Evaluation of the effect of genetic variants in genes TP53, XRCC1 and RAD51 and clinical factors on the efficacy and toxicity of platinum-based chemotherapy in patients with advanced non-small cell lung cancer

Uvod: Cilj ovog istraživanja je bio ispitati da li se određeni klinički i genetski faktori mogu koristiti kao minimalno invazivni prediktori prognoze i toksičnosti platinske hemioterapije kod pacijenata sa odmaklim adenokarcinomom pluća. Materijal i metode: U ovo istraživanje prospektivno-retrospektivnog karaktera uključen je 121 pacijent sa odmaklim adenokarcinomom pluća. Pacijenti su primali hemioterapiju platinskim dubletom u prvoj liniji do progresije bolesti ili maksimalno 6 ciklusa. Efikasnost terapije je procenjivana korišćenjem RECIST kriterijuma 1.1 a toksičnost pomoću CTCAE v.5.0. Genotipizacija gena XRCC1, RAD51 i TP53 je vršena primenom RT-PCR. Rezultati: Medijana vremena do progresije bolesti (PFS) je bila 5.6 meseci (95%CI 4.8 – 6.5), a medijana ukupnog preživljavanja (OS) 10.0 meseci (95%CI 8.1 – 12.0). Statistički značajno kraće preživljavanje je registrovano kod pacijenata lošeg performans statusa [ECOG PS2 vs. PS1 vs. PS0, 10.02 (9.28-10.76) vs. 5.55 (4.73-6.37) vs. 2.63 (3.91-4.31) meseci]. Nosioci Arg/Arg genotipa XRCC1 gena imali su statistički značajno duži PFS i OS. Nije dokazan uticaj ispitanih polimorfizama RAD51 i TP53 gena na dužinu PFS i OS. Nosioci 399Arg alela XRCC1 gena su bili statistički značajno podložniji razvoju neuropatije i anemije (Pearson χ2 test, p=0.025 i p=0.004 respektivno). Nosioci 135G alela gena RAD51 su statistički značajno manje podložni razvoju neuropatije. Mučnina i trombocitopenija, naročito visokog gradusa, su statistički značajno češće registrovani kod nosilaca 72Pro alela gena TP53 (p-0.037 i p=0.051 respektivno). Zaključak: Detektovana je statistički značajna povezanost polimorfizama Arg399Gln gena XRCC1, G135C gena RAD51 i Arg72Pro gena TP53 sa efikasnošću i specifičnim toksičnostima platinske hemioterapije kod pacijenata sa odmaklim adenokarcinomom pluća. Radi se o minimalno-invazivnim i finansijski isplativim prognostičkim i prediktivnim parametrima koji bi, kao takvi, mogli biti deo algoritama lečenja pacijenata sa odmaklim NSCLC.Introduction: This investigation was conducted in order to determine whether certain clinical and genetic factors can be used as minimally invasive predictors of efficacy and toxicity of platinum-based chemotherapy in patients with advanced lung adenocarcinoma. Materials and methods: A total of 121 advanced lung adenocarcinoma patients were enrolled in this prospective and retrospective investigation. All patients were treated with platinum- based chemotherapy doublet in first line until progression or up to 6 cycles. Response to treatment was evaluated using RECIST1.1 and toxicity graded according to CTCAE v.5.0. RT- PCR was used for XRCC1, TP53 and RAD51 genotyping. Results: Median progression-free survival (PFS) was 5.6 months (95%CI 4.8 – 6.5), and median overall survival (OS) 10.0 months (95%CI 8.1 – 12.0). Patients with poor ECOG PS had a statistically shorter OS [ECOG PS2 vs. PS1 vs. PS0, 10.02 (9.28-10.76) vs. 5.55 (4.73-6.37) vs. 2.63 (3.91-4.31) months]. XRCC1 Arg399Gln Arg/Arg carriers had a statistically longer PFS and OS, while there was no influence of the investigated polymorphisms of RAD51 and TP53 on PFS or OS. TP53 Arg72Pro Pro allele carriers were more prone to nausea (p=0.037) and thrombocytopenia (p=0.051), especially high-grade. Anemia and neuropathy occurred more frequently in XRCC1 Arg399Gln Arg allele carriers (Pearson χ2 test, p=0.025 and p=0.004 respectively). RAD51 G135C G allele carriers were statistically less prone to developing neuropathy. Conclusion: We detected a statistically significant association between gene polymorphisms Arg399Gln of XRCC1 gene, G135C of RAD51 gene and Arg72Pro gena TP53 and the efficacy and certain toxicities of platinum-based chemotherapy in advanced lung adenocarcinoma patients. These parameters might prove useful for the construction of population-specific, time- and cost-efficient prognostic and predictive algorithms in the treatment of advanced lung adenocarcinoma

Competencies for Creating an Integrated Approach in the Educational Process of Preschool Student Teachers

The preschool teacher is the main initiator of the dynamics and efficiency of the educational process. The children need to acquire more functional knowledge, which raises questions about the preschool teacher students’ competencIes. The paper emphasizes the necessity of raising awareness of preschool student teacherS about the importance of their role in enriching children’s experiences, and bringing scientific, musical and linguistic phenomena closer. This further implies modernization of university education by encouraging and raising students’ motivation to apply innovative approaches to work and the creation of specific competencies and skills. The competence of preschool student teachers in the realization of activities is not only reflected in building moral values and habits among children, but also in activating children’s potentials and encouraging creativity. The aim of the research was to examine the attitudes of preschool student teachers towards their competencies necessary for implementation of an integrated approach. The method of theoretical analysis and scaling techniques are used. The paper emphasizes the importance of extending specific professional competencies of preschool teacher students, as well as the importance of the continuous development of pedagogical knowledge for supporting holistic development of children, through monitoring, listening and supporting various children’s expression (sound and voice, dance, movement, narration, etc).Publishe

EDITORIAL

We would like to thank, first of all, authors of the articles published in this Issue of the Journal. At the same time, we feel grateful to all the referees for their valuable help in selecting the papers and improving their quality

Biocatalytic potential of Streptomyces spp. isolates from rhizosphere of plants and mycorrhizosphere of fungi

Biocatalytic potential of Streptomyces strains isolated from the rhizosphere of plants and from mycorrhizosphere of fungi has been investigated. A total of 118 Streptomyces isolates were selected and functionally screened for 10 different biotechnologically important enzymatic activities: hydrolase (cellulase, cutinase, gelatinase, lipase, protease, polyhydroxyalkanoate (PHA) depolymerase), phenol oxidase and peroxidase (laccase, tyrosinase, and lignin peroxidase), and aminotransferase. Out of 118 tested Streptomyces spp., 90% showed at least one enzymatic activity. The most abundant were enzymes involved in the biomass degradation, as the production of cutinase, cellulase, and lignin peroxidase were detected in 31%, 40%, and 48% of the isolates, respectively. The improved specific activities of lipase (isolates BV315 and BV100) and tyrosinase (isolates BV87 and BV88) were shown in comparison with the industrially relevant activities of Pseudomonas strains. Plant rhizosphere soils were more prolific source of Streptomyces strains with biocatalytic potential in comparison with mycorrhizosphere soils. Overall, 284 enzyme activities among 118 Streptomyces isolates have been detected. This is the first comprehensive screening of Streptomyces isolates from rhizosphere and mycorrhizosphere soils for novel biocatalysts, showing that specific environmental habitats, such as rhizosphere soils, are treasure troves of Streptomyces with biocatalytic potential.This is the peer reviewed version of the paper: Biocatalytic potential of Streptomyces spp. Isolates from rhizosphere of plants and mycorrhizosphere of fungi—Spasic—2018—Biotechnology and Applied Biochemistry—Wiley Online Library. (без датума). Преузето 08. Децембар 2022., од [https://iubmb.onlinelibrary.wiley.com/doi/10.1002/bab.1664

Importance of N-terminal proline for the promiscuous activity of 4-oxalocrotonate tautomerase (4-OT)

Michael addition of aldehydes to nitro-olefins is an effective method to obtain useful chiral gamma-nitroaldehydes. gamma-Nitroaldehydes are precursors for chiral gamma-aminobutyric acid analogues, which have numerous pharmacological activities and are used for the treatment of neurological disorders. A whole-cell system based on recombinantly expressed 4-oxalocrotonate tautomerase (4-OT) was developed and shown to be an effective biocatalyst for the Michael addition of branched aldehydes to beta-nitrostyrenes. The aim of this study was to investigate the influence of the substitution of the N-terminal proline with lysine and arginine, both containing a reactive epsilon-amino group, on the Michael addition catalyzed by 4-OT. First, the effects of these mutations were examined by in silico analysis, followed by the generation of three terminal lysine mutants. The generated mutants, 4-OT_K, 4-OT_PK and 4-OT_KK were tested for their ability to utilise beta-nitrostyrene (1), (E)-1-nitro-2-(2-thienyl)ethene (2) and trans-p-chloro-beta-nitrostyrene (3) as Michael acceptors with isobutanal (2-methylpropanal) as the donor. For comparison, the lithium salt of lysine was used in the same organocatalytic reactions. In general, the introduction of lysine had a negative effect on Michael additions based on overall product yields. However, additional lysine residues at the N-terminus of the protein resulted in structural changes that enhanced the activity towards 2 and 3. Therefore, the N-terminal proline is important for 4-OT-catalysed Michael-additions, but it is not essential

Effect of storage process on nutritive properties of preterm human milk

Freeze storage and pasteurization of human milk are common treatments in milk banks. Thermal treatment changes the quality of milk for preterm infants’ nutrition, and the aim of this paper was to examine the nutritional profile and antioxidant potential of preterm human milk after storage and pasteurization, and also after supplementation with fortifier. The effects of storage processes were estimated on mature preterm milk of 30 breastfeeding women. Total proteins, lipids and lactose were determined after thermal processing and supplementation of mature preterm milk with fortifier. The antioxidant capacity was determined using the ferric reducing antioxidant potential method and lipid peroxidation inhibition assay. Protein concentration decreased after frozen storage and pasteurization (p<0.05). Pasteurization further reduced the lipid concentration after freezing. The ferric reducing antioxidant potential decreased after thermal treatments (p<0.05). Supplementation of mature milk with fortifier increased the concentration of proteins, lipids and lactose. Our findings demonstrated that storage and pasteurization processes affect the basic nutritional composition and antioxidant capacity of preterm human milk. In order to ensure adequate nutrition for preterm infants with preterm human milk, supplementation, especially with high concentrations of proteins and lipids, is necessary after thermal treatments

Antičke staklene bočice za etarska ulja iz Viminacijuma I –VI V.N.E.

The archeological site Viminacium is located on the banks of the Danube near Požarevac, and represents a Roman camp and city founded in the 1st and lasted until the 7th century. It was the largest city of the Roman province of Upper Moesia. Of special significance are the discoveries from the Viminacium city, which had about 40 000 inhabitants. Glass bottles from the 1st century are few and represent the property of the first immigrants from the military and administrative apparatus. During the research of the necropolis in Viminacium, numerous glass vessels were discovered, and toilet bottles represent the most numerous and diverse group, with over eighteen types, different in size, shape of the abdomen and neck. They are made by free blowing and less often by blowing into a mold. The bottles mostly come from the graves of inhumed and cremated deceased, from the period from the end of the 1st to the beginning of the 4th century. The richness of the form, but also the simplicity of the style indicate the serial production that could have originated in Viminacium itself, while the more luxurious examples were part of the Celtic, Galician and Syrian production circles. Chemical analysis of glass bottles from Viminacium determined that the raw material for making glass mostly came from Egypt. The presence of numerous glass bottles for essential oils manifests the historical – political and economic situation, and indicates the degree of urbanization and involvement in ancient civilization.Arheološko nalazište Viminacijum nalazi se na obali Dunava u blizini Požarevca, i predstavlja rimski logor i grad nastao u I i trajao do VII veka. Bio je najveći grad rimske provincije Gornje Mezije. Poseban značaj imaju otkrića iz Viminacijuma grada koji je brojao oko 40 000 stanovnika. Staklene bočice pronađene iz perioda I veka su malobrojne i predstavljaju vlasništvo prvih doseljenika pripadnika vojnog i admistrativnog aparata. Kao recipijensi za držanje etarskih ulja, mirisa i kozmetičkih preparata korišćenih u svakodnevnom životu, ali i tokom pogrebnih rituala. Tokom istraživanja nekropola u Viminacijumu otkrivene su brojne posude od stakla, a toaletne boćice predstavljaju najbrojniju i najraznovrsniju grupu, sa preko osamnaest tipova, različitih prema dimenzijama, obliku trbuha i vrata. Izrađene su slobodnim duvanjem a ređe duvanjem u kalup. Bočice pretežno potiču iz grobova inhumiranih i kremiranih pokojnika, iz perioda od kraja I do početka IV veka, a manji broj iz žrtvenih slojeva nad grobovima. Bogatstvo formi ali i jednostavnost stila ukazuju na serijsku proizvodnju koja je mogla nastati i u samom Viminacijumu, dok su luksuzniji primerci bili deo kelnskog, galskog i sirijskog proizvodnog kruga. Hemijskim analizama staklenih bočica iz Viminacijuma utvrđeno je da je sirovina za izradu stakla uglavnom poticala iz Egipta. Zastupljenost brojnih staklenih bočica za etarska ulja, manifestuje istorijsko-političku i ekonomsku situaciju, i ukazuje na stepen urbanizacije, i uključenosti u antičku civilizaciju. Brojnost i raznovrsnost staklenih bočica otkrivenih na lokalitetu Viminacijum ukazuju na široku upotrebu etarskih ulja i kozmetičkih preparata na prostoru tog grada i njegove okoline.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Efficient Removal of Water Soluble Fraction of Diesel Oil by Biochar Sorption Supported by Microbiological Degradation

he contamination of the water bodies by diesel oil (DO) and its water-soluble fraction (WSF) represents one of the most challenging tasks in the management of polluted water streams. This paper contains data related to the synthesis and characteristics of the plum stone biochar material (PmS-B), which was made from waste plum stones (PmS), along with its possible application in the sorption of the WSF of DO from contaminated water. Techniques applied in sample characterisation and comparisons were: Elemental Organic Analysis (EOA), Scanning Electron Microscopy−Energy Dispersive X-ray Spectroscopy (SEM-EDX), Fourier Transform Infrared Spectroscopy (FTIR), pH (pHsus) and point of zero charge (pHpzc). In order to increase the overall efficiency of the removal process, sorption and bioremediation were subsequently combined. Firstly, PmS-B was used as a sorbent of WSF, and then the remaining solution was additionally treated with a specific consortium of microorganisms. After the first treatment phase, the initial concentration of diesel WSF was reduced by more than 90%, where most of the aromatic components of DO were removed by sorption. The sorption equilibrium results were best fitted by the Sips isotherm model, where the maximum sorption capacity was found to be 40.72 mg/g. The rest of the hydrocarbon components that remained in the solution were further subjected to the biodegradation process by a consortium of microorganisms. Microbial degradation lasted 19 days and reduced the total diesel WSF concentration to 0.46 mg/L. In order to confirm the non-toxicity of the water sample after this two-stage treatment, eco-toxicity tests based on a microbial biosensor (Aliivibrio fischeri) were applied, confirming the high efficiency of the proposed method

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

Objective: Therapeutic monoclonal antibodies in oncology are slowly becoming the dominant treatment option for many different cancer types. The main route of administration, infusion, requires extensive product preparations, patient hospitalization and close monitoring. Patient comfort improvement, staff workload reduction and cost savings dictated the development of subcutaneous formulations. The aim of this review is to present pharmacokinetic characteristics of subcutaneous products, discuss the differences between intravenous and subcutaneous routes and to point out the advantages as well as challenges of administration route shift from the formulation development and pharmacometric angle. Data sources: Food and Drug administration's Purple book database and electronic medicines compendium were used to identify monoclonal antibodies in oncology approved as subcutaneous forms. Using keywords subcutaneous, monoclonal antibodies, pharmacokinetics, model, as well as specific drugs previously identified, both PubMed and ScienceDirect databases were researched. Data summary: There are currently six approved subcutaneous onco-monoclonal antibodies on the market. For each of them, exposure to the drug was similar in relation to infusion, treatment effectiveness was the same, administration was well tolerated by the patients and costs of the medical service were reduced. Conclusion: Development of subcutaneous forms for existing and emerging new monoclonal antibodies for cancer treatment as well as shifting from administration via infusion should be encouraged due to patient preference, lower costs and overall lack of substantial differences in efficacy and safety between the two routes