation and atherosclerosis. A review of randomized controlled trials with vitamin D supplementation showed ambiguous results. This may partly be explained by heterogeneous study groups. It is suggested that subgroups of diabetic patients may benefit more from vitamin D supplementation. Moreover, some studies have indicated that calcitriol rather than cholecalciferol exerts more potent beneficial effects on atherosclerosis and CAD. Therefore, further studies are required to clarify these assumptions.
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http://dx.doi.org/10.3390/nu12010099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019525PMC
December 2019

Short-term effects of simulated microgravity on morphology and gene expression in human breast cancer cells.

Physiol Int 2019 Dec 3;106(4):311-322. Epub 2020 Jan 3.

Department of Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University, Magdeburg, Germany.

Introduction: Microgravity has been shown to impose various effects on breast cancer cells. We exposed human breast cancer cells to simulated microgravity and studied morphology and alterations in gene expression.

Materials And Methods: Human breast cancer cells were exposed to simulated microgravity in a random positioning machine (RPM) for 24 h. Morphology was observed under light microscopy, and gene alteration was studied by qPCR.

Results: After 24 h, formation of three-dimensional structures (spheroids) occurred. BRCA1 expression was significantly increased (1.9×,  < 0.05) in the adherent cells under simulated microgravity compared to the control. Expression of KRAS was significantly decreased (0.6×,  < 0.05) in the adherent cells compared to the control. VCAM1 was significantly upregulated (6.6×, 2.0×,  < 0.05 each) in the adherent cells under simulated microgravity and in the spheroids. VIM expression was significantly downregulated (0.45×, 0.44×,  < 0.05 each) in the adherent cells under simulated microgravity and in the spheroids. There was no significant alteration in the expression of , , , and .

Conclusions: Simulated microgravity induces spheroid formation in human breast cancer cells within 24 h and alters gene expression toward modified adhesion properties, enhanced cell repair, and phenotype preservation. Further insights into the underlying mechanisms could open up the way toward new therapies.
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December 2019

Multikinase Inhibitor Treatment in Thyroid Cancer.

Int J Mol Sci 2019 Dec 18;21(1). Epub 2019 Dec 18.

Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, 8000 Aarhus C, Denmark.

Thyroid cancer is the most common endocrine malignancy. Most thyroid cancer types respond well to conventional treatment consisting of surgery and radioactive iodine (RAI) therapy. Unfortunately, some thyroid cancer types are resistant to surgical and RAI therapy. Multikinase inhibitors (MKIs) can be used in the treatment of advanced refractory thyroid cancers. The objective of this review is to give an update on MKI treatment (lenvatinib, sorafenib, sunitinib, cabozantinib, pazopanib, vandetanib) of thyroid cancer, regarding its efficacy and safety profile. We evaluated 212 articles through a PubMed search. A total of 20 articles met the inclusion and none the exclusion criteria. The studies showed promising progression-free survival rates compared to placebo treatment from earlier studies and similar or better results compared to the SELECT and DECISION trials. Adverse effects (AEs) are substantial in the treatment with MKIs. Almost all patients treated with these novel drugs experienced AEs. It is therefore crucial to focus on the management of AEs for a decent long-term outcome. The AEs are often more severe in patients with high efficacy of MKIs, which could indicate a correlation. Taken together, the novel therapeutic regimen with MKIs has shown favorable results in otherwise treatment-resistant thyroid cancer.
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http://dx.doi.org/10.3390/ijms21010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982227PMC
December 2019

The Role of C-X-C Chemokine Receptor Type 4 (CXCR4) in Cell Adherence and Spheroid Formation of Human Ewing's Sarcoma Cells under Simulated Microgravity.

Int J Mol Sci 2019 Dec 2;20(23). Epub 2019 Dec 2.

Department of Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University, Leipziger Strasse 44, D-39120 Magdeburg, Germany.

We studied the behavior of Ewing's Sarcoma cells of the line A673 under simulated microgravity (s-µg). These cells express two prominent markers-the oncogene EWS/FLI1 and the chemokine receptor CXCR4, which is used as a target of treatment in several types of cancer. The cells were exposed to s-µg in a random-positioning machine (RPM) for 24 h in the absence and presence of the CXCR4 inhibitor AMD3100. Then, their morphology and cytoskeleton were examined. The expression of selected mutually interacting genes was measured by qRT-PCR and protein accumulation was determined by western blotting. After 24 h incubation on the RPM, a splitting of the A673 cell population in adherent and spheroid cells was observed. Compared to 1 g control cells, was significantly upregulated in the adherent cells and in the spheroids, while and expression were significantly enhanced in spheroids only. Transcription of was upregulated and and were down-regulated in both, adherent in spheroid cells, respectively. Regarding, protein accumulation EWS/FLI1 was enhanced in adherent cells only, but CD44 decreased in spheroids and adherent cells. Inhibition of CXCR4 did not change spheroid count, or structure. Under s-µg, the tumor marker EWS/FLI1 is intensified, while targeting CXCR4, which influences adhesion proteins, did not affect spheroid formation.
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http://dx.doi.org/10.3390/ijms20236073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929163PMC
December 2019

Short-Term Microgravity Influences Cell Adhesion in Human Breast Cancer Cells.

Int J Mol Sci 2019 Nov 15;20(22). Epub 2019 Nov 15.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.

With the commercialization of spaceflight and the exploration of space, it is important to understand the changes occurring in human cells exposed to real microgravity (r-µ) conditions. We examined the influence of r-µ, simulated microgravity (s-µ, incubator random positioning machine (iRPM)), hypergravity (hyper-), and vibration (VIB) on triple-negative breast cancer (TNBC) cells (MDA-MB-231 cell line) with the aim to study early changes in the gene expression of factors associated with cell adhesion, apoptosis, nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. We had the opportunity to attend a parabolic flight (PF) mission and to study changes in RNA transcription in the MDA-MB cells exposed to PF maneuvers (29th Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). PF maneuvers induced an early up-regulation of , and mRNAs after the first parabola (P1) and a delayed upregulation of , and after the last parabola (P31). ICAM-1, VCAM-1 and CD44 protein levels were elevated, whereas the NF-κB subunit p-65 and annexin-A2 protein levels were reduced after the 31st parabola (P31). The , , mRNA were not changed and cleaved caspase-3 was not detectable in MDA-MB-231 cells exposed to PF maneuvers. Hyper--exposure of the cells elevated the expression of and mRNAs, iRPM-exposure downregulated and , whereas VIB did not affect the TNBC cells. The early changes in ICAM-1 and VCAM-1 and the rapid decrease in the NF-κB subunit p-65 might be considered as fast-reacting, gravity-regulated and cell-protective mechanisms of TNBC cells exposed to altered gravity conditions. This data suggest a key role for the detected gravity-signaling elements in three-dimensional growth and metastasis.
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http://dx.doi.org/10.3390/ijms20225730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887954PMC
November 2019

What does a (general and abdominal) surgeon need to know on plastic surgery?

Pol Przegl Chir 2019 Jun;91(5):41-50

Dept. of General, Abdominal and Vascular Surgery, University Hospital at Magdeburg, Magdeburg (Germany).

Background: Plastic surgery was first introduced as a sub-specialty of general surgery in Germany in 1978. Since then, this surgical subspecialty/discipline has evolved enormous potential, e.g. in collaboration with other disciplines such as general andabdominal surgery.

Aim: To highlight and summarize the basic potential, technical options and novel aspects of plastic surgery, which are relevant for the common interdisciplinary surgical strategies of plastic and general as well as abdominal surgery in clinical practice.

Method: Short and compact narrative review based on 1) a selection of relevant references from the medical scientific literature and 2) surgical experiences obtained in daily practice. R esults (selected corner points): 1) Biological protection procedures in vascular surgery by flap coverage after meticulous debridement with or without autogenic vascular reconstruction are used to overcome infection of a vascular prosthesis, a serious problem, associated with the risk of anastomotic rupture and bleeding by transfer of immunological competence due to tissue coverage and finally to induce healing in the area of an infected vascular prosthesis. 2) Fistula treatment for aorto-tracheal or aorto-duodenal fistulas, a big challenge for the referring general surgeon, can be treated by flap coverage, i.e. interposition of the pectoralis-major flap and the omentum-majus flap, respectively. 3) With regard to nerve surgery, encouraging results have been reported after early microsurgical recurrent laryngeal nerve repair, i.e. improved subjective voice quality or reconstitution of respiratory capacity in diaphragmatic. 4) Lymphatic surgery for lymphedema occurring either primarily due to an absence or lack of lymphatic vessels or secondarily due to infection, trauma, radiation therapy or surgery can be indicated in specialized microsurgical centers, e.g. for surgical repair of the lymphatic pathway: I) the interrupted lymphatic system can be reconstructed by an interposition, or II) the lymphatic fluid can be drained extraanatomically (e.g. by a lymphatic-venous anastomosis). Further techniques are the following: free lymph node transplantation included in a free vascularized groin flap or autologous lymphatic vessel transfer or vein graft interposition (used for lymphatic vessel interposition). 5) Mass reduction such as dermolipectomy with subsequent split-thickness is a valuable option, which provides excellent volume reduction. 6) Defect coverage: A. Split- or full-thickness skin grafts are a common method of defect coverage (in cases of clean and well-vascularized wound bed and lacking donor skin, or if the graft bed is of questionable quality) using various allogenic or xenogenic skin substitute materials. B. Further methods offer a wide-range armamentarium of local and free fasciocutaneous and musculocutaneous flaps, e.g. after abdomino-perineal rectum extirpation using the vertical rectus-abdominis myocutaneous flap (VRAM) or propeller flaps according to the "angiosome". 7) Abdominal wall hernia closure with instable skin coverage, flap closure, either alone or in combination with mesh is superior to mesh closure only. 8) Free flaps: If there is no option for a local or pedicled flap available, free flaps can be well used for abdominal wall defect closure (complication rate in experienced hands is low).

Conclusion: Plastic surgery is an indispensable partner for specific surgical problems and clinical situations of general and abdominal surgery, which indicates that each general and abdominal surgeon should be well notified on great options and surgical techniques offered by modern plastic surgery to achieve best outcomes and quality of life for patients and should combine the expertise of these two surgical disciplines.
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http://dx.doi.org/10.5604/01.3001.0013.2365DOI Listing
June 2019

Augmenting cancer cell proteomics with cellular images - A semantic approach to understand focal adhesion.

J Biomed Inform 2019 12 24;100:103320. Epub 2019 Oct 24.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University Magdeburg, D-39120 Magdeburg, Germany; Department of Biomedicine, Aarhus University, Hoeg-Guldbergsgade 10, DK-8000 Aarhus C, Denmark; Gravitational Biology and Translational Regenerative Medicine, Faculty of Medicine and Mechanical Engineering, Otto-von-Guericke-University-Magdeburg, D-39120 Magdeburg, Germany. Electronic address:

If monolayers of cancer cells are exposed to microgravity, some of the cells cease adhering to the bottom of a culture flask and join three-dimensional aggregates floating in the culture medium. Searching reasons for this change in phenotype, we performed proteome analyses and learnt that accumulation and posttranslational modification of proteins involved in cell-matrix and cell-cell adhesion are affected. To further investigate these proteins, we developed a methodology to find histological images about focal adhesion complex (FA) proteins. Selecting proteins expressed by human FTC-133 and MCF-7 cancer cells and known to be incorporated in FA, we transformed the experimental data to RDF to establish a core semantic knowledgebase. Applying iterative SPARQL queries to Linked Open Databases, we augmented these data with additional functional, transformation- and aggregation-related relationships. Using reasoning, we retrieved publications with images about the spatial arrangement of proteins incorporated in FA. Contextualizing those images enabled us to gain insights about FA of cells changing their site of growth, and to independently validate our experimental results. This new way to link experimental proteome data to biomedical knowledge from various sources via searching images may generally be applied in science when images are a tool of knowledge dissemination.
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http://dx.doi.org/10.1016/j.jbi.2019.103320DOI Listing
December 2019

Bioactive Candy: Effects of Licorice on the Cardiovascular System.

Foods 2019 Oct 14;8(10). Epub 2019 Oct 14.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39120 Magdeburg, Germany.

Licorice, today chiefly utilized as a flavoring additive in tea, tobacco and candy, is one of the oldest used herbs for medicinal purposes and consists of up to 300 active compounds. The main active constituent of licorice is the prodrug glycyrrhizin, which is successively converted to 3β-monoglucuronyl-18β-glycyrrhetinic acid (3MGA) and 18β-glycyrrhetinic acid (GA) in the intestines. Despite many reported health benefits, 3MGA and GA inhibit the 11-β-hydrogenase type II enzyme (11β-HSD2) oxidizing cortisol to cortisone. Through activation of mineralocorticoid receptors, high cortisol levels induce a mild form of apparent mineralocorticoid excess in the kidney and increase systemic vascular resistance. Continuous inhibition of 11β-HSD2 related to excess licorice consumption will create a state of hypernatremia, hypokalemia and increased fluid volume, which can cause serious life-threatening complications especially in patients already suffering from cardiovascular diseases. Two recent meta-analyses of 18 and 26 studies investigating the correlation between licorice intake and blood pressure revealed statistically significant increases both in systolic (5.45 mmHg) and in diastolic blood pressure (3.19/1.74 mmHg). This review summarizes and evaluates current literature about the acute and chronic effects of licorice ingestion on the cardiovascular system with special focus on blood pressure. Starting from the molecular actions of licorice (metabolites) inside the cells, it describes how licorice intake is affecting the human body and shows the boundaries between the health benefits of licorice and possible harmful effects.
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http://dx.doi.org/10.3390/foods8100495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836258PMC
October 2019

Alteration of Cytoskeleton Morphology and Gene Expression in Human Breast Cancer Cells under Simulated Microgravity.

Cell J 2020 Apr 8;22(1):106-114. Epub 2019 Sep 8.

Department of Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University, Magdeburg, Germany.Electronic

Objective: Weightlessness simulation due to the simulated microgravity has been shown to considerably affect behavior of tumor cells. It is aim of this study to evaluate characteristics of human breast cancer cells in this scaffoldfree 3D culture model.

Materials And Methods: In this experimental study, the cells were exposed to simulated microgravity in a randompositioning machine (RPM) for five days. Morphology was observed under phase-contrast and confocal microscopy. Cytofilament staining was performed and changes in expression level of cytofilament genes, proliferation/differentiation genes, oncogenes and tumor suppressor genes were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR), followed by western blot confirmation.

Results: After five days, distinct spheroid formation was observed. Rearrangement of the cytoskeleton into spherical shape was visible. gene expression was significantly up-regulated for adherent cells and spheroids (3.3x and 3.6x respectively, P<0.05 each). also showed significant gene up-regulation for adherent cells and spheroids (3.2x and 3.9x respectively, P<0.05 each). showed significant gene up-regulation in adherent cells and spheroids (2.1x and 4.1x respectively, P<0.05 each). showed significant gene up-regulation (2.4x, P<0.05) in the spheroids, but not in the adherent cells. showed no significant alteration in gene expression. ) showed significant gene up-regulation in adherent cells and spheroids (3.2x, 3.0x, P<0.05 each). gene expression was down-regulated under simulated microgravity, without significance. Alterations of gene expressions could be confirmed on protein level for vimentin and MAPK1. Protein production was not increased for BRCA1, human epidermal growth factor receptor 2 (HER2) and VEGF. Contradictory changes were determined for and its related protein.

Conclusion: Microgravity provides an easy-to handle, scaffold-free 3D-culture model for human breast cancer cells. There were considerable changes in morphology, cytoskeleton shape and gene expressions. Identification of the underlying mechanisms could provide new therapeutic options.
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http://dx.doi.org/10.22074/cellj.2020.6537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791064PMC
April 2020

Beneficial Effects of Low Frequency Vibration on Human Chondrocytes in Vitro.

Cell Physiol Biochem 2019 ;53(4):623-637

Clinic for Plastic, Aesthetic and Hand Surgery, Otto‒von‒Guericke‒University Magdeburg, Magdeburg, Germany.

Background/aims: In articular cartilage, chondrocytes are the predominant cell type. A long-term stay in space can lead to bone loss and cartilage breakdown. Due to the poor regenerative capacity of cartilage, this may impair the crewmembers' mobility and influence mission activities. Beside microgravity other factors such as cosmic radiation and vibration might be important for cartilage degeneration. Vibration at different frequencies showed various effects on cartilage in vivo, but knowledge about its impact on chondrocytes in vitro is sparse.

Methods: Human chondrocytes were exposed to a vibration device, simulating the vibration profile occurring during parabolic flights, for 24 h (VIB) and compared to static controls. Phase-contrast microscopy, immunofluorescence, F-actin and TUNEL staining as well as quantitative real-time PCR were performed to examine effects on morphology, cell viability and shape as well as gene expression. The results were compared to earlier studies using semantic analyses.

Results: No morphological changes or cytoskeletal alterations were observed in VIB and no apoptotic cells were found. A reorganization and increase in fibronectin were detected in VIB samples by immunofluorescence technique. PXN, VCL, ANXA1, ANXA2, BAX, and BCL2 revealed differential regulations.

Conclusion: Long-term VIB did not damage human chondrocytes in vitro. The reduction of ANXA2, and up-regulation of ANXA1, PXN and VCL mRNAs suggest that long-term vibration might even positively influence cultured chondrocytes.
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http://dx.doi.org/10.33594/000000161DOI Listing
November 2019

Drug-Induced Hypertension Caused by Multikinase Inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in Renal Cell Carcinoma Treatment.

Int J Mol Sci 2019 Sep 23;20(19). Epub 2019 Sep 23.

Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Nørrebrogade 44, 8000 Aarhus C, Denmark.

This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.
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http://dx.doi.org/10.3390/ijms20194712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801695PMC
September 2019

Morphological and Molecular Changes in Juvenile Normal Human Fibroblasts Exposed to Simulated Microgravity.

Sci Rep 2019 08 15;9(1):11882. Epub 2019 Aug 15.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany.

The literature suggests morphological alterations and molecular biological changes within the cellular milieu of human cells, exposed to microgravity (µg), as many cell types assemble to multicellular spheroids (MCS). In this study we investigated juvenile normal human dermal fibroblasts (NHDF) grown in simulated µg (s-µg) on a random positioning machine (RPM), aiming to study changes in cell morphology, cytoskeleton, extracellular matrix (ECM), focal adhesion and growth factors. On the RPM, NHDF formed an adherent monolayer and compact MCS. For the two cell populations we found a differential regulation of fibronectin, laminin, collagen-IV, aggrecan, osteopontin, TIMP-1, integrin-β, caveolin-1, E-cadherin, talin-1, vimentin, α-SM actin, TGF-β, IL-8, MCP-1, MMP-1, and MMP-14 both on the transcriptional and/or translational level. Immunofluorescence staining revealed only slight structural changes in cytoskeletal components. Flow cytometry showed various membrane-bound proteins with considerable variations. In silico analyses of the regulated proteins revealed an interaction network, contributing to MCS growth via signals mediated by integrin-β, E-cadherin, caveolin-1 and talin-1. In conclusion, s-µg-conditions induced changes in the cytoskeleton, ECM, focal adhesion and growth behavior of NHDF and we identified for the first time factors involved in fibroblast 3D-assembly. This new knowledge might be of importance in tissue engineering, wound healing and cancer metastasis.
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http://dx.doi.org/10.1038/s41598-019-48378-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695420PMC
August 2019

The prostacyclin analogue treprostinil in the treatment of pulmonary arterial hypertension.

Basic Clin Pharmacol Toxicol 2019 Aug 12. Epub 2019 Aug 12.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke University, Magdeburg, Germany.

Pulmonary arterial hypertension (PAH) is a rare but life-threatening disease that progresses rapidly and is currently without a cure. Pharmacological treatments aim to slow down disease progression and to reduce symptoms by targeting the prostacyclin, the endothelin or the nitric oxide pathway. Drugs targeting the prostacyclin pathway have been shown to be favourable for PAH patients by causing vasodilatative, anti-proliferative as well as anti-inflammatory effects, but tend to be underused, partially due to adverse effects and difficulties associated with their intravenous administration. Treprostinil, a stable prostacyclin analogue, was FDA-approved in 2002 to improve exercise capacity in PAH patients and is available in intravenous, subcutaneous, inhaled and oral form. The four different possible ways of administration, a long half-life and its stability at room temperature give treprostinil an advantage over epoprostenol, iloprost and selexipag, the three other FDA-approved drugs targeting the prostacyclin pathway. In clinical trials, treprostinil improved exercise capacity, quality of life (QOL), functional class and clinical status. While the different forms of treprostinil lead to specific complications, its general adverse effects are dizziness, nausea, pain in the jaw and extremities, diarrhoea, flushing and headache. This MiniReview will assess the benefits and drawbacks of treprostinil in the treatment of PAH by examining its specific mechanism of action and pharmacological properties, such as pharmacokinetics, pharmacodynamics, adverse effects and interactions. In addition, we will analyse and discuss results from different clinical trials, comparing treprostinil's four different forms to each other as well as to other drugs targeting the prostacyclin pathway.
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http://dx.doi.org/10.1111/bcpt.13305DOI Listing
August 2019

Apoptosis Induction and Alteration of Cell Adherence in Human Lung Cancer Cells under Simulated Microgravity.

Int J Mol Sci 2019 Jul 23;20(14). Epub 2019 Jul 23.

Department of Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University, Leipziger Strasse 44, D-39120 Magdeburg, Germany.

Background: Lung cancer cells are known to change proliferation and migration under simulated microgravity. In this study, we sought to evaluate cell adherence, apoptosis, cytoskeleton arrangement, and gene expression under simulated microgravity.

Methods: Human lung cancer cells were exposed to simulated microgravity in a random-positioning machine (RPM). Cell morphology and adherence were observed under phase-contrast microscopy, cytoskeleton staining was performed, apoptosis rate was determined, and changes in gene and protein expression were detected by real-time PCR with western blot confirmation.

Results: Three-dimensional (3D)-spheroid formation was observed under simulated microgravity. Cell viability was not impaired. Actin filaments showed a shift in alignment from longitudinal to spherical. Apoptosis rate was significantly increased in the spheroids compared to the control. , , and gene expression was significantly upregulated in the adherent cells under simulated microgravity with an increase in corresponding protein production for p14 and RB1. expression was significantly upregulated in the adherent cells, but protein was not. Gene expressions of , and remained unaltered.

Conclusion: Simulated microgravity induces alteration in cell adherence, increases apoptosis rate, and leads to upregulation of tumor suppressor genes in human lung cancer cells.
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http://dx.doi.org/10.3390/ijms20143601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678991PMC
July 2019

The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure.

Nutrients 2019 Jul 22;11(7). Epub 2019 Jul 22.

Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.

Nitric oxide (NO) is a well-known vasodilator produced by the vascular endothelium via the enzyme endothelial nitric oxide synthase (eNOS). The inadequate production of NO has been linked to elevated blood pressure (BP) in both human and animal studies, and might be due to substrate inaccessibility. This review aimed to investigate whether oral administration of the amino acids l-arginine (Arg) and l-citrulline (Cit), which are potential substrates for eNOS, could effectively reduce BP by increasing NO production. Both Arg and Cit are effective at increasing plasma Arg. Cit is approximately twice as potent, which is most likely due to a lower first-pass metabolism. The current data suggest that oral Arg supplementation can lower BP by 5.39/2.66 mmHg, which is an effect that is comparable with diet changes and exercise implementation. The antihypertensive properties of Cit are more questionable, but are likely in the range of 4.1/2.08 to 7.54/3.77 mmHg. The exact mechanism by which Cit and Arg exert their effect is not fully understood, as normal plasma Arg concentration greatly exceeds the Michaelis constant (K) of eNOS. Thus, elevated plasma Arg concentrations would not be expected to increase endogenous NO production significantly, but have nonetheless been observed in other studies. This phenomenon is known as the "l-arginine paradox".
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http://dx.doi.org/10.3390/nu11071679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683098PMC
July 2019

Real Microgravity Influences the Cytoskeleton and Focal Adhesions in Human Breast Cancer Cells.

Int J Mol Sci 2019 Jun 28;20(13). Epub 2019 Jun 28.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, D-39120 Magdeburg, Germany.

With the increasing number of spaceflights, it is crucial to understand the changes occurring in human cells exposed to real microgravity (r-µ) conditions. We tested the effect of r-µ on MCF-7 breast cancer cells with the objective to investigate cytoskeletal alterations and early changes in the gene expression of factors belonging to the cytoskeleton, extracellular matrix, focal adhesion, and cytokines. In the Technische Experimente unter Schwerelosigkeit (TEXUS) 54 rocket mission, we had the opportunity to conduct our experiment during 6 min of r-µ and focused on cytoskeletal alterations of MCF-7 breast cancer cells expressing the Lifeact-GFP marker protein for the visualization of F-actin as well as the mCherry-tubulin fusion protein using the Fluorescence Microscopy Analysis System (FLUMIAS) for fast live-cell imaging under r-µ. Moreover, in a second mission we investigated changes in RNA transcription and morphology in breast cancer cells exposed to parabolic flight (PF) maneuvers (31st Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). The MCF-7 cells showed a rearrangement of the F-actin and tubulin with holes, accumulations in the tubulin network, and the appearance of filopodia- and lamellipodia-like structures in the F-actin cytoskeleton shortly after the beginning of the r-µ period. PF maneuvers induced an early up-regulation of mRNAs, and a down-regulation of after the first parabola. E-cadherin protein was significantly reduced and is involved in cell adhesion processes, and plays a significant role in tumorigenesis. Changes in the E-cadherin protein synthesis can lead to tumor progression. Pathway analyses indicate that VCL protein has an activating effect on . In conclusion, live-cell imaging visualized similar changes as those occurring in thyroid cancer cells in r-µ. This result indicates the presence of a common mechanism of gravity perception and sensation.
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http://dx.doi.org/10.3390/ijms20133156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651518PMC
June 2019

A focus on riociguat in the treatment of pulmonary arterial hypertension.

Basic Clin Pharmacol Toxicol 2019 Sep 4;125(3):202-214. Epub 2019 Jul 4.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT-1 trial (NCT00810693), riociguat improved significantly the 6-minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST-1 trial (NCT00125918) and the SUPER-1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE-5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti-proliferative, anti-inflammatory and anti-fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.
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http://dx.doi.org/10.1111/bcpt.13272DOI Listing
September 2019

Fighting Thyroid Cancer with Microgravity Research.

Int J Mol Sci 2019 May 24;20(10). Epub 2019 May 24.

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39120 Magdeburg, Germany.

Microgravity in space or simulated by special ground-based devices provides an unusual but unique environment to study and influence tumour cell processes. By investigating thyroid cancer cells in microgravity for nearly 20 years, researchers got insights into tumour biology that had not been possible under normal laboratory conditions: adherently growing cancer cells detach from their surface and form three-dimensional structures. The cells included in these multicellular spheroids (MCS) were not only altered but behave also differently to those grown in flat sheets in normal gravity, more closely mimicking the conditions in the human body. Therefore, MCS became an invaluable model for studying metastasis and developing new cancer treatment strategies via drug targeting. Microgravity intervenes deeply in processes such as apoptosis and in structural changes involving the cytoskeleton and the extracellular matrix, which influence cell growth. Most interestingly, follicular thyroid cancer cells grown under microgravity conditions were shifted towards a less-malignant phenotype. Results from microgravity research can be used to rethink conventional cancer research and may help to pinpoint the cellular changes that cause cancer. This in turn could lead to novel therapies that will enhance the quality of life for patients or potentially develop new preventive countermeasures.
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http://dx.doi.org/10.3390/ijms20102553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566201PMC
May 2019