Foreign direct investments in Serbia: what has been done so far and what can we expect

Strategic approach to foreign investments in Serbia has changed significantly at the beginning of XXI century. Before 2000 Serbia was a country that used high level of custom and non-custom barriers to protect its economy. During the period of nine transitional years Serbia shifted to completely liberal approach of an open market economy. A starting impulse to foreign investments in Serbia was given by the new approach to privatization process of state companies, which attracted over 3 billion euros of investments. Stable and transparent political model that was created made significant impact to an increase of foreign investments into the country and growth of foreign capital share in the market as a whole, with over € 13 billion of inflow. Since transition in Serbia in its full scale begun with ten years delay compared to other eastern and southeastern European countries, so was the first stage of the transition process completed with significant delay. For that reason it is important to understand in which way Serbia will approach second stage of transition, which is critical for sustainable development in the next period. Past experience of other countries should be used to understand what should and what should not be done in order to achieve so called “Virtual Circle of Foreign Investments”. Clear strategy and vision of Serbia in the future is required in order to attract not only those FDI which are seeking for fast turnover and use of natural resources, but rather those which are able to provide high level of added value and able to transfer technology and skills to economy as a whole

Assessment of prevalence and predictors of clinically significant drug-drug interactions and their impact on clinical outcomes in cardiovascular disease patients

Lek-lek interakcije (LLI) su čest uzrok pojave neželjenih ishoda terapije kroz izmenu u efikasnosti ili bezbednosti terapije, a koji se može prevenirati. Posledice LLI nisu dovoljno istražene zbog njihovog neprepoznavanja. Lekovi u terapiji bolesti kardiovaskularnog sistema imaju veliki potencijal za stupanje u LLI, zbog svojih farmakokinetičkih i/ili farmakodinamskih karakteristika. Cilj istraživanja bila je identifikacija potencijalnih i klinički značajnih LLI, procena prevalence, karakteristika i prediktora u populaciji pacijenata sa kardiovaskularnim bolestima, kao i njihov uticaj na ishode terapije. Podaci o pacijentima su prikupljeni retrospektivno iz medicinske dokumentacije. Za identifikaciju LLI korišćena je baza Lexi-Interact, dok je statistička obrada podataka izvršena u programu PASW Statistics. Određena je visoka prevalenca potencijalno relevantnih LLI u populaciji pacijenata sa kardiovaskularnim bolestima, kako u trenutku prijema pacijenata na odeljenje kardiologije (60,7%), tako i tokom bolničkog lečenja (83,9%). Identifikovane su vrste, mehanizam, nivo rizika i stepen ozbiljnosti potencijalnih i ispoljenih LLI, identifikovani su prediktori za njihovu pojavu, izdvojene su subpopulacije pacijenata sa većom prevalencom, i ispitano je prisustvo dodatnih faktora rizika koji povećavaju rizik od manifestacije LLI. Procenjena je primena Lexi-Interact baze kao alata za identifikaciju LLI i optimizaciju terapije izborom alternativnog leka, a razmotrene su i mogućnosti unapređenja alerta uključivanjem karakteristika pacijenata kao modifikatora rizika. Prevalenca klinički značajnih LLI koje su bile povezane sa pojavom neželjenih reakcija na lek u trenutku hospitalizacije pacijenta iznosila je 9,7%. Razvijen je skor koji predviđa verovatnoću budućeg neželjenog događaja usled prisustva kumulativnog rizika od većeg broja potencijalnih LLI. Identifikacija pacijenata sa većim rizikom od pojave neželjenog događaja može olakšati prepoznavanje LLI i unaprediti primenu elektronskih baza podataka u kliničkoj praksi.outcomes, through deteriorated efficacy and safety. The true extent of harm related to DDIs is not well established due to a lack of recognition. Cardiovascular disease (CVD) drugs are prone to interact in adverse way due to their pharmacokinetic/pharmacodynamic properties, and have been frequently implicated in adverse drug events. The study aimed to identify both potential and clinically significant DDIs, to assess their type, prevalence and predictors, and their impact on therapy outcomes. Data were retrospectively obtained from medical records. Lexi-Interact was used as the screening tool for DDIs, and statistics were performed using PASW. We found a high prevalence of potential DDIs in CVD patients: at the admission 60.7% and during hospital stay 83.9%. The study revealed the type, characteristics, risk rating and severity of DDIs; identified patients with higher exposure to DDIs, the predictors for their occurrence, as well as the presence of additional risk factors for DDIs manifestation. We assessed the utility of Lexi-Interact database in identifying potentially relevant DDIs, and the possibility of therapy optimization using an alternative drug. Our findings indicate the necessity of including the patients laboratory results or clinical data as DDIs risk modifier, to improve DDIs alert quality. DDI-related adverse drug reactions were found in 9.7% of patients at the admission. Given the high prevalence of CVD, DDI-related harm might be a significant burden worldwide. A prediction tool was developed to identify patients having high cumulative risk for the occurrence of an adverse event due to DDIs. Identification of high-risk patients might ease the recognition of DDI-related harm and improve the use of electronic databases in clinical practice

Деградација протеина индукована PROTAC молекулима као нова стратегија у развоју лекова

The traditional concept of drug discovery is based on the occupancydriven pharmacology model. It implies the development of inhibitors occupying binding sites that directly affect protein functions. Therefore, proteins that do not have such binding sites are generally considered as pharmacologically intractable. Furthermore, drugs that act in this way must be administered in dosage regimens that often result in high systemic drug exposures in order to maintain sufficient protein inhibition. Thus, there is a risk of the onset of off-target binding and side effects. The landscape of drug discovery has been markedly changed since proteolysis targeting chimera (PROTAC) molecules emerged twenty years ago as a part of the event-driven pharmacology model. These are bifunctional molecules that harness the ubiquitin-proteasome system, and are composed of a ligand that binds the protein of interest (POI), a ligand that recruits E3 ubiquitin ligase (E3UL) and a linker that connects these two parts. Pharmacologically, PROTACs bring POI and E3UL into close proximity, which triggers the formation of a functional ternary complex POI-PROTAC-E3UL. This event drives polyubiquitination and subsequent POI degradation by the 26S proteasome. The development and exceptional properties of PROTAC molecules that brought them to clinical studies will be discussed in this paper. © 2022 Serbian Chemical Society. All rights reserved.Традиционални концепт открића лекова базиран је на фармаколошком моделу заснованом на окупираности циљних протеина. То подразумева развој инхибитора који окупирају везујућа места директно повезана са функцијама протеина. Стога, протеини који немају таква везујућа места се генерално сматрају фармаколошки недодирљивим. Осим тога, лекови који делују на овакав начин морају се примењивати у режимима дозирања који често доводе до претеране системске изложености леку ради одржања довољне инхибиције протеина. Дакле, постоји ризик од појаве везивања лека ван свог примарног места дејства и нежељених ефеката. Окосница развоја лекова је значајно измењена откако су се појавили PROTAC (енг. proteolysis targeting chimera) молекули пре двадесет година као део фармаколошког модела заснованог на покретању догађаја који доводе до разградње циљних протеина. Ово су бифункционални молекули који користе убиквитин-протеазом систем, а састоје се од лиганда који се везује за протеин од инте- реса (POI), лиганда који регрутује Е3 убиквитин лигазу (E3UL) и линкера који повезује ова два дела. Фармаколошки, PROTAC молекули доводе POI и Е3UL у близину, што води формирању функционалног тернарног комплекса POI–PROTAC–Е3UL. Овај догађај води полиубиквитинацији и следственој деградацији POI 26S протеазомом. Развој и изу- зетна својства PROTAC молекула која су их довела до клиничких студија дискутовани су овом раду

SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation

Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM

Activation of the HSV-TK promoter in control reporter vector pBLCAT5 by liganded nuclear retinoid receptor RXRα

Vektorski sistemi koji sadrže reporterske gene su široko korišćeni za ispitivanje regulatornih DNK elemenata. Promotori patogenih virusa sisara najčešće se koriste kao bazalni promotori u ovim reporterskim sistemima. Opšte je prihvaćena pretpostavka da se pouzdani rezultati mogu dobiti samo pod uslovom da na aktivnost virusnog promotora ne utiču faktori koji deluju in trans ili bilo koji drugi primenjeni eksperimentalni tretmani. U ovom radu smo pokazali da ligandom indukovani nuklearni receptor RXRa aktivira HSV-TK promotor u kontrolnom reporterskom vektoru pBLCAT5. Na osnovu prikazanih rezultata može se zaključiti da vektorske sisteme koji imaju TK kao bazalni promotor treba koristiti samo posle detaljnog testiranja regulacije ekspresije ovog promotora. Pri tome je neophodno primeniti eksperimentalne uslove specifične za pojedina istraživanja da bi se izbegle pogrešne interpretacije rezultata.Widely used reporter vector systems for studying the putative regulatory DNA elements usually contain basal promoters from pathogenic mammalian viruses. It is a common assumption that reliable results can be achieved only if the viral promoter activity is unaffected by transacting factors or any experimental treatment. Here we report that liganded nuclear retinoid receptor RXRa stimulates the HSV-TK promoter in control reporter vector pBLCAT5. Thus, TK driven reporter vectors should be employed only after thorough testing of the regulation of this promoter under experimental stimuli for a particular research purpose in order to avoid unreliable interpretation of the assay results

Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression

The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array) we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene

Trans-activation of the human SOX3 promoter by MAZ in NT2/D1 cells

U ovom radu proučavana je uloga tri visoko konzervisana potencijalna mesta vezivanja za "Myc-associated zinc finger protein" (MAZ) u regulaciji ekspresije humanog SOX3 gena. Eseji izmenjene elektroforetske pokretljivosti u prisustvu antitela na MAZ ukazuju da kompleksi koji se formiraju na dva od tri proučavana mesta u okviru SOX3 promotora sadrže MAZ protein. Takođe, u eksperimentima kotransfekcije smo pokazali da MAZ ima ulogu pozitivnog regulatora transkripcije SOX3 gena, kako u nediferenciranim, tako i u diferenciranim NT2/D1 ćelijama. Iako je MAZ povećao i bazalnu i retinoičnom kiselinom indukovanu promotorsku aktivnost, naši rezultati ukazuju da ovaj transkripcioni faktor ne doprinosi inducibilnosti SOX3 promotora tokom neuralne diferencijacije u prisustvu retinoične kiseline.In this study, we examine the role of three highly conserved putative binding sites for Myc-associated zinc finger protein (MAZ) in regulation of the human SOX3 gene expression. Electrophoretic mobility shift and supershift assays indicate that complexes formed at two out of three MAZ sites of the human SOX3 promoter involve ubiquitously expressed MAZ protein. Furthermore, in cotransfection experiments we demonstrate that MAZ acts as a positive regulator of SOX3 gene transcription in both undifferentiated and RA-differentiated NT2/D1 cells. Although MAZ increased both basal and RA-induced promoter activity, our results suggest that MAZ does not contribute to RA inducibility of the SOX3 promoter during neuronal differentiation of NT2/D1 cells

Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression

The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array) we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene

Persistent strabismus after cataract extraction

Background. Transient ocular misalignment as a complication of parabulbar and peribulbar anesthesia has already been reported in the literature. The aim of our study was to present a case of irreversible iatrogenic vertical strabismus after cataract surgery, which had to be operated on. Methods. Clinical and orthoptic evaluation of a female patient with vertical diplopia after phacoemulsification cataract surgery. Results. One week after the uneventful surgery, a 68-year-old patient complained of a sudden vertical deviation in the operated eye. The patient had not had a history of previous motility disorders. On examination, the patient showed hypertropia in the left eye of 15−20 degrees in primary position. Three and 6 months postoperatively, there was no a spontaneous improvement, while the persistent vertical deviation was 40 prism dioptres. Strabismus surgery was required 1 year after the cataract surgery. Conclusion. Diplopia is a complication of peribulbar anesthesia which could be persistent. The superior and inferior rectus muscle are especially vulnerable. Its occurrence may be technique - related and the incidence increases when hyaluronidase is not available