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Host genetics, an important contributor to the COVID-19 clinical susceptibility and severity, currently is the focus of multiple genome-wide association studies (GWAS) in populations affected by the pandemic. This is the first study from Serbia that performed a GWAS of COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128 hospitalized COVID-19 patients from the Serbian population was enrolled in the study. We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients, using a genotyping array followed by imputation of missing genotypes. We have detected a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with a peak residing upstream of the gene KLHL1 (p = 1.91 x 10(-8)). Our study also replicated a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 x 10(-6)) and severe COVID-19 (p = 6.88 x 10(-7)), respectively. Suggestive association with COVID-19 pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6, MRPL36, p = 2.81 x 10(-6)), 5q11.2 (ESM1, p = 6.59 x 10(-6)), and 9p23 (TYRP1, LURAP1L, p = 8.69 x 10(-6)). The genes located in or near the risk loci are expressed in neural or lung tissues, and have been previously associated with respiratory diseases such as asthma and COVID-19 or reported as differentially expressed in COVID-19 gene expression profiling studies. Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which could contribute to a better understanding of the COVID-19 host genetics in different populations.

Cilj ovog master rada je razvoj objedinjene sinteze dva tipa tricikličnih terpena: cedrena i silfinena, preko zajedničkog bicikličniog intermedijera dobijenog intramolekulskom aldolnom kondenzacijom. Sintetički put divergira kod reakcije alkilovanja. Proizvod alkilovanja sa 4-brom-1-butenom nije dobijen. Alkilovanje sa strukturnim homolozima, alil-bromidom i 5-brom-1-pentenom, je dalo odgovarajuće proizvode. Iz alilovanog proizvoda, dobijen je silfinenski intermedijer.

Cilj ovog master rada je razvoj objedinjene sinteze dva tipa tricikličnih terpena: cedrena i silfinena, preko zajedničkog bicikličniog intermedijera dobijenog intramolekulskom aldolnom kondenzacijom. Sintetički put divergira kod reakcije alkilovanja. Proizvod alkilovanja sa 4-brom-1-butenom nije dobijen. Alkilovanje sa strukturnim homolozima, alil-bromidom i 5-brom-1-pentenom, je dalo odgovarajuće proizvode. Iz alilovanog proizvoda, dobijen je silfinenski intermedijer.

Background: COVID-19 pandemic has proved to be an unrelenting health threat for more than a year now. The emerging amount of data indicates that vitamin D, zinc and selenium could be important for clinical presentation of COVID-19. Here, we investigated association of genetic variants related to the altered level and bioavailability of vitamin D, zinc and selenium with clinical severity of COVID-19. Methods: We analyzed variants in genes significant for the status of vitamin D (DHCR7/NADSYN1 rs12785878, GC rs2282679, CYP2R1 rs10741657, and VDR rs2228570), zinc (PPCDC rs2120019) and selenium (DMGDH rs17823744) in 120 Serbian adult and pediatric COVID-19 patients using allelic discrimination. Furthermore, we carried out comparative population genetic analysis among European and other worldwide populations to investigate variation in allelic frequencies of selected variants. Results: Study showed that DHCR7/NADSYN rs12785878 and CYP2R1 rs10741657 variants were associated with severe COVID-19 in adults (p = 0.03, p = 0.017, respectively); carriers of DHCR7/NADSYN TG+GG and CYP2R1 GG genotypes had 0.21 and 5.9 the odds for developing severe disease, OR 0.21 (0.05-0.9) and OR 5.9 (1.4-25.2), respectively. There were no associations between selected genetic variants and disease severity in pediatric patients. Comparative population genetic analysis revealed that Serbian population had the lowest frequency of CYP2R1 rs10741657 G allele compared to other non-Finish Europeans (0.58 compared to 0.69 and 0.66 in Spanish and Italian population, respectively), suggesting that other populations should also investigate the relationship of CYP2R1 variant and the COVID-19 disease course. Conclusion: The results of the study indicated that vitamin D related genetic variants were implicated in severe COVID-19 in adults. This could direct prevention strategies based on population specific nutrigenetic profiles.

Cilj ovog master rada je razvoj objedinjene sinteze dva tipa tricikličnih terpena: cedrena i silfinena, preko zajedničkog bicikličniog intermedijera dobijenog intramolekulskom aldolnom kondenzacijom. Sintetički put divergira kod reakcije alkilovanja. Proizvod alkilovanja sa 4-brom-1-butenom nije dobijen. Alkilovanje sa strukturnim homolozima, alil-bromidom i 5-brom-1-pentenom, je dalo odgovarajuće proizvode. Iz alilovanog proizvoda, dobijen je silfinenski intermedijer.

Sarkoidoza je retka multisistemska granulomatozna bolest nepoznate etiologije. Karakteriše je stvaranje granuloma, koji se mogu javiti u bilo kom delu tela, a najčešće se javljaju u plućima i limfnim čvorovima. Pacijenti često pate od kašlja, nedostatka daha, bolova u grudima i izraženog umora i preti im rizik od razvoja fibroze pluća ili nepovratnog oštećenja drugih organa. Kod mnogih pacijenata bolest spontano prođe, često i bez kliničke dijagnoze, dok kod 10–30% slučajeva sarkoidoza postaje hronična i progresivna, i ponekad dovodi do smrti. Smrtnost je relativno mala, od 1-8%, zavisno od intenziteta bolesti, starosti pacijenta, pola i etničke pripadnosti. Prema brojnim studijama, vitamin D i sarkoidoza su u bliskoj vezi. Sarkoidoza se najčešće javlja u zimskim mesecima kada je nivo vitamina D nizak. Dalje, sarkoidoza je češća u oblastima koje su dalje od ekvatora. Nedostatak vitamina D i rizik od razvoja sarkoidoze je uobičajen kod tamno pigmentiranih pojedinaca i posebno je visok kod Afro-Amerikanaca koji žive na severnim geografskim širinama i koji imaju veću učestalost nedostatka vitamina D. Kod njih je sarkoidoza ozbiljna multisistemska bolest sa hroničnim tokom. Uloga molekularnih markera u deficijenciji vitamina D, odnosno varijanti u genima koji kodiraju za proteine uključene u metabolizam vitamina D, je nedovoljno istražena u etiologiji sarkoidoze. Smatra se da brojni proteini, među kojima su CYP2R1, DBP, CYP27B1 i VDR imaju ulogu u metabolizmu i signalnim putevima vitamina D. Naime, nakon primarne aktivacije vitmina D u koži, pro- vitamin podleže dvostrukoj hidroksilaciji. Prava se odigrava u jetri posredstvom enzima CYP2R1, a druga u bubrezima, posredstvom CYP27B1 enzima. Vitamin D-vezujući protein (DBP) je glavni nosač vitamina D, koji vezuje metabolite vitamina D i transportuje ih kroz cirkulaciju do ćelija. Receptor za vitamin D (VDR) pripada familiji nuklearnih receptora i nakon vezivanja liganda – aktivne forme vitamina D, stvara heterodimer sa ret, Sarcoidosis is a rare multisystem granulomatous disease of unknown etiology. It is characterized by the formation of granulomas, which can occur in any part of the body, most commonly occurring in the lungs and lymph nodes. Patients often suffer from coughing, shortness of breath, chest pain, and severe fatigue and are at risk of developing lung fibrosis or irreversible damage to other organs. In many patients, the disease resolves spontaneously, often without clinical diagnosis, while in 10-30% of cases, sarcoidosis becomes chronic and progressive, sometimes leading to death. Mortality is relatively low, from 1-8%, depending on the intensity of the disease, the patient’s age, gender and ethnicity. According to numerous studies, vitamin D and sarcoidosis are in close relationship. Sarcoidosis most commonly occurs in the winter months when vitamin D levels are low. Further, sarcoidosis is more common in areas beyond the equator. Vitamin D deficiency and the risk of sarcoidosis are common in dark pigmented individuals and are particularly high in African Americans living in northern latitudes and with a higher incidence of vitamin D. For those individuals sarcoidosis is a serious multisystemic disease with a chronic course. The role of molecular markers in vitamin D deficiency, that is, variants in genes encoding for proteins involved in vitamin D metabolism, has not been sufficiently investigated in the etiology of sarcoidosis. A number of proteins, including CYP2R1, DBP, CYP27B1, and VDR, are thought to play a role in the metabolism and signaling pathways of vitamin D. Namely, after primary activation of vitamin D in the skin, pro-vitamin D undergoes double hydroxylation. The first one is taking place in the liver by the CYP2R1 enzyme and the other one is in the kidney by the CYP27B1 enzyme. Vitamin D-binding protein (DBP) is a major carrier of vitamin D, which binds all vitamin D metabolites and transports them through the circulation to the cells. The vitamin D re

Uvod/Cilj. Upitnik za procenu hronične opstruktivne bolesti pluća (HOBP) (engl. COPD Assessment Test - CAT) je jednostavan i pouzdan test namenjen za merenje ukupnog zdravstvenog stanja bolesnika sa HOBP i koristan je za upotrebu u svakodnevnoj kliničkoj praksi. Cilj ovog istraživanja bio je da se proceni validnost i opravdanost primene srpske verzije CAT. Metode. U studiji je učestvovalo 140 bolesnika u stabilnom stanju HOBP, ispitivanih u ambulantnim uslovima na Klinici za pulmologiju, Kliničkog centra Srbije u Beogradu i Institutu za plućne bolesti Vojvodine u Sremskoj Kamenici. Tokom prvog pregleda bolesnicima je učinjeno ispitivanje plućne funkcije (spirometrija), popunili su CAT upitnik i mMMR (modified Medical Research Council) skalu za procenu stepena dispneje. Pouzdanost CAT test-retesta je ispitivana kod 20 bolesnika od strane istog istraživača. Rezultati. Pokazali smo da srpska verzija CAT ima visoku internu konzistentnost sa Cronbach-ovim alfa 0.88. Test-retest analiza pokazala je dobru korelaciju između CAT rezultata u dve vremenske tačke (Spearmanov r = 0,681; p < 0,01). CAT je umereno korelirao sa mMRC skalom (r = + 0,57), blago sa forsiranim ekspiratornim volumenom u prvoj sekundi (FEV1), (r -0,214), uz pozitivnu korelaciju sa ukupnim brojem pogoršanja HOBP, ali bez jasne regularnosti sa promenom GOLD (Global Initiative for Chronic Obstructive Lung Disease) stadijuma. Zaključak. Srpska verzija CAT je pokazala visoku internu konzistentnost i test-retest pouzdanost. Ona predstavlja pouzdano, jednostavno i lako sredstvo za upotrebu koje se može koristiti u svakodnevnoj kliničkoj praksi za procenu zdravstvenog stanja kod bolesnika sa HOBP u Srbiji., Background/Aim. The Chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a simple and reliable tool designed to measure overall COPD related health status and complement physician assessment in rou-tine clinical practice. Objective of this study was to evaluate the validity of the Serbian version of CAT. Methods. Study included 140 outpatients in the stable COPD, recruited from two centres: Clinic for Pulmonology, Clinical Center of Serbia, Belgrade, and Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica. All patients completed pulmonary function testing – spirometry, the CAT and the modified Medical Research Council (mMRC) dyspnea scale at baseline visit. The CAT test-retest reliability was tested in 20 patients by the same investigator (physician). Results.We demonstrated that Serbian version of CAT had high internal consistency with Cronbach’s alpha 0.88. Test-retest analysis showed good correlation between CAT scores in two time points (Spearman’s ρ = 0.681, p < 0.01). In our study the CAT correlated moderately to mMRC scale (ρ = +0.57), weakly to FEV1 (ρ -0.214), was positively related to number of exacerbations, but did not showed exact regularity with change in the Global Initiative for Chronic Obstructive lung disease (GOLD) stage. Conclusion.The Serbian version of CAT is a reliable, simple and easy-to-use tool that can be used in everyday clinical practice to assess the health status of COPD patients in Serbia.

Introduction: Tuberculosis (TBC) is a contagious chronic respiratory disease which despite the known cause, Mycobacterium tuberculosis (Mtb), and many decades of successful therapy, remains one of the leading global health problems. Immune responses against Mtb infection involve both of types of immunity, but cellular immunity, in which certain cytokines and Th1 cells play a key role, is crucial. A better understanding of the functions of the cytokine network involved in the state and progression of TBC could identify specific molecular markers for monitoring of disease activity as well as therapy outcomes in TBC patients. Methodology: We investigated expression of TNF-alpha, IL-6 and IRAK1 genes using an RT-qPCR technique in peripheral blood mononuclear cells of 33 TBC patients and 10 healthy individuals. Results: Comparison between TBC patients and healthy individuals revealed statistically significant differences for all analyzed genes. The levels of expression of TNF-alpha and IL-6 mRNA were higher, while the level of IRAK1 mRNA was lower in the TBC group compared to controls. Moreover, a strong positive correlation was observed between TNF-alpha and IL-6 gene expression. When clinical parameters were analyzed, increased levels of TNF-alpha mRNA were detected in patients with a longer duration of therapy ( gt 2 months) compared to those with a shorter therapy duration ( lt 2 months), and in patients without anemia. Conclusions: Our results indicate that the inflammatory genes we examined play a crucial role in the pathogenesis of tuberculosis, and that the expression of the TNF-alpha gene could be a marker for monitoring the clinical effect of the ant-tuberculosis drugs during therapy.

Introduction: Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients. Material and methods: For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method. Results: Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients. Conclusions: These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis.

Background: Until now, a proper biomarker(s) to evaluate sarcoidosis activity has not been recognized. The aims of this study were to evaluate the sensitivity and specificity of the two biomarkers of sarcoidosis activity already in use (serum angiotensin converting enzyme - ACE and serum chitotriosidase) in a population of 430 sarcoidosis patients. The activities of these markers were also analyzed in a group of 264 healthy controls. Methods: Four hundred and thirty biopsy positive sarcoidosis patients were divided into groups with active and inactive disease, and groups with acute or chronic disease. In a subgroup of 55 sarcoidosis patients, activity was also assessed by F-18 fluorodeoxyglucose positron emission tomography (F-18-FDG-PET) scanning. Both serum chitotriosidase and ACE levels showed non-normal distribution, so nonparametric tests were used in statistical analysis. Results: Serum chitotriosidase activities were almost 6 times higher in patients with active sarcoidosis than in healthy controls and inactive disease. A serum chitotriosidase value of 100 nmol/mL/h had the sensitivity of 82.5% and specificity of 70.0%. A serum ACE activity cutoff value of 32.0 U/L had the sensitivity of 66.0% and the specificity of 54%. A statistically significant correlation was obtained between the focal granulomatous activity detected on F-18-FDG PET/CT and serum chitotriosidase levels, but no such correlation was found with ACE. The levels of serum chitotriosidase activity significantly correlated with the disease duration (P lt 0.0001). Also, serum chitotriosidase significantly correlated with clinical outcome status (COS) categories (rho=0.272, P=0.001). Conclusions: Serum chitotriosidase proved to be a reliable biomarker of sarcoidosis activity and disease chronicity.

Post-projektnu analizu čine sve aktivnosti čiji je cilj sagledavanje parametara kako je objekat izveden, uključujući i to u kojoj meri on ispunjava projektovane zahteve, kao i to u kom stepenu su sami korisnici zadovoljni “gotovim proizvodom”. Preduzeća koja podjednaku važnost pripisuju post-projektnoj analizi kao i samoj realizaciji projekta ne ponavljaju greške! U toku realizacije projekta “Rekonstrukcije i modernizacije deonice Gilje-Ćuprija-Paraćin, pruga Beograd-Niš”, započeta je izrada post-projektne analize. Način izrade i zaključci su prikazani u radu.

Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a rare autosomal dominant disorder characterized by numerous basal cell carcinomas, keratocystic odontogenic tumors of the jaws, and diverse developmental defects. This disorder is associated with mutations in tumor suppressor gene Patched 1 (PTCH1). We present two patients with Gorlin syndrome, one sporadic and one familial. Clinical examination, radiological and CT imaging, and mutation screening of PTCH1 gene were performed. Family members, as well as eleven healthy controls were included in the study. Both patients fulfilled the specific criteria for diagnosis of Gorlin syndrome. Molecular analysis of the first patient showed a novel frameshift mutation in exon 6 of PTCH1gene (c.903delT). Additionally, a somatic frameshift mutation in exon 21 (c.3524delT) along with germline mutation in exon 6 was detected in tumor-derived tissue sample of this patient. Analysis of the second patient, as well as two affected family members, revealed a novel nonsense germline mutation in exon 8 (c.1148 C gt A).

Tuberculosis (TB) is granulomatous diseases caused by Mycobacterium tuberculosis (MTB). TB is a highly infectious disease that primarily affects the lungs. One-third of human population is infected with MTB, therefore it is of utmost significance to determine the factors that influence the individual susceptibility to the disease. Host genetic factors have been recognized as essential for susceptibility to TB, since only 5% to 10% of infected individuals develop the disease. A number of candidate genes has been intensively studied, the most of which were connected with the function of macrophages, thus participating in immune response. Here we examined the gene variants of VDR (FokI) and NRAMP1 (INT4, D543N, 3'UTR) genes in aim to make the correlation between these genetic factors and risk of TB in Serbian patients. This study included 110 TB patients and 67 healthy controls. Pulmonary TB was diagnosed by clinical symptoms, radiological evidence of TB and bacteriological criteria (Culture-positive/smear-positive). Genotyping was performed using PCR-RFLP method. Our findings revealed significant prevalence of ff genotype and variant allele f of the FokI VDR gene variant in patients compared to control group. Based on the our results the carriers of ff genotype are five times more at risk to tuberculosis than carriers of FF and Ff genotype in our population. The results of analyzed SNPs in NRAMP1 gene showed no statistically significant difference in distribution of the gene variants between patient and control groups. Therefore, we could conclude that the genotype ff of the VDR gene is factor that strongly contribute to susceptibility to TB in Serbian population.