41. The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastomaDiana A. Aderetti, Vashendriya V. V. Hira, Remco J. Molenaar, Cornelis J. F. van Noorden, 2018, pregledni znanstveni članek Povzetek: Glioblastoma is the most lethal primary brain tumor and poor survival of glioblastoma patients is attributed to the presence of glioma stem cells (GSCs). These therapy-resistant, quiescent and pluripotent cells reside in GSC niches, which are specific microenvironments that protect GSCs against radiotherapy and chemotherapy. We previously showed the existence of hypoxic peri-arteriolar GSC niches in glioblastoma tumor samples. However, other studies have described peri-vascular niches, peri-hypoxic niches, peri-immune niches and extracellular matrix niches of GSCs. The aim of this review was to critically evaluate the literature on these five different types of GSC niches. In the present review, we describe that the five niche types are not distinct from one another, but should be considered to be parts of one integral GSC niche model, the hypoxic peri-arteriolar GSC niche. Moreover, hypoxic peri-arteriolar GSC niches are structural and functional look-alikes of hematopoietic stem cell (HSC) niches in the bone marrow. GSCs are maintained in peri-arteriolar niches by the same receptor-ligand interactions as HSCs in bone marrow. Our concept should be rigidly tested in the near future and applied to develop therapies to expel and keep GSCs out of their protective niches to render them more vulnerable to standard therapies.
Ključne besede: glioblastoma, glioma stem cells, niches, blood vessels, extracellular matrix, tumor microenvironment, hypoxia, therapy resistance, vasculature
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42. The role of plasmalemma vesicle-associated protein in pathological breakdown of blood-brain and blood-retinal barriers : potential novel therapeutic target for cerebral edema and diabetic macular edemaEsmeralda K. Bosma, Cornelis J. F. van Noorden, Reinier O. Schlingemann, Ingeborg Klaassen, 2018, pregledni znanstveni članek Povzetek: Breakdown of the blood–brain barrier (BBB) or inner blood–retinal barrier (BRB), induced by pathologically elevated levels of vascular endothelial growth factor (VEGF) or other mediators, can lead to vasogenic edema and significant clinical problems such as neuronal morbidity and mortality, or vision loss. Restoration of the barrier function with corticosteroids in the brain, or by blocking VEGF in the eye are currently the predominant treatment options for brain edema and diabetic macular edema, respectively. However, corticosteroids have side effects, and VEGF has important neuroprotective, vascular protective and wound healing functions, implying that long-term anti-VEGF therapy may also induce adverse effects. We postulate that targeting downstream effector proteins of VEGF and other mediators that are directly involved in the regulation of BBB and BRB integrity provide more attractive and safer treatment options for vasogenic cerebral edema and diabetic macular edema. The endothelial cell-specific protein plasmalemma vesicle-associated protein (PLVAP), a protein associated with trans-endothelial transport, emerges as candidate for this approach. PLVAP is expressed in a subset of endothelial cells throughout the body where it forms the diaphragms of caveolae, fenestrae and trans-endothelial channels. However, PLVAP expression in brain and eye barrier endothelia only occurs in pathological conditions associated with a compromised barrier function such as cancer, ischemic stroke and diabetic retinopathy. Here, we discuss the current understanding of PLVAP as a structural component of endothelial cells and regulator of vascular permeability in health and central nervous system disease. Besides providing a perspective on PLVAP identification, structure and function, and the regulatory processes involved, we also explore its potential as a novel therapeutic target for vasogenic cerebral edema and retinal macular edema.
Ključne besede: plasmalemma vesicle-associated protein, blood-brain barrier, blood-retinal barrier, cerebral edema, diabetic macular edema
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43. The genus Wallemia - from contamination of food to health threatJanja Zajc, Nina Gunde-Cimerman, 2018, pregledni znanstveni članek Povzetek: The fungal genus Wallemia of the order Wallemiales (Wallemiomycotina, Basidiomycota) comprises the most xerotolerant, xerophilic and also halophilic species worldwide. Wallemia spp. are found in various osmotically challenged environments, such as dry, salted, or highly sugared foods, dry feed, hypersaline waters of solar salterns, salt crystals, indoor and outdoor air, and agriculture aerosols. Recently, eight species were recognized for the genus Wallemia, among which four are commonly associated with foods: W. sebi, W. mellicola, W. muriae and W. ichthyophaga. To date, only strains of W. sebi, W. mellicola and W. muriae have been reported to be related to human health problems, as either allergological conditions (e.g., farmer’s lung disease) or rare subcutaneous/cutaneous infections. Therefore, this allergological and infective potential, together with the toxins that the majority of Wallemia spp. produce even under saline conditions, defines these fungi as filamentous food-borne pathogenic fungi.
Ključne besede: food, air, pathogen, xerophile, halophile, mycotoxin, farmerʼs lung disease, subcutaneous infection
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44. Effects of the green tea polyphenol epigallocatechin-3-gallate on glioma : a critical evaluation of the literatureChung T. Le, William P. J. Leenders, Remco J. Molenaar, Cornelis J. F. van Noorden, 2018, pregledni znanstveni članek Povzetek: The review discusses the effects of Epigallocatechin-3-gallate Gallate (EGCG) on glioma as a basis for future research on clinical application of EGCG. Epidemiological studies on the effects of green tea or EGCG on the risk of glioma is inconclusive due to the limited number of studies, the inclusion of all tea types in these studies, and the focus on caffeine rather than EGCG. In vivo experiments using EGCG monotherapy are inconclusive. Nevertheless, EGCG induces cell death, prevents cellular proliferation, and limits invasion in multiple glioma cell lines. Furthermore, EGCG enhances the efficacy of anti-glioma therapies, including irradiation, temozolomide, carmustine, cisplatin, tamoxifen, and TNF-related apoptosis-inducing ligand, but reduces the effect of bortezomib. Pro-drugs, co-treatment, and encapsulation are being investigated to enhance clinical applicability of EGCG. Mechanisms of actions of EGCG have been partly elucidated. EGCG has both anti-oxidant and oxidant properties. EGCG inhibits pro-survival proteins, such as telomerase, survivin, GRP78, PEA15, and P-gp. EGCG inhibits signaling of PDGFR, IGF-1R, and 67LR. EGCG reduces invasiveness of cancer cells by inhibiting the activities of various metalloproteinases, cytokines, and chemokines. Last, EGCG inhibits some NADPH-producing enzymes, thus disturbing redox status and metabolism of glioma cells. In conclusion, EGCG may be a suitable adjuvant to potentiate anti-glioma therapies.
Ključne besede: green tea, glioma
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45. Critical assessment of digital PCR for the detection and quantification of genetically modified organismsTigst Demeke, David Dobnik, 2018, pregledni znanstveni članek Povzetek: The number of genetically modified organisms (GMOs) on the market is steadily increasing. Because of regulation of cultivation and trade of GMOs in several countries, there is pressure for their accurate detection and quantification. Today, DNA-based approaches are more popular for this purpose than protein-based methods, and real-time quantitative PCR (qPCR) is still the gold standard in GMO analytics. However, digital PCR (dPCR) offers several advantages over qPCR, making this new technique appealing also for GMO analysis. This critical review focuses on the use of dPCR for the purpose of GMO quantification and addresses parameters which are important for achieving accurate and reliable results, such as the quality and purity of DNA and reaction optimization. Three critical factors are explored and discussed in more depth: correct classification of partitions as positive, correctly determined partition volume, and dilution factor. This review could serve as a guide for all laboratories implementing dPCR. Most of the parameters discussed are applicable to fields other than purely GMO testing.
Ključne besede: digital PCR, droplet digital PCR, chip-based digital PCR, genetically modified organisms, quantification
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46. Review of heterobranch molluscs fauna in the Boka Kotorska Bay, MontenegroMilica Jovanović, Vesna Mačić, Domen Trkov, Martina Orlando-Bonaca, Lovrenc Lipej, 2019, pregledni znanstveni članek Povzetek: Heterobranch molluscs fauna in Montenegro has been poorly investigated so far. The aim of the present paper is to improve the knowledge about species diversity of these marine organisms in the Boka Kotorska Bay, specific fjord-like entity in the southern Adriatic Sea. New records of seven heterobranch species were obtained by field surveys in 2017, while three new records were provided by analysing underwater photographs from previous periods. The resulted checklist summarizes the knowledge of the diversity of heterobranchs in the Boka Kotorska Bay from the oldest record in 1967 to the present day, and consists of a total of 62 heterobranch species.
Ključne besede: heterobranch fauna, Boka Kotorska Bay, Montenegro
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47. Stink bug communication with multimodal signals transmitted through air and substrateAndrej Čokl, Alenka Žunič Kosi, Raúl Alberto Laumann, 2019, pregledni znanstveni članek Povzetek: This review represents complex mechanisms and processes of multimodal communication in stink bugs. During reproductive behavior the airborne and substrate-borne signals enable mate recognition, mediate directionality of movement, eliminate rivals and motivate partners for copulation. Species specific characteristics prevent hybridization at various levels of mating behavior. Male sex and/or aggregation pheromones as uni- or multicomponent signals attract mates to land on the same plant and there, trigger females to call males by vibratory signals, transmitted through the plant. Communication during courtship runs at short distance with visual, airborne, substrate-borne and contact chemical and mechanical signals. Abdomen vibrations produce the main repertoire of female and male calling, courtship and rival vibratory signals. To increase their informational value, stink bugs tune signal frequency, amplitude and temporal characteristics with mechanical properties of plants. The airborne component of species non-specific and high amplitude signals, produced by body tremulation and wing buzzing enables communication contact between mates standing on mechanically isolated plants. Female vibratory signals increase the amount of male emitted pheromone and the latter keeps female calling. Interaction, synergy and characteristics of visual, contact chemical and vibratory signals, exchanged during courtship remain under-investigated. Female and male competition for access to copulation in imbalanced sex conditions is characterized by duetting with rival song vibratory signals. Different receptors in and on different parts of the body are able to detect with high sensitivity multimodal airborne and substrate-borne communication signals. The relevance of the multimodal communication for the reproductive success of stink bugs is discussed.
Ključne besede: insects, Pentatomidae, communication, signals, multimodality, transmission medium, environment
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48. Cytokine CCL5 and receptor CCR5 axis in glioblastoma multiformeMiha Koprivnikar Krajnc, Metka Novak, Richard G. Pestell, Tamara Lah Turnšek, 2019, pregledni znanstveni članek Povzetek: 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.
Ključne besede: cytokines, CCL5-RANTES, glioblastoma, tumour microenvironment, mesenchymal stem cells, signalling
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49. Challenges for sustained observing and forecasting systems in the Mediterranean SeaJoaquín Tintoré, Nadia Pinardi, Enrique Álvarez-Fanjul, Eva Aguiar, Diego Álvarez-Berastegui, Marco Bajo, Rosa Balbin, Roberto Bozzano, Bruno Buongiorno Nardelli, Vanessa Cardin, Vlado Malačič, 2019, pregledni znanstveni članek Povzetek: The Mediterranean community represented in this paper is the result of more than 30 years of EU and nationally funded coordination, which has led to key contributions in science concepts and operational initiatives. Together with the establishment of operational services, the community has coordinated with universities, research centers, research infrastructures and private companies to implement advanced multi-platform and integrated observing and forecasting systems that facilitate the advancement of operational services, scientific achievements and mission-oriented innovation. Thus, the community can respond to societal challenges and stakeholders needs, developing a variety of fit-for-purpose services such as the Copernicus Marine Service. The combination of state-of-the-art observations and forecasting provides new opportunities for downstream services in response to the needs of the heavily populated Mediterranean coastal areas and to climate change. The challenge over the next decade is to sustain ocean observations within the research community, to monitor the variability at small scales, e.g., the mesoscale/submesoscale, to resolve the sub-basin/seasonal and inter-annual variability in the circulation, and thus establish the decadal variability, understand and correct the model-associated biases and to enhance model-data integration and ensemble forecasting for uncertainty estimation. Better knowledge and understanding of the level of Mediterranean variability will enable a subsequent evaluation of the impacts and mitigation of the effect of human activities and climate change on the biodiversity and the ecosystem, which will support environmental assessments and decisions. Further challenges include extending the science-based added-value products into societal relevant downstream services and engaging with communities to build initiatives that will contribute to the 2030 Agenda and more specifically to SDG14 and the UN's Decade of Ocean Science for sustainable development, by this contributing to bridge the science-policy gap. The Mediterranean observing and forecasting capacity was built on the basis of community best practices in monitoring and modeling, and can serve as a basis for the development of an integrated global ocean observing system.
Ključne besede: observing and forecasting systems, sustained observations, ocean variability, FAIR data, climate, operational services, science with and for society, SDG's
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50. 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
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