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, izvirni znanstveni članek Povzetek: 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.
Ključne besede: cellular physiology, cellular toxicology, in vitro toxicology including 3D culture, technical aspects of cell biology, cancer
Objavljeno v DiRROS: 09.09.2024; Ogledov: 128; Prenosov: 77
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2. Ultrasound-mediated spatial and temporal control of engineered cells in vivoFilip Ivanovski, Maja Meško, Tina Lebar, Marko Rupnik, Duško Lainšček, Miha Gradišek, Roman Jerala, Mojca Benčina, 2024, izvirni znanstveni članek Objavljeno v DiRROS: 09.09.2024; Ogledov: 138; Prenosov: 3928
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3. Groundwater is a hidden global keystone ecosystemMattia Saccò, Stefano Mammola, Florian Altermatt, Roman Alther, Rossano Bolpagni, Anton Brancelj, David Brankovits, Cene Fišer, Vasilis Gerovasileiou, Špela Borko, Maja Zagmajster, 2024, pregledni znanstveni članek Povzetek: Groundwater is a vital ecosystem of the global water cycle, hosting unique biodiversity and providing essential services to societies. Despite being the largest unfrozen freshwater resource, in a period of depletion by extraction and pollution, groundwater environments have been repeatedly overlooked in global biodiversity conservation agendas. Disregarding the importance of groundwater as an ecosystem ignores its critical role in preserving surface biomes. To foster timely global conservation of groundwater, we propose elevating the concept of keystone species into the realm of ecosystems, claiming groundwater as a keystone ecosystem that influences the integrity of many dependent ecosystems. Our global analysis shows that over half of land surface areas (52.6%) has a medium-to-high interaction with groundwater, reaching up to 74.9% when deserts and high mountains are excluded. We postulate that the intrinsic transboundary features of groundwater are critical for shifting perspectives towards more holistic approaches in aquatic ecology and beyond. Furthermore, we propose eight key themes to develop a science-policy integrated groundwater conservation agenda. Given ecosystems above and below the ground intersect at many levels, considering groundwater as an essential component of planetary health is pivotal to reduce biodiversity loss and buffer against climate change.
Ključne besede: groundwater, keystone ecosystem, surface-subterranean connectivity
Objavljeno v DiRROS: 07.08.2024; Ogledov: 222; Prenosov: 211
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4. Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessmentEdward J. Perkins, Roman Ashauer, Lyle Burgoon, Rory Conolly, Brigitte Landesmann, Cameron Mackay, Cheryl A. Murphy, Nathan Pollesch, James R. Wheeler, Anže Županič, Stefan Scholz, 2019, pregledni znanstveni članek Povzetek: An important goal in toxicology is the development of new ways to increase the speed, accuracy, and applicability of chemical hazard and risk assessment approaches. A promising route is the integration of in vitro assays with biological pathway information. We examined how the adverse outcome pathway (AOP) framework can be used to develop pathway-based quantitative models useful for regulatory chemical safety assessment. By using AOPs as initial conceptual models and the AOP knowledge base as a source of data on key event relationships, different methods can be applied to develop computational quantitative AOP models (qAOPs) relevant for decision making. A qAOP model may not necessarily have the same structure as the AOP it is based on. Useful AOP modeling methods range from statistical, Bayesian networks, regression, and ordinary differential equations to individual-based models and should be chosen according to the questions being asked and the data available. We discuss the need for toxicokinetic models to provide linkages between exposure and qAOPs, to extrapolate from in vitro to in vivo, and to extrapolate across species. Finally, we identify best practices for modeling and model building and the necessity for transparent and comprehensive documentation to gain confidence in the use of qAOP models and ultimately their use in regulatory applications. Environ Toxicol Chem 2019;38:1850–1865. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
Ključne besede: Quantitative Adverse Outcome pathways, TKTD modelling, alternatives to animal testing, predictive toxicology, species extrapolation, prioritization of chemicals
Objavljeno v DiRROS: 06.08.2024; Ogledov: 161; Prenosov: 121
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5. Sequestration of membrane cholesterol by cholesterol-binding proteins inhibits SARS-CoV-2 entry into Vero E6 cellsMagdalena Kulma, Aleksandra Šakanović, Apolonija Bedina Zavec, Simon Caserman, Neža Omersa, Gašper Šolinc, Sara Orehek, Iva Hafner Bratkovič, Urška Kuhar, Brigita Slavec, Uroš Krapež, Matjaž Ocepek, Toshihide Kobayashi, Katarzyna Kwiatkowska, Roman Jerala, Marjetka Podobnik, Gregor Anderluh, 2024, izvirni znanstveni članek Objavljeno v DiRROS: 05.08.2024; Ogledov: 225; Prenosov: 160
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6. Protein gas vesicles of bacillus megaterium as enhancers of ultrasound-induced transcriptional regulationVid Jazbec, Nina Varda, Ernest Šprager, Maja Meško, Sara Vidmar, Rok Romih, Marjetka Podobnik, Andreja Kežar, Roman Jerala, Mojca Benčina, 2024, izvirni znanstveni članek Objavljeno v DiRROS: 01.08.2024; Ogledov: 238; Prenosov: 244
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7. Awake craniotomy for operative treatment of brain gliomas - experience from University Medical Centre LjubljanaTilen Žele, Tomaž Velnar, Blaž Koritnik, Roman Bošnjak, Jasmina Markovič Božič, 2023, izvirni znanstveni članek Povzetek: Background. Awake craniotomy is a neurosurgical technique that allows neurophysiological testing with patient cooperation during the resection of brain tumour in regional anaesthesia. This allows identification of vital functional (i.e. eloquent) brain areas during surgery and avoidance of their injury. The aim of the study was to present clinical experience with awake craniotomy for the treatment of gliomas at the University Medical Centre Ljubljana from 2015 to 2019.Patients and methods. Awake craniotomy was considered in patients with a gliomas near or within the language brain areas, in all cases of insular lesions and selected patients with lesions near or within primary motor brain cortex. Each patient was assessed before and after surgery.Results. During the 5-year period, 24 awake craniotomies were performed (18 male and 6 female patients; average age 41). The patient’s cooperation, discomfort and perceived pain assessed during the awake craniotomy were in majority of the cases excellent, slight, and moderate, respectively. After surgery, mild neurological worsening was observed in 13% (3/24) of patients. Gross total resection, in cases of malignant gliomas, was feasible in 60% (6/10) and in cases of low-grade gliomas in 29% (4/14). The surgery did not have important negative impact on functional status or quality of life as assessed by Karnofsky score and Short-Form 36 health survey, respectively (p > 0.05). Conclusions. The results suggest that awake craniotomy for treatment of gliomas is feasible and safe neurosurgical technique. The proper selection of patients, preoperative preparation with planning, and cooperation of medical team members are necessary for best treatment outcome.
Ključne besede: awake craniotomy, surgery of gliomas, intraoperative neurophysiological testing, primary brain tumours, clinical experiences
Objavljeno v DiRROS: 25.07.2024; Ogledov: 189; Prenosov: 349
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8. Localization patterns of cathepsins K and X and their predictive value in glioblastomaBarbara Breznik, Clara Limbaeck Stanic, Andrej Porčnik, Andrej Blejec, Miha Koprivnikar Krajnc, Roman Bošnjak, Janko Kos, Cornelis J. F. van Noorden, Tamara Lah Turnšek, 2018, izvirni znanstveni članek Povzetek: Background
Glioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.
Materials and methods
Gene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.
Results
Highest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.
Conclusions
The presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.
Ključne besede: cathepsins, glioblastoma, immunohistochemistry, patient survival, cancer stem cell niches
Objavljeno v DiRROS: 24.07.2024; Ogledov: 235; Prenosov: 172
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9. Cysteine cathepsins B, X and K expression in peri-arteriolar glioblastoma stem cell nichesBarbara Breznik, Clara Limbaeck Stanic, Janko Kos, Mohammed Khurshed, Vashendriya V. V. Hira, Roman Bošnjak, Tamara Lah Turnšek, Cornelis J. F. van Noorden, 2018, izvirni znanstveni članek Povzetek: Glioblastoma (GBM) is the most lethal brain tumor also due to malignant and therapy-resistant GBM stem cells (GSCs) that are localized in protecting hypoxic GSC niches. Some members of the cysteine cathepsin family of proteases have been found to be upregulated in GBM. Cathepsin K gene expression is highly elevated in GBM tissue versus normal brain and it has been suggested to regulate GSC migration out of the niches. Here, we investigated the cellular distribution of cathepsins B, X and K in GBM tissue and whether these cathepsins are co-localized in GSC niches. Therefore, we determined expression of these cathepsins in serial paraffin sections of 14 human GBM samples and serial cryostat sections of two samples using immunohistochemistry and metabolic mapping of cathepsin activity using selective fluorogenic substrates. We detected cathepsins B, X and K in peri-arteriolar GSC niches in 9 out of 16 GBM samples, which were defined by co-expression of the GSC marker CD133, the niche marker stromal-derived factor-1α (SDF-1α) and smooth muscle actin as a marker for arterioles. The expression of cathepsin B and X was detected in stromal cells and cancer cells throughout the GBM sections, whereas cathepsin K expression was more restricted to arteriole-rich regions in the GBM sections. Metabolic mapping showed that cathepsin B, but not cathepsin K is active in GSC niches. On the basis of these findings, it is concluded that cathepsins B, X and K have distinct functions in GBM and that cathepsin K is the most likely GSC niche-related cathepsin of the three cathepsins investigated.
Ključne besede: cysteine cathepsins, glioblastoma stem cells, niches, stroma, proteolytic activity
Objavljeno v DiRROS: 24.07.2024; Ogledov: 211; Prenosov: 163
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10. Systems toxicology approach for assessing developmental neurotoxicity in Larval zebrafishRoman Li, Marja Talikka, Vincenzo Belcastro, Colette vom Berg, Florian Martin, Manuel C. Peitsch, Julia Hoeng, Anže Županič, 2021, izvirni znanstveni članek Povzetek: Adverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of molecules, pathways, and biological processes within these networks. The developing brain is a prime example of an extremely complex network, which makes developmental neurotoxicity one of the most challenging areas in toxicology. We have developed a systems toxicology method that uses a computable biological network to represent molecular interactions in the developing brain of zebrafish larvae. The network is curated from scientific literature and describes interactions between biological processes, signaling pathways, and adverse outcomes associated with neurotoxicity. This allows us to identify important signaling hubs, pathway interactions, and emergent adverse outcomes, providing a more complete understanding of neurotoxicity. Here, we describe the construction of a zebrafish developmental neurotoxicity network and its validation by integration with publicly available neurotoxicity-related transcriptomic datasets. Our network analysis identified consistent regulation of tumor suppressors p53 and retinoblastoma 1 (Rb1) as well as the oncogene Krüppel-like factor (Klf8) in response to chemically induced developmental neurotoxicity. The developed network can be used to interpret transcriptomic data in a neurotoxicological context.
Objavljeno v DiRROS: 19.07.2024; Ogledov: 190; Prenosov: 151
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