Toksikološki aspekt imunomodulatora: prijatelj ili neprijatelj u povećanju efikasnosti imunoterapije karcinoma

Malignant diseases world incidence is constantly increasing and it is assumed that combining immunomodulators with immunotherapy would improve cancer therapy effectiveness. We present a research-development project of international cooperation with the People's Republic of China entitled "Increasing the effectiveness of cancer immunotherapy with a combination of CAR-T cells or PD-1/PD-L1 inhibitors using immunomodulators", led by Faculty of Pharmacy, University of Belgrade. Sulforaphane (SFN), isothiocyanate from cabbage vegetables, and a type of inactivated bacterium Pseudomonas aeruginosa (PA-MSHA) have been recognized as immunomodulators with high immune system stimulating potential, i.e. antitumor effect. However, there are few data on their individual safe use, and no data on the potential side/harmful effects of their combination, especially in patients with malignant diseases and significant immune system impairment. The Chinese team is investigating the effectiveness of improving immunotherapy with combination of immunomodulators, with their first published results proving SFN positive effect when administered with CAR-T cells (1), while Serbian team aims to examine toxicological profiles of single and/or combined SFN and PA MSHA, in silico, in vitro and in vivo on two experimental models - zebrafish and rat. The project will specifically examine adverse effects potential of single and/or combined use of the tested immunomodulators or lack of their efficacy in cancer patients, especially colon cancer. The first in silico results of the Serbian team indicated benefit/risk of SFN in patients with colon cancer depending on individual genes expression and identified gene set which change may indicate a positive or negative effect of immunomodulators (2).Incidenca malignih oboljenja u svetu je u stalnom porastu i pretpostavlja se da bi kombinacija imunomodulatora sa imunoterapijom poboljšala efikasnost terapije kod pacijenata obolelih od raka. Ovaj rad prezentuje istraživačko-razvojni projekat međunarodne saradnje sa NR Kinom pod nazivom „Povećanje efikasnosti imunoterapije karcinoma kombinacijom CAR-T ćelija ili PD-1/PD-L1 inhibitora pomoću imunomodulatora” čiji je nosilac Farmaceutski fakultet Univerziteta u Beogradu. Sulforafan (SFN), izotiocijanat iz kupusastog povrća, i vrsta inaktivisane bakterije Pseudomonas aeruginosa (PA-MSHA) prepoznati su kao imunomodulatori sa velikim stimulativnim potencijalom imunskog sistema, odnosno antitumorskim efektom. Međutim, malo je podataka o njihovoj pojedinačnoj bezbednoj primeni, dok nema podataka o potencijalnim neželjenim i štetnim efektima njihove kombinovane primene, posebno kod pacijenata obolelih od malignih bolesti sa značajno narušenim imunskim sistemom. Kineski tim ispituje efikasnost poboljašanja imunoterapije kombinacijom sa imunomodulatorima, pri čemu je njihovim prvim publikovanim rezultatima dokazano pozitivno dejstvo SFN kada se primenjuje sa CAR-T ćelijama (1), dok je zadatak srpskog tima da ispita toksikolški profile pojedinačne ili kombinovane primene SFN i PA-MSHA in silico, in vitro i in vivo na dva eksperimentalna modela – zebrica i pacova. Projekat će posebno ispitati potencijal za pojavu štetnih efekata pojedinačne i/ili kombinovane primene ispitivanih imunomodulatora ili pak izostanak efikasnosti terapije kod pacijenata sa rakom, posebno rakom debelog creva. Prvi in silico rezultati srpskog istraživačkog tima ukazuju da korist ili rizik primene SFN kod pacijenata sa rakom debelog creva zavisi od ekspresije pojedinih gena kod pacijenta i identifikuje setove gena čija promena može ukazati na pozitivan ili čak negativan efekat primene imunomodulatora (2).VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Dekodiranje molekulskog aspekta oštećenja oka prouzročenog ionizirajućim zračenjem pomoću rudarenja genomskih podataka

Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated with radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Some of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights into the adverse effects of radiation exposure.Izloženost ionizirajućem zračenju čak i pri niskim razinama može pridonijeti nastanku oštećenja oka. Međutim, osnovni molekulski mehanizmi i dalje nisu potpuno razjašnjeni. Cilj našega istraživanja bio je ispuniti tu nedostajuću kariku primjenom sveobuhvatnog in silico pristupa problemu. U tu svrhu, pomoću genomskih baza podataka, portala i poslužitelja (Comparative Toxicogenomics Database, ToppGene Suite portal, Cytoscape, GeneMANIA i Metascape), identificirano je šest ključnih regulacijskih gena koji su povezani s oštećenjem oka prouzročenog ionizirajućim zračenjem (ATM, CRYAB, SIRT1, TGFB1, TREX1 i YAP1) i koji su svi bili u fizičkoj interakciji. Neke od identificiranih molekulskih funkcija odnosile su se na mehanizme popravka oštećenja DNA, a druge su bile uključene u vezanje proteina, enzimsku aktivnost, metaboličke procese i posttranslacijske modifikacije proteina. Biološki procesi uglavnom su bili povezani s odgovorom na oštećenje DNA, pogotovo sa signalnim putem p53. Uočena je i značajna uloga nekoliko miRNA, poput hsa-miR-183 i hsa-miR-589, u mehanizmima povezanima s oštećenjem oka prouzročenog ionizirajućim zračenjem. Osim toga, u ovom je istraživanju opisana korisna metoda za ispitivanje štetnih učinaka izloženosti zračenju

Influence of nutrition and various substrates on spruce seedling growth

The results of the influence of main macronutrients (N, P, and K) on growth and development of spruce (Picea abies L. Karst) one-year old seedlings are presented. They were grown in containers, in nursery conditions, on four different substrates. There is a good influence on biogenous element contents, height, root collar diameter, needle length and mass, root mass as well as physiological vitality of spruce seedlings. It was observed that the effect of nutrition depends also on the type of substrate

Zašto je potrebna toksikološka procena rizika za kozmetički proizvod?

Bearing in mind that cosmetic products are applied throughout the lifetime and that they can contain potentially harmful and toxic substances, valid EU regulation in this area has set strict requirements regarding their safety. Manufacturers are required to provide a cosmetic product safety report containing a toxicological assessment made by experts. Toxicological assessment is based on existing in vivo toxicological data, and in particular in silico and in vitro, since EU regulations in the field of cosmetic products prohibit new animal studies. Although sporadic cases of serious poisoning after the application of cosmetic products have been recorded, adverse effects after normal and reasonably foreseeable use of cosmetic products are usually mild (allergic reactions and skin irritation) and completely reversible. EU regulations require mandatory reporting of serious adverse effects (functional incapacity, hospitalization, disability, etc.) in order to detect ingredients of cosmetic products that potentially endanger human health and prevent similar effects from recurred. The paper describes the procedure of toxicological risk assessment for cosmetic ingredients because the assessment of the safety of the cosmetic product is based on the assessment of the safety of its ingredients.Imajući u vidu da se kozmetički proizvodi primenjuju tokom celog života a da mogu sadržati potencijalno štetne i toksične supstance, važeća regulativa EU u ovoj oblasti (Uredba (EC) 1223/2009) postavila je stroge zahteve u pogledu njihove bezbednosti. Proizvođači su u obavezi da dostave izveštaj o bezbednosti koji sadrži toksikološku procenu koju rade osobe kvalifikovane za ovu vrstu poslova. Toksikološka procena se vrši na osnovu postojećih podataka in vivo toksikoloških ispitivanja, i posebno in silico i in vitro budući da EU regulativa u oblasti kozmetičkih proizvoda zabranjuje nova ispitivanja na životinjama. Iako se sporadično javljaju i ozbiljni slučajevi trovanja nakon primene kozmetičkih proizvoda, neželjeni efekti pri uobičajenoj i predvidivoj upotrebi kozmetičkog proizvoda su obično blagi (alergijske reakcije i iritacija kože) i potpuno reverzibilni. Regulativa EU zahteva obavezno prijavljivanje ozbiljnih neželjenih efekata (privremena sprečenost za rad, hospitalizacija, invaliditet itd.) u cilju otkrivanja sastojaka kozmetičkih proizvoda koji potencijalno ugrožavaju zdravlje ljudi i preduzimanja određenih mera kako bi se sprečilo da se slični efekti ponovo jave. U radu je opisana procedura toksikološke procene rizika za kozmetičke sastojke jer se procena bezbednosti kozmetičkog proizvoda zasniva na proceni bezbednosti njegovih sastojaka

Grading as factor of student motivation: theoretical principles and legal regulation

Predmet ovog istraživanja je motivacija učenika u školskom ocenjivanju sa stanovišta teorija motivacionih potreba i važećih zakonskih akata. Cilj rada je da se razmotri da li su učenici motivisani tokom školskog ocenjivanja. Motivaciju razmatramo u skladu sa teorijom samoodređenja (integrativna motivaciona teorija) čime se omogućava istraživanje uloge nastavnika. Metodom analize sadržaja istraženi su: a) Zakon o osnovama sistema obrazovanja i vaspitanja, Zakon o osnovnoj i srednjoj školi, Zakon o prosvetnoj inspekciji; b) pravilnici o ocenjivanju učenika u osnovnoj i srednjoj školi; c) pravilnici koji uređuju rad nastavnika i ustanova (Pravilnik o standardima kompetencija za profesiju nastavnika i njihovog profesionalnog razvoja, Pravilnik o stalnom stručnom usavršavanju i napredovanju u zvanja nastavnika, vaspitača i stručnih saradnika, Pravilnik o stručno-pedagoškom nadzoru, Pravilnik o standardima kvaliteta rada ustanova, Pravilnik o vrednovanju kvaliteta rada ustanova). Praćenje razvoja i postignućaučenika u toku školske godine ostvaruje se formativnim i sumativnim ocenjivanjem (Zakon o osnovama sistema obrazovanja i vaspitanja, Zakon o osnovnoj školi), a Zakon o srednjoj školi definiše formativno i sumativno ocenjivanje u srednjоškolskom obrazovanju. Pravilnici o ocenjivanju uređuju svrhu, principe, vrste, kriterijume, način i postupak ocenjivanja. Za razliku od osnovne škole, u srednjoj školi se ocenom, pored ostvarenosti ciljeva, ishoda i angažovanja učenika, izražava i napredovanje i preporuka za dalje napredovanje. Motivacija učenika u ocenjivanju pominje se u više standarda za nastavničku profesiju. Najširi okvir dat je u standardima kvaliteta rada ustanova, oblast Nastava i učenje, standard 2.4. Postupci vrednovanja su u funkciji daljeg učenja. Odnos motivacije učenika, ocenjivanja i učenja bi trebalo precizno regulisati podzakonskim aktima. Načelne kriterijume u oba pravilnika o ocenjivanju treba menjati uvođenjem razumljivih, konkretnih i obaveznih kriterijuma ocenjivanja. U standarde kompetencija za profesiju nastavnik trebalo bi uvesti indikator o motivaciji učenika tokom ocenjivanja i usaglasiti ostale pravilnike. Da motivacija učenika ne bi ostalalična strategija uspešnih nastavnika, potrebno je zakonski definisati balans između priznavanja angažovanja učenika i evaluacije znanja sa stanovišta naučne discipline.The subject of this research is analysis of student motivation in school grading from the standpoint of theories of motivational needs and legal acts. The aim of this paper is to consider whether the students are motivated in school grading. We appraise motivation in accordance with the theory of self-determination (integrative motivational theory), which enables appraising the role of teachers as well. The method of content analysis was used on: a) Law on the fundamentals of the education system, Laws on primary and secondary education, and the Law on Educational Inspection; b) rulebooks on student assessment in primary and secondary education; c) rulebooks governing the work of teachers and institutions (Rulebook on the standards of competencies for the profession of teacher and their professional development, Rulebook on continuous in-service training and advancement to titles of teachers, educators and professional associates, Rulebook on professional pedagogical supervision, Rulebook on quality standards of institutions, Rulebook on assessing the quality of work of educational institutions). Monitoring development and achievement of students during the school year is achieved by formative and summative assessment (Law on fundamentals of the education system, Law on Primary Education); the Law on Secondary Education defines formative and summative assessment in secondary education. Grading rulebooks regulate the purpose, principles, types, criteria, manner and procedure of grading. In secondary school, unlike the primary school, in addition to achievement of goals, the grade expresses outcomes and engagement of students, as well as the progress and recommendations for further progress. Student motivation in grading is mentioned in several standards for the profession of a teacher. The broadest framework is given in the standards regarding quality of work of educational institutions, section Teaching and Learning, standard 2.4. Evaluation procedures are in function of further learning. Relation between student motivation, grading and learning should be precisely regulated by by-laws. Basic criteria in both grading rulebooks should be changed by introducing understandable, concrete and mandatory grading criteria. The indicator of student motivation in grading should be included in the standards of teaching profession competencies, and the other rulebooks should conform. In order for the student motivation not to remain a personal strategy of successful teachers, it is necessary to legally define balance between the recognition of student engagement and evaluation of knowledge from the scientific discipline point of view.Knjiga rezimea, 25. Međunarodna naučna konferencija "Pedagoška istraživanja i školska praksa"Book of abstracts / 25th International Scientific Conference "Educational Research and School Practice

Making heritage more valuable and sustainable trough intersectoral networking

The subject of this paper is to show the importance of inter-sectoral and partnership activities, and added value of the heritage. The main goal is to emphasize the importance of the inter-departmental relations and forms of participatory governance that contribute to each pillar of sustainable development, in particular by activities related to the: preservation, conservation, restoration, greater visibility and valorization of the natural and cultural heritage. The work mainly rely on a qualitative analysis of previous empirical scientific research and practical examples of successful Worlds cases. We think that it is necessary to complement the operation of theory, practice and public policy papers, as well as international recommendations, to make all the relevant phenomena considered, so we will try to do that in relation to the subject and main goal of the paper. Paper reflects basic theory, examples and best practices in order to capture the importance of partnership strategies in participatory governance, with active participation in the decision-making process in order to make heritage more valuable. Our main hypothesis is: Long-term preservation of heritage seeks for necessary interdisciplinary approach, and the actual market visibility by linkages of diferent departments such as: culture, economy, CCI environment, society, through responsible forms of tourism (eco-cultural)

Oksidativni mehanizmi toksičnosti metala

Mechanisms of metal toxicity have not been fully understood. It was proven in the last decades that certain metals induce increased generation of free radicals, which react lipids, proteins and nucleic acids in the organism inducing tissue-damaging effects and cell death. Metals such as iron copper, chromium, etc. undergo redox cycling and directly catalyze production of free radicals, while mercury, nickel, lead and some others act indirectly by inhibition of antioxidative mechanisims. This paper presents basic understanding of free radicals, their influence on the organism and antioxidative system. Particular attention is given to oxidative mechanisms in which iron, copper, chromium, mercury and lead play role in generation of free radicals and oxidative stress, contrary to zinc which has a significant role in antioxidative cell protection.Mehanizmi toksičnosti metala su još uvek nedovoljno proučeni. Poslednjih decenija dokazano je da određeni metali indukuju i povećanu produkciju slobodnih radikala koji reaguju sa lipidima, proteinima i nukleinskim kiselinama organizma, što rezultira različitim oštećenjima, pa i smrću ćelija. Metali sa promenljivom valencom, kao što su gvožđe, bakar, hrom i dr. direktno katalizuju produkciju slobodnih radikala u reakcijama redoks-ciklusa, dok kadmijum, živa, nikl, olovo i neki drugi metali deluju indirektno tako što inhibiraju antioksidativne mehanizme organizma. U radu su izneta osnovna saznanja o slobodnim radikalima, njihovom dejstvu na organizam i antioksidativnom sistemu organizma. Posebno su obrađeni oksidativni mehanizmi kojima metali gvožđe, bakar, hrom, kadmijum, živa i olovo ostvaruju ulogu u nastanku slobodnih radikala i oksidativnog stresa za razliku od cinka koji ima značajnu ulogu u antioksidativnoj zaštiti ćelija

PFAS Molecules: A Major Concern for the Human Health and the Environment

Per- and polyfluoroalkyl substances (PFAS) are a group of over 4700 heterogeneous compounds with amphipathic properties and exceptional stability to chemical and thermal degradation. The unique properties of PFAS compounds has been exploited for almost 60 years and has largely contributed to their wide applicability over a vast range of industrial, professional and non-professional uses. However, increasing evidence indicate that these compounds represent also a serious concern for both wildlife and human health as a result of their ubiquitous distribution, their extreme persistence and their bioaccumulative potential. In light of the adverse effects that have been already documented in biota and human populations or that might occur in absence of prompt interventions, the competent authorities in matter of health and environment protection, the industries as well as scientists are cooperating to identify the most appropriate regulatory measures, substitution plans and remediation technologies to mitigate PFAS impacts. In this review, starting from PFAS chemistry, uses and environmental fate, we summarize the current knowledge on PFAS occurrence in different environmental media and their effects on living organisms, with a particular emphasis on humans. Also, we describe present and provisional legislative measures in the European Union framework strategy to regulate PFAS manufacture, import and use as well as some of the most promising treatment technologies designed to remediate PFAS contamination in different environmental compartments

Dekodiranje molekulskog aspekta oštećenja oka prouzročenog ionizirajućim zračenjem pomoću rudarenja genomskih podataka

Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated with radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Some of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights into the adverse effects of radiation exposure.Izloženost ionizirajućem zračenju čak i pri niskim razinama može pridonijeti nastanku oštećenja oka. Međutim, osnovni molekulski mehanizmi i dalje nisu potpuno razjašnjeni. Cilj našega istraživanja bio je ispuniti tu nedostajuću kariku primjenom sveobuhvatnog in silico pristupa problemu. U tu svrhu, pomoću genomskih baza podataka, portala i poslužitelja (Comparative Toxicogenomics Database, ToppGene Suite portal, Cytoscape, GeneMANIA i Metascape), identificirano je šest ključnih regulacijskih gena koji su povezani s oštećenjem oka prouzročenog ionizirajućim zračenjem (ATM, CRYAB, SIRT1, TGFB1, TREX1 i YAP1) i koji su svi bili u fizičkoj interakciji. Neke od identificiranih molekulskih funkcija odnosile su se na mehanizme popravka oštećenja DNA, a druge su bile uključene u vezanje proteina, enzimsku aktivnost, metaboličke procese i posttranslacijske modifikacije proteina. Biološki procesi uglavnom su bili povezani s odgovorom na oštećenje DNA, pogotovo sa signalnim putem p53. Uočena je i značajna uloga nekoliko miRNA, poput hsa-miR-183 i hsa-miR-589, u mehanizmima povezanima s oštećenjem oka prouzročenog ionizirajućim zračenjem. Osim toga, u ovom je istraživanju opisana korisna metoda za ispitivanje štetnih učinaka izloženosti zračenju

Dekodiranje molekulskog aspekta oštećenja oka prouzročenog ionizirajućim zračenjem pomoću rudarenja genomskih podataka

Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fullyunderstood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the ComparativeToxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associatedwith radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Someof the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymaticactivities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response toDNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insightsinto the adverse effects of radiation exposure.Izloženost ionizirajućem zračenju čak i pri niskim razinama može pridonijeti nastanku oštećenja oka. Međutim, osnovni molekulskimehanizmi i dalje nisu potpuno razjašnjeni. Cilj našega istraživanja bio je ispuniti tu nedostajuću kariku primjenom sveobuhvatnog in silicopristupa problemu. U tu svrhu, pomoću genomskih baza podataka, portala i poslužitelja (Comparative Toxicogenomics Database, ToppGeneSuite portal, Cytoscape, GeneMANIA i Metascape), identificirano je šest ključnih regulacijskih gena koji su povezani s oštećenjem okaprouzročenog ionizirajućim zračenjem (ATM, CRYAB, SIRT1, TGFB1, TREX1 i YAP1) i koji su svi bili u fizičkoj interakciji. Neke odidentificiranih molekulskih funkcija odnosile su se na mehanizme popravka oštećenja DNA, a druge su bile uključene u vezanje proteina,enzimsku aktivnost, metaboličke procese i posttranslacijske modifikacije proteina. Biološki procesi uglavnom su bili povezani s odgovoromna oštećenje DNA, pogotovo sa signalnim putem p53. Uočena je i značajna uloga nekoliko miRNA, poput hsa-miR-183 i hsa-miR-589,u mehanizmima povezanima s oštećenjem oka prouzročenog ionizirajućim zračenjem. Osim toga, u ovom je istraživanju opisana korisnametoda za ispitivanje štetnih učinaka izloženosti zračenju