Reforma Vijeća sigurnosti Kokotović, Filip; Mikulandra, Iva
Međunarodne studije,
09/2015, Letnik:
XV, Številka:
1
Journal Article
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Izvršena je analiza reforme organizacije Ujedinjenih naroda, a posebice reforme Vijeća sigurnosti. Reforma Vijeća sigurnosti poistovjećuje se isključivo s njegovim proširenjem, pri čemu se ne ...razmatraju alternativne metode razvoja efikasnosti i funkcionalnosti. Analizama relevantnih rezolucija Ujedinjenih naroda, različitih interesnih skupina poput skupine G-4 te pokušajem shvaćanja procesa dosadašnjih promjena Povelje Ujedinjenih naroda postaje jasno kako nije potrebno samo jačanje transparentnosti i legitimnosti Vijeća sigurnosti njegovim proširenjem, nego je potrebna i dubinska reforma Ujedinjenih naroda koja uključuje redefiniranje uloge veta. Zaključak je ovoga rada kako ni jedna vrsta reforme nije moguća bez postojanja širokoga konsenzusa među državama članicama Ujedinjenih naroda koje bi oko toga ključnog pitanja tre-bale postupiti kao i 1963. godine, kad je u Općoj skupštini Ujedinjenih naroda izglasana najznačajnija rezolucija o potrebi reforme Vijeća sigurnosti.
Izvršena je analiza reforme organizacije Ujedinjenih naroda, a posebice refor-me Vijeća sigurnosti. Reforma Vijeća sigurnosti poistovjećuje se isključivo s njegovim proširenjem, pri čemu se ne ...razmatraju alternativne metode razvoja efikasnosti i funkcionalnosti. Analizama relevantnih rezolucija Ujedinjenih naroda, različitih interesnih skupina poput skupine G-4 te pokušajem shvaćanja procesa dosadašnjih promjena Povelje Ujedinjenih naroda postaje jasno kako nije potrebno samo jačanje transparentnosti i legitimnosti Vijeća sigurnosti njegovim proširenjem, nego je potrebna i dubinska reforma Ujedinjenih naroda koja uključuje redefiniranje uloge veta. Zaključak je ovoga rada kako ni jedna vrsta reforme nije moguća bez postojanja širokoga konsenzusa među državama članicama Ujedinjenih naroda koje bi oko toga ključnog pitanja tre-bale postupiti kao i 1963. godine, kad je u Općoj skupštini Ujedinjenih naroda izglasana najznačajnija rezolucija o potrebi reforme Vijeća sigurnosti.
The structure and interactions of several aminopropyl–azithromycin derivatives (1a–c) have been studied by using NMR spectroscopy and docking calculations. Compounds 1a–c are precursors in the ...synthesis of macrozones, novel bioactive azithromycin–thiosemicarbazone conjugates active against some resistant bacterial strains. Today, bacterial resistance is considered as one of the major threats to human health. Knowledge on drug binding mode and conformations is one of the key factors in the process of designing molecules to fight resistance. In solution state, compounds 1a and 1c exist in the 3-endo-folded-out conformation, while 1b adopts a classical folded-out conformation. 13C and 15N CPMAS NMR spectra pointed towards similar structures in the solid state. The transferred NOESY NMR spectra confirmed binding to the E. coli ribosome and suggest that dominant conformations in the bound state resemble those in the free one. STD experiments identified reactive groups of 1a–c in close contact with the ribosome resembling binding epitopes observed for the related 15-membered macrolides. Docking studies revealed that the studied compounds bind to the same ribosome binding pocket similarly to erythromycin in the crystal state, and that the binding is achieved through H-bonds and van der Waals interactions. The bound conformation is the same as determined by NMR. STD enhancements observed for methylene protons in the aminopropyl side chain indicate additional interactions which contribute to the overall binding energy.
LC-SPE/cryo NMR and MS methodologies have been developed and employed for a rapid structure determination of 4″-tetrahydrofurfuryl macrozone reaction mixture components. Macrozones, novel conjugates ...of azithromycin, and thiosemicarbazones have shown very good in vitro antibacterial activities against susceptible and some resistant bacterial strains and are promising agents for further development. The post-column multiple trapping of the chromatographically separated reaction mixture components on the SPE cartridges increased the sensitivity and together with cryogenically cooled NMR probe made it possible to identify and structurally characterize main 4″-tetrahydrofurfuryl macrozone reaction mixture compounds including those present at very low concentration level. This approach has several advantages over a classical off-line procedure, efficiency and low solvent consumption being the two most important ones. All identified components were process-related. It has been demonstrated that two different kinds of compounds with respect to structure were identified, i.e., macrolide-related and thiosemicarbazone-related ones. This methodology can serve as a platform for reliable and effective macrolides reaction components structure profiling, serving as both isolation and identification tools.
The abscopal effect is a phenomenon that describes the systemic antitumor response that can occur as a result of a localized radiotherapy. Although sporadic cases of abscopal effect have been ...reported since 1960’s, the number of reported cases are significantly increasing in the immunotherapy era. Immunotherapy seems to enhance the immunogenic effects of radiotherapy, thus increasing systemic antitumor response. Although combination of radiotherapy and immunotherapy is a promising strategy in the treatment of metastatic cancers, many questions regarding the optimal treatment remain unanswered. Increasing number of ongoing studies will hopefully provide answers to these questions, enabling the utilization of this strategy in systemic anticancer treatment.
•Bacterial resistance to antibiotics presents a serious threat to human health.•Macrozones, new bioactive azithromycin conjugates, were designed, prepared and biologically evaluated.•Excellent ...antibacterial activity against susceptible and resistant pathogens was achieved.•Good basis for further efforts directed toward the discovery of new antibiotics.
Increasing bacterial resistance to existing antibiotics presents a serious threat to human health, and new antibacterial agents are desperately needed. Unfortunately, the number of newly marketed antibiotics has decreased dramatically in recent years. Withdrawal of the macrolide antibiotic telithromycin and the inability of solithromycin to gain marketing approval have prompted our efforts to search for new anti-infective macrolide compounds. Here we present the design, synthesis and biological evaluation of a novel hybrid class of azithromycin conjugates, the macrozones. Evaluation of prepared compounds against a panel of pathogenic bacteria revealed that these molecules showed excellent activities against susceptible Streptococcus pneumoniae, Streptococcus pyogenes and Enterococcus faecalis strains comparable with or better than azithromycin. Furthermore, prepared macrozones exhibited excellent activity against efflux resistant S. pneumoniae, which was 32 times better than that of azithromycin, and very good activity against an efflux resistant Staphylococcus aureus strain against which azithromycin is inactive. The results described here can serve as a good basis to guide further activities directed toward the discovery of more potent macrolide anti-infectives.
A well-known class of antibacterials, 14- and 15-membered macrolides are widely prescribed to treat upper and lower respiratory tract infections. Azithromycin is a 15-membered macrolide antibiotic ...possessing a broad spectrum of antibacterial potency and favorable pharmacokinetics. Bacterial resistance to marketed antibiotics is growing rapidly and represents one of the major global hazards to human health. Today, there is a high need for discovery of new anti-infective agents to combat resistance. Recently discovered conjugates of azithromycin and thiosemicarbazones, the macrozones, represent one such class that exhibits promising activities against resistant pathogens. In this paper, we employed an approach which combined LC-SPE/cryo NMR, MS/MS and molecular modeling for rapid separation, identification and characterization of bioactive macrozones and their diastereomers. Multitrapping of the chromatographic peaks on SPE cartridges enabled sufficient sample quantities for structure elucidation and biological testing. Furthermore, two-dimensional NOESY NMR data and molecular dynamics simulations revealed stereogenic centers with inversion of chirality. Differences in biological activities among diastereomers were detected. These results should be considered in the process of designing new macrolide compounds with bioactivity. We have shown that this methodology can be used for a fast screening and identification of the macrolide reaction components, including stereoisomers, which can serve as a source of new antibacterials.
Management of cancer of unknown primary Andrašek, Iva; Ravlić, Mirna; Mikulandra, Martina ...
Libri oncologici,
2020, Letnik:
48, Številka:
2-3
Journal Article
Recenzirano
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Cancer of an unknown primary site is most commonly an aggressive metastatic tumor with a median patient survival of 6 to 9 months. Histologically, it is predominantly adenocarcinoma, and if the ...primary site is subsequently diagnosed, it is usually the pancreas or lung. Biopsy should be performed whenever possible to classify a tumor of unknown primary origin into one of the following entities: adenocarcinoma, poorly differentiated carcinoma with characteristics similar to adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, poorly differentiated neoplasm. After determining the primary tumor type, the subtype is determined by immunohistochemical staining. In oligometastatic disease, there is a possibility of surgical treatment. Radiotherapy is used as a part of combined modality treatment. Most patients with cancer of unknown primary have an unfavorable prognosis despite multiple chemotherapy agents, and no protocol can be recommended as standard therapy.
Rak nepoznatog primarnog sijela je najčešće agresivni metastatski tumor sa srednjim preživljenjem bolesnika od 6 do 9 mjeseci. Histološki se uglavnom radi o adenokarcinomu, a ako se dijagnosticira ...primarno sijelo, to je najčešće gušterača ili pluća. Kad god je to moguće, potrebno je učiniti biospiju, kako bi se tumor nepoznatog primarnog sijela klasificirao na jedan od slijedećih entiteta: adenokarcinom, slabo diferencirani karcinom s karakteristikama sličnim adenokarcinomu, karcinom pločastih stanica, neuroendokrini karcinom ili slabo diferencirani tumor. Nakon određivanja glavnog tipa tumora, pomoću
imunohistokemijskih metoda određuje se podtip. Kod oligometastatske bolesti postoji mogućnost kirurškog liječenja. Radioterapija se koristi kao dio multimodalnog liječenja. Većina bolesnika s tumorom nepoznatog primarnog sijela ima nepovoljnu prognozu, unatoč primjeni više kombinacija kemoterapijskih lijekova, a niti jedan protokol se ne može preporučiti kao standardna terapija.
Apskopalni učinak je fenomen koji opisuje sustavni antitumorski odgovor koji može nastati kao rezultat lokalizirane radioterapije. Premda su sporadični slučajevi prijavljivani još od 1960-tih godina, ...njihov je broj značajno porastao u eri imunoterapije. Čini se da imunoterapija stimulira imunogenične učinke radioterapije, pojačavajući na taj način sistemski antitumorski odgovor. Iako je kombinacija radioterapije i imunoterapije obećavajuća strategija u liječenju metastatskih tumora, još uvijek nemamo odgovore na brojna pitanja vezana za optimalni protokol liječenja. Sve veći broj istraživanja koja su u tijeku vjerojatno će dati odgovore ta neriješena pitanja, što će omogućiti korištenje ove strategije u sustavnom liječenju raka.
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