1. Patient-derived tumor organoids mimic treatment-induced DNA damage response in glioblastomaBernarda Majc, Anamarija Habič, Marta Malavolta, Miloš Vittori, Andrej Porčnik, Roman Bošnjak, Jernej Mlakar, Alenka Matjašič, Andrej Zupan, Marija Skoblar Vidmar, Tamara Lah Turnšek, Aleksander Sadikov, Barbara Breznik, Metka Novak, 2024, original scientific article Abstract: Glioblastoma (GB) is the most common primary malignant brain tumor, characterized by resistance to therapy. Despite aggressive treatment options, GB remains an incurable disease. Invasiveness and heterogeneity are key GB features that cannot be studied in preclinical in vitro models. In this study, we investigated the effects of standard therapy using patient-derived GB organoids (GBOs). GBOs reflect the complexity and heterogeneity of the original tumor tissue. No significant effect on GBO viability or invasion was observed after irradiation and temozolomide treatment. E3 ubiquitin-protein ligase (MDM2), cyclin-dependent kinase inhibitor 1A (CDKN1A), and the serine/threonine kinases ATM and ATR were upregulated at the gene and protein levels after treatment. Our results show that the p53 pathway and DNA-damage response mechanisms were triggered, suggesting that GBOs recapitulate GB therapy resistance. GBOs thus provide a highly efficient platform to assess the specific responses of GB patients to therapy and to further explore therapy resistance.
Keywords: cellular physiology, cellular toxicology, in vitro toxicology including 3D culture, technical aspects of cell biology, cancer
Published in DiRROS: 09.09.2024; Views: 150; Downloads: 85
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3. Fate and effects of cytostatic pharmaceuticals in the environment and the identification of biomarkers for and improved risk assessment on environmental exposureMetka Filipič, 2014, treatise, preliminary study, study Abstract: CytoThreat (www.cytothreat.eu) project addresses the needs of the European society for assessing the risks associated with the release of pharmaceuticals into environment focusing on cytostatic pharmaceuticals. The mechanisms of action of most of the anticancer drugs are by interference with genetic material and cell signalling, which are very similar in all organisms and theoretically exposure to anticancer drug residues may affect also nontarget organisms. The aims are to provide new analytical methods needed for to determine the actual environmental exposure of these drugs, their metabolites and transformation products detection, to provide missing ecotoxicity data needed for accurate environmental risk assessment and identify biomarkers of delayed effects that may be used for development of early warning systems.
Keywords: health risks, cytostatics
Published in DiRROS: 03.09.2024; Views: 89; Downloads: 60
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4. Predlog načrta za hitro odzivanje ob najdbi azijskega sršena (Vespa velutina) : Projekt LIFE ARTEMIS, izdelek akcije A2Maarten De Groot, Simon Zidar, Danilo Bevk, Mojca Pibernik, Metka Pislak, Jana Kus Veenvliet, 2020, treatise, preliminary study, study Abstract: A proposal of a rapid response plan for the Asian hornet (Vespa velutina) was prepared in the LIFE ARTEMIS Project. The Asian hornet is an invasive alien species which is on the priority list of the IAS EU legislation 1143/2014. In the proposal the EWRR system is described for the finding and the rapid response for the asian hornet. First findings of the asian hornet will be submitted to the information system »Invazivke« or to the National Veterinary Institute (NVI). When data is checked, it will be send to the coordinating governmental body - Slovenian Environment Agency (ARSO) within two days.
During the rapid response proces, two tactical meetings will be organised. First ARSO will inform The Ministry of the Environment and Spatial Planning (MOP) about the finding, which will send it to the European commission. On the first tactical meeting the coordinator for the rapid response actions will be determined. Institute of the Republic of Slovenia for Nature Conservation (ZRSVN) will prepare a first survey in which the status of the population will be determined. Furthermore, all inform general public, landowners and local communities in the invaded area. Within two days to 14 days after the submission of the survey report, the second tactical meeting will be held. During this meeting the possible eradication actions will be discussed and the tasks will be divided. After that the organisation responsible for the rapid response action will prepare the final plan of eradication.
The organisation responsible for the eradication action will take action. Information on the eradication action are written in the report. After that it will be checked whether the eradication was successful. In case this was not, more eradication actions will take place. If it will be successful the area will be monitored for the coming 5 years to be sure that the species is really eradicated. All information will be send to ARSO, who will inform MOP. MOP will inform the European commission and the member states.
Keywords: azijski sršen, invazivni organizmi, tujerodni organizmi
Published in DiRROS: 03.09.2024; Views: 119; Downloads: 890
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6. Cancer chemopreventionAmr Amin, Metka Filipič, Su S. Chen, Regine Schneider-Stock, 2012, other scientific articles Abstract: Cancers are characterized by the dysregulation of cell signaling pathways at multiple steps. Most current anticancer therapies however involve the modulation of a single target. The lack of safety and high cost of monotargeted therapies have encouraged alternative approaches. Both natural compounds, extracted from plants or animals, and synthetic compounds, derived from natural prototype structures, are now being used as cancer therapeutics and as chemopreventive compounds.
Published in DiRROS: 07.08.2024; Views: 197; Downloads: 139
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7. Titanium dioxide in our everyday life : is it safe?Matej Skočaj, Metka Filipič, Jana Nunić, Saša Novak, 2011, review article Abstract: Background. Titanium dioxide (TiO2) is considered as an inert and safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO2 nanoparticles, with numerous novel and useful properties, are increasingly manufactured and used. Therefore increased human and environmental exposure can be expected, which has put TiO2 nanoparticles under toxicological scrutiny. Mechanistic toxicological studies show that TiO2 nanoparticles predominantly cause adverse effects via induction of oxidative stress resulting in cell damage, genotoxicity, inflammation, immune response etc. The extent and type of damage strongly depends on physical and chemical characteristics of TiO2 nanoparticles, which govern their bioavailability and reactivity. Based on the experimental evidence from animal inhalation studies TiO2 nanoparticles are classified as "possible carcinogenic to humans" by the International Agency for Research on Cancer and as occupational carcinogen by the National Institute for Occupational Safety and Health. The studies on dermal exposure to TiO2 nanoparticles, which is in humans substantial through the use of sunscreens, generally indicate negligible transdermal penetration; however data are needed on long-term exposure and potential adverse effects of photo-oxidation products. Although TiO2 is permitted as an additive (E171) in food and pharmaceutical products we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure. TiO2 may also enter environment, and while it exerts low acute toxicity to aquatic organisms, upon long-term exposure it induces a range of sub-lethal effects.
Conclusions. Until relevant toxicological and human exposure data that would enable reliable risk assessment are obtained, TiO2 nanoparticles should be used with great care.
Published in DiRROS: 06.08.2024; Views: 187; Downloads: 116
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8. Cytokine CCL5 and receptor CCR5 axis in glioblastoma multiformeMiha Koprivnikar Krajnc, Metka Novak, Richard G. Pestell, Tamara Lah Turnšek, 2019, review article Abstract: Background
Glioblastoma is the most frequent and aggressive brain tumour in humans with median survival from 12 to 15 months after the diagnosis. This is mostly due to therapy resistant glioblastoma stem cells in addition to intertumour heterogeneity that is due to infiltration of a plethora of host cells. Besides endothelial cells, mesenchymal stem cells and their differentiated progenies, immune cells of various differentiation states, including monocytes, comprise resident, brain tumour microenvironment. There are compelling evidence for CCL5/CCR5 in the invasive and metastatic behaviour of many cancer types. CCR5, a G-protein coupled receptor, known to function as an essential co-receptor for HIV entry, is now known to participate in driving tumour heterogeneity, the formation of cancer stem cells and the promotion of cancer invasion and metastasis. Clinical trials have recently opened targeting CCR5 using a humanized monoclonal antibody (leronlimab) for metastatic triple negative breast cancer (TNBC) or a small molecule inhibitor (maraviroc) for metastatic colon cancer. There are important CCL5 and CCR5 structure and signalling mechanisms in glioblastoma. In addition, the CCL5/CCR5 axis directs infiltration and interactions with monocytes/macrophages and mesenchymal stem cells, comprising glioblastoma stem cell niches.
Conclusions
CCR5 is highly expressed in glioblastoma and is associated with poor prognosis of patients. CCL5/CCR5 is suggested to be an excellent new target for glioblastoma therapy. The molecular mechanisms, by which chemoattractant and receptor respond within the complex tissue microenvironment to promote cancer stem cells and tumour heterogeneity, should be considered in forthcoming studies.
Keywords: cytokines, CCL5-RANTES, glioblastoma, tumour microenvironment, mesenchymal stem cells, signalling
Published in DiRROS: 06.08.2024; Views: 182; Downloads: 92
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9. Brain malignancies : glioblastoma and brain metastasesTamara Lah Turnšek, Metka Novak, Barbara Breznik, 2020, review article Abstract: Brain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor – glioblastoma and metastases from other organs to the brain are lethal leaving the patients with very short time of survival. The brain tissue landscape is very different from any other tissues and the specific microenvironment, comprising stem cells niches and blood-brain barrier, significantly influences the low rate of glioblastoma metastasis out of the brain, but better accommodates brain-invading cancer. In contrast to low frequency (0.5%) of all glioblastoma metastases, 10%–45% of other primary cancers do metastasize to the brain. This review addresses general cellular and molecular pathways that are to some extent similar in both types of metastases, involving circulating tumor cells (CTCs) with cancer stem cells (CSCs) characteristics, and metastatic niches. The invasion is a dynamic process involving reversible epithelial-to-mesenchymal (EMT) cell process, creating a transient gradient state that is inter-connected with epigenetic plasticity of the metastasizing (m)CSCs. These cells can switch between stationary, low proliferating/dormant state to a migratory, mesenchymal-like state. Settling in their respective niches as dormant CSCs in the secondary organ is a common feature in all types of metastases. In glioblastoma metastasis, the malignant mGSC cells express markers of mesenchymal GSC subtype (MES-GSC), such as CD44 and YK-40 and their major obstacle seems to be propagating in the in various organs’ microenvironments, different from the niches that home GSCs in the primary glioblastoma. Focusing on one stromal component in the glioblastoma niches, the mesenchymal stem cells (MSCs), we report herein on their differential effects on glioblastoma cells, highly depending on their genetic subtype. On the other hand, in brain metastases, the major hindrance to metastatic progression of mCSCs seem to be crossing the blood-brain-barrier. Novel therapeutic approaches for brain metastases from various cancer types are advancing slowly, and the general trends involve targeting metastatic sub-clones and selective determinants of their niches. The update on the four most common brain metastases from lung, breast, melanoma and colorectal carcinoma is presented.
Keywords: glioblastoma, cancer stem cells, invasion, metastasis, tumor microenvironment
Published in DiRROS: 06.08.2024; Views: 266; Downloads: 178
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10. Energy metabolism in IDH1 wild-type and IDH1-mutated glioblastoma stem cells : a novel target for therapy?Cornelis J. F. van Noorden, Vashendriya V. V. Hira, Amber J. van Dijck, Metka Novak, Barbara Breznik, Remco J. Molenaar, 2021, review article Abstract: Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.
Keywords: glioblastoma stem cells, IDH1-mutation, energy metabolism
Published in DiRROS: 05.08.2024; Views: 236; Downloads: 208
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