Acinetobacter baumannii (AB) is an opportunistic pathogen with growing clinical relevance due to its increasing level of antimicrobial resistance in the last few decades. In the event of an AB hospital outbreak, fast detection and localization of the pathogen is crucial, to prevent its further spread. However, contemporary diagnostic tools do not always meet the requirements for rapid and accurate diagnosis. For this reason, we report here the possibility of using gallium-68 labeled siderophores, bacterial iron chelators, for positron emission tomography imaging of AB infections. In our study, we radiolabeled several siderophores and tested their in vitro uptake in AB cultures. Based on the results and the in vitro properties of studied siderophores, we selected two of them for further in vivo testing in infectious models. Both selected siderophores, ferrioxamine E and ferrirubin, showed promising in vitro characteristics. In vivo, we observed rapid pharmacokinetics and no excessive accumulation in organs other than the excretory organs in normal mice. We demonstrated that the radiolabeled siderophores accumulate in AB-infected tissue in three animal models: a murine model of myositis, a murine model of dorsal wound infection and a rat model of pneumonia. These results suggest that both siderophores radiolabeled with Ga-68 could be used for PET imaging of AB infection.

• MeSH
• Acinetobacter baumannii * MeSH
• infekce bakteriemi rodu Acinetobacter * diagnostické zobrazování   mikrobiologie   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• pozitronová emisní tomografie * metody   MeSH
• radioizotopy galia * chemie   MeSH
• siderofory * chemie   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Advanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are characterized by low immunogenicity. This study investigates bis-diethyldithiocarbamate (CuET), a novel anticancer compound, and its impact on the colorectal cancer tumor microenvironment (TME). CuET is shown to convert immunologically inactive tumors into hotbeds of antitumor immune responses, marked by increased lymphocyte infiltration, heightened cytotoxicity of natural killer (NK) and T cells, and enhanced non-self recognition by lymphocytes. The potent anticancer cytotoxicity and in vivo safety and efficacy of CuET are established. In summary, CuET transforms the colorectal cancer TME, bolstering NK and T cell cytotoxicity and refining tumor cell recognition through non-classical activation via the NKG2D/NKG2DL axis. This study unveils a novel mechanism of action for CuET: a potent immunomodulator capable of turning cold tumors hot.

• MeSH
• buňky NK imunologie   účinky léků   metabolismus   MeSH
• dithiokarb * farmakologie   MeSH
• kolorektální nádory * farmakoterapie   imunologie   metabolismus   patologie   MeSH
• lektinové receptory NK-buněk - podrodina K * metabolismus   MeSH
• lidé MeSH
• měď MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí * účinky léků   imunologie   MeSH
• protinádorové látky farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Peptides that form transmembrane barrel-stave pores are potential alternative therapeutics for bacterial infections and cancer. However, their optimization for clinical translation is hampered by a lack of sequence-function understanding. Recently, we have de novo designed the first synthetic barrel-stave pore-forming antimicrobial peptide with an identified function of all residues. Here, we systematically mutate the peptide to improve pore-forming ability in anticipation of enhanced activity. Using computer simulations, supported by liposome leakage and atomic force microscopy experiments, we find that pore-forming ability, while critical, is not the limiting factor for improving activity in the submicromolar range. Affinity for bacterial and cancer cell membranes needs to be optimized simultaneously. Optimized peptides more effectively killed antibiotic-resistant ESKAPEE bacteria at submicromolar concentrations, showing low cytotoxicity to human cells and skin model. Peptides showed systemic anti-infective activity in a preclinical mouse model of Acinetobacter baumannii infection. We also demonstrate peptide optimization for pH-dependent antimicrobial and anticancer activity.

• MeSH
• Acinetobacter baumannii účinky léků   MeSH
• antibakteriální látky farmakologie   chemie   chemická syntéza   MeSH
• antimikrobiální peptidy chemie   farmakologie   chemická syntéza   MeSH
• kationické antimikrobiální peptidy farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• racionální návrh léčiv * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Siderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two cis-trans isomeric siderophores of the ferrichrome type. RESULTS: Tested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [68Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [68Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [68Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by S. aureus, K. pneumoniae and P. aeruginosa with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [68Ga]Ga-FR, whereas [68Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [68Ga]Ga-FR and [68Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of S. aureus myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection. CONCLUSIONS: The 68Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [68Ga]Ga-complexes accumulate at the site of S. aureus infection, highlighting the potential of [68Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [68Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.

• Publikační typ
• časopisecké články MeSH

Bacteria from the Burkholderia cepacia complex are generally considered to be non-pathogenic to the healthy population. However, some of these species may cause serious nosocomial infections in immunocompromised patients; as such, it is essential to diagnose these infections rapidly so that adequate treatment can be initiated. We report here the use of a radiolabeled siderophore, ornibactin (ORNB), for positron emission tomography imaging. We successfully radiolabeled ORNB with gallium-68 with high radiochemical purity and proved that the resulting complex has optimal in vitro characteristics. In mice, the complex did not show excessive accumulation in organs and was excreted in the urine. We demonstrated that the [68Ga]Ga-ORNB complex accumulates at the site of Burkholderia multivorans infection, including pneumonia, in two animal infection models. These results suggest that [68Ga]Ga-ORNB is a promising tool for the diagnosis, monitoring, and evaluation of the therapeutic response to B. cepacia complex infection.

• MeSH
• Burkholderia cepacia komplex * MeSH
• infekce bakteriemi rodu Burkholderia * diagnostické zobrazování   epidemiologie   MeSH
• myši MeSH
• pozitronová emisní tomografie MeSH
• radioizotopy galia MeSH
• siderofory MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cieľom štúdie bolo zmapovať postoje voči nanotechnológiám. Zaujímalo nás, ako jednotlivé faktory zasahujú do formovania postojov, pričom sme sa zamerali na vplyv miery informovanosti a dôvery voči informáciám zo strany odborníkov. Skúmali sme, aké sú rozdiely vo vnímaní rizík a benefitov nanotechnológií medzi pohlaviami, a akú rolu zohráva religiozita. Dáta sme zbierali prostredníctvom dotazníka a fókusových skupín. Kvantitatívnej časti výskumu sa zúčastnilo 189 participantov a kvalitatívnej časti za zúčastnilo 18 participantov. Výsledky výskumu potvrdili súvis medzi dôverou voči informáciám zo strany odborníkov a postojmi voči nanotechnológiám, ako aj súvis medzi mierou informovanosti a postojmi voči aplikáciám nanotechnológií v medicíne. Participanti vnímali medicínu ako oblasť, v ktorej môžu nanotechnológie priniesť najväčšie pokroky, zatiaľ č o za oblasť s najväčším poč tom rizík považovali oblasť obrany a národnej bezpečnosti.

The aim of the study was to map attitudes towards nanotechnology. We were interested in how different factors interfere in shaping attitudes, focusing on the impact of the level of awareness and trust in information by experts. We explored gender differences in perceptions of the risks and benefits of nanotechnology, and the role played by religiosity. We collected data through a questionnaire and focus groups. 189 participants took part in the quantitative part of the research and 18 participants took part in the qualitative part. The results of the research confirmed the association between trust towards information from experts and attitudes towards nanotechnology, as well as the association between the level of information and attitudes towards nanotechnology applications in medicine. Participants perceived medicine as the area in which nanotechnology could bring the greatest advances, while they considered defence and national security as the areas with the greatest number of risks.

• MeSH
• důvěra psychologie   MeSH
• hodnocení rizik MeSH
• informace pro uživatele zdravotní péče MeSH
• lidé MeSH
• nanomedicína MeSH
• nanotechnologie * MeSH
• postoj ke zdraví MeSH
• zjišťování skupinových postojů MeSH
• zpráva o sobě MeSH
• Check Tag
• lidé MeSH

PURPOSE: With the increase of especially hospital-acquired infections, timely and accurate diagnosis of bacterial infections is crucial for effective patient care. Molecular imaging has the potential for specific and sensitive detection of infections. Siderophores are iron-specific chelators recognized by specific bacterial transporters, representing one of few fundamental differences between bacterial and mammalian cells. Replacing iron by gallium-68 without loss of bioactivity is possible allowing molecular imaging by positron emission tomography (PET). Here, we report on the preclinical evaluation of the clinically used siderophore, desferrioxamine-B (Desferal®, DFO-B), radiolabelled with 68Ga for imaging of bacterial infections. METHODS: In vitro characterization of [68Ga]Ga-DFO-B included partition coefficient, protein binding and stability determination. Specific uptake of [68Ga]Ga-DFO-B was tested in vitro in different microbial cultures. In vivo biodistribution was studied in healthy mice and dosimetric estimation for human setting performed. PET/CT imaging was carried out in animal infection models, representing the most common pathogens. RESULTS: DFO-B was labelled with 68Ga with high radiochemical purity and displayed hydrophilic properties, low protein binding and high stability in human serum and PBS. The high in vitro uptake of [68Ga]Ga-DFO-B in selected strains of Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus agalactiae could be blocked with an excess of iron-DFO-B. [68Ga]Ga-DFO-B showed rapid renal excretion and minimal retention in blood and other organs in healthy mice. Estimated human absorbed dose was 0.02 mSv/MBq. PET/CT images of animal infection models displayed high and specific accumulation of [68Ga]Ga-DFO-B in both P. aeruginosa and S. aureus infections with excellent image contrast. No uptake was found in sterile inflammation, heat-inactivated P. aeruginosa or S. aureus and Escherichia coli lacking DFO-B transporters. CONCLUSION: DFO-B can be easily radiolabelled with 68Ga and displayed suitable in vitro characteristics and excellent pharmacokinetics in mice. The high and specific uptake of [68Ga]Ga-DFO-B by P. aeruginosa and S. aureus was confirmed both in vitro and in vivo, proving the potential of [68Ga]Ga-DFO-B for specific imaging of bacterial infections. As DFO-B is used in clinic for many years and the estimated radiation dose is lower than for other 68Ga-labelled radiopharmaceuticals, we believe that [68Ga]Ga-DFO-B has a great potential for clinical translation.

• MeSH
• deferoxamin * MeSH
• myši MeSH
• PET/CT MeSH
• počítačová rentgenová tomografie MeSH
• pozitronová emisní tomografie MeSH
• radioizotopy galia * MeSH
• Staphylococcus aureus MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Perceived threats from out-groups play a significant role in negative intergroup relations. The aim of our study was to explore what types of threats young Slovaks feel from three out-groups: immigrants from African and Arab countries, the Roma, and Slovak Hungarians. By conducting six focus groups (N = 42) with university students (M = 22), we identified several concerns about these out-groups. We found out that they can be categorized into four threat types in line with Stephan et al. (2009): (1) symbolic group threats, (2) symbolic individual threats, (3) realistic group threats, and (4) realistic individual threats. However, we identified threats which have not been identified in previous threat literature, e. g. language barrier, sexual harassment, and annoyance, or were not researched as threat, e. g. theft, abuse of social system, and lack of trust. Therefore, we aim to develop a new measure which allows researchers to focus on a broader scale of perceived threats in prejudice reduction. As we have explored different concerns posed by different out-groups, we argue that in prejudice reduction it is important to focus on those threats that are felt by the majority from a particular out- group, and not to perceive intergroup threat as one general factor.

• Klíčová slova
• university students,
• MeSH
• Arabové MeSH
• dospělí psychologie   MeSH
• emigranti a imigranti MeSH
• etnické a rasové minority MeSH
• etnické násilí * psychologie   MeSH
• lidé MeSH
• mladý dospělý psychologie   MeSH
• postoj MeSH
• rasismus psychologie   MeSH
• Romové MeSH
• rozhovory jako téma MeSH
• skupinové procesy MeSH
• studenti psychologie   MeSH
• Check Tag
• dospělí psychologie   MeSH
• lidé MeSH
• mladý dospělý psychologie   MeSH
• Geografické názvy
• Slovenská republika MeSH

Nanoparticles (NPs) represent an emerging platform for diagnosis and treatment of various diseases such as cancer, where they can take advantage of enhanced permeability and retention (EPR) effect for solid tumor accumulation. To improve their colloidal stability, prolong their blood circulation time and avoid premature entrapment into reticuloendothelial system, coating with hydrophilic biocompatible polymers is often essential. Most studies, however, employ just one type of coating polymer. The main purpose of this study is to head-to-head compare biological behavior of three leading polymers commonly used as "stealth" coating materials for biocompatibilization of NPs poly(ethylene oxide), poly(2-ethyl-2-oxazoline) and poly[N-(2-hydroxypropyl)methacrylamide] in an in vivo animal solid tumor model. We used radiolabeled biodegradable hydroxyapatite NPs as a model nanoparticle core within this study and we anchored the polymers to the NPs core by hydroxybisphosphonate end groups. The general suitability of polymers for coating of NPs intended for solid tumor accumulation is that poly(2-ethyl-2-oxazoline) and poly(ethylene oxide) gave comparably similar very good results, while poly[N-(2-hydroxypropyl)methacrylamide] was significantly worse. We did not observe a strong effect of molecular weight of the coating polymers on tumor and organ accumulation, blood circulation time, biodistribution and biodegradation of the NPs.

• Publikační typ
• časopisecké články MeSH

In this study, we have compared four 68Ga-labeled peptides (three Arg-Gly-Asp (RGD) peptides and substance-P) with two 18F-tracers clinically approved for tumor imaging. We have studied in vitro and in vivo characteristics of selected radiolabeled tracers in a glioblastoma multiforme tumor model. The in vitro part of the study was mainly focused on the evaluation of radiotracers stability under various conditions. We have also determined in vivo stability of studied 68Ga-radiotracers by analysis of murine urine collected at various time points after injection. The in vivo behavior of tested 68Ga-peptides was evaluated through ex vivo biodistribution studies and PET/CT imaging. The obtained data were compared with clinically used 18F-tracers. 68Ga-RGD peptides showed better imaging properties compared to 18F-tracers, i.e., higher tumor/background ratios and no accumulation in non-target organs except for excretory organs.

• MeSH
• glioblastom diagnostické zobrazování   metabolismus   MeSH
• lidé MeSH
• myši SCID MeSH
• nádorové buněčné linie MeSH
• nádory mozku diagnostické zobrazování   metabolismus   MeSH
• oligopeptidy chemie   MeSH
• PET/CT MeSH
• počítačová rentgenová tomografie MeSH
• pozitronová emisní tomografie metody   MeSH
• radiofarmaka chemie   MeSH
• radioizotopy fluoru MeSH
• radioizotopy galia chemie   MeSH
• tkáňová distribuce MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH