21. Potentiation of electrochemotherapy effectiveness by immunostimulation with IL-12 gene electrotransfer in mice is dependent on tumor immune statusKatja Uršič Valentinuzzi, Špela Kos, Urška Kamenšek, Maja Čemažar, Simona Miceska, Boštjan Markelc, Simon Buček, Barbara Starešinič, Veronika Kloboves-Prevodnik, Richard Heller, Gregor Serša, 2021, izvirni znanstveni članek Povzetek: Electrochemotherapy (ECT) exhibits high therapeutic effectiveness in the clinic, achieving up to 80% local tumor control but without a systemic (abscopal) effect. Therefore, we designed a combination therapy consisting of ECT via intratumoral application of bleomycin, oxaliplatin or cisplatin with peritumoral gene electrotransfer of a plasmid encoding interleukin-12 (p. t. IL-12 GET). Our hypothesis was that p. t. IL-12 GET potentiates the effect of ECT on local and systemic levels and that the potentiation varies depending on tumor immune status. Therefore, the combination therapy was tested in three immunologically different murine tumor models. In poorly immunogenic B16F10 melanoma, IL-12 potentiated the antitumor effect of ECT with biologically equivalent low doses of cisplatin, oxaliplatin or bleomycin. The most pronounced potentiation was observed after ECT using cisplatin, resulting in a complete response rate of 38% and an abscopal effect. Compared to B16F10 melanoma, better responsiveness to ECT was observed in more immunogenic 4%T1 mammary carcinoma and CT26 colorectal carcinoma. In both models, p. t. IL-12 GET did not significantly improve the therapeutic outcome of ECT using any of the chemotherapeutic drugs. Collectively, the effectiveness of the combination therapy depends on tumor immune status. ECT was more effective in more immunogenic tumors, but GET exhibited greater contribution in less immunogenic tumors. Thus, the selection of the therapy, namely, either ECT alone or combination therapy with p. t. IL-12, should be predominantly based on tumor immune status.
Ključne besede: electrochemotherapy, gene electrotransfer, interleukin-12
Objavljeno v DiRROS: 21.09.2022; Ogledov: 556; Prenosov: 193
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22. Non-clinical in vitro evaluation of antibiotic resistance gene-free plasmids encoding human or murine IL-12 intended for first-in-human clinical studyŠpela Kos, Maša Omerzel, Tanja Jesenko, Boštjan Markelc, Urška Kamenšek, Katarina Žnidar, Urška Matkovič, Andrej Renčelj, Gregor Serša, Rosana Hudej, Aneja Tuljak, Matjaž Peterka, Maja Čemažar, 2021, izvirni znanstveni članek Povzetek: Interleukin 12 (IL-12) is a key cytokine that mediates antitumor activity of immune cells. To fulfill its clinical potential, the development is focused on localized delivery systems, such as gene electrotransfer, which can provide localized delivery of IL-12 to the tumor microenvironment. Gene electrotransfer of the plasmid encoding human IL-12 is already in clinical trials in USA, demonstrating positive results in the treatment of melanoma patients. To comply with EU regulatory requirements for clinical application, which recommend the use of antibiotic resistance gene-free plasmids, we constructed and developed the production process for the clinical grade quality antibiotic resistance gene-free plasmid encoding human IL-12 (p21-hIL-12-ORT) and its ortholog encoding murine IL-12 (p21-mIL-12-ORT). To demonstrate the suitability of the p21-hIL-12-ORT or p21-mIL-12-ORT plasmid for the first-in-human clinical trial, the biological activity of the expressed transgene, its level of expression and plasmid copy number were determined in vitro in the human squamous cell carcinoma cell line FaDu and the murine colon carcinoma cell line CT26. The results of the non-clinical evaluation in vitro set the basis for further in vivo testing and evaluation of antitumor activity of therapeutic molecules in murine models as well as provide crucial data for further clinical trials of the constructed antibiotic resistance gene-free plasmid in humans.
Ključne besede: interleukin 12, gene electrotransfer, antibiotic resistance, plasmids
Objavljeno v DiRROS: 07.09.2022; Ogledov: 485; Prenosov: 290
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23. Genska terapija v onkologiji, prvi razvojni koraki v SlovenijiMaja Čemažar, Tanja Jesenko, Maša Omerzel, Boštjan Markelc, Urška Kamenšek, Simona Kranjc Brezar, Špela Kos, Urša Lampreht Tratar, Katarina Žnidar, Andrej Renčelj, Urška Matkovič, Teja Valant, Kristina Levpušček, Živa Modic, Tilen Komel, Tim Božič, Urša Kešar, Barbara Starešinič, Katja Uršič Valentinuzzi, Monika Savarin, Primož Strojan, Gorana Gašljević, Maja Ota, Aleš Grošelj, Črt Jamšek, Rosana Hudej, Matjaž Peterka, Franc Smrekar, Barbara Hubad, Marjan Hosta, Jaka Kužnik, Alojz Hosta, Damijan Miklavčič, Matej Reberšek, Aleksandra Cvetkoska, Anja Zajc, Janja Dermol-Černe, Nataša Tozon, Nina Milevoj, Alenka Nemec Svete, Gregor Serša, 2022, strokovni članek Povzetek: Genska terapija postaja čedalje bolj zanimiva tudi v onkologiji. Med aplikacijami je morda najzanimivejša imunostimulacija. Pripravimo lahko plazmidno DNA, ki nosi zapis za različne imunostimulatorne molekule, ki jih vnesemo v celice tumorjev ali normalnih tkiv. Ta tkiva postanejo proizvajalci teh molekul, ki lahko delujejo lokalno ali pa se izločajo tudi sistemsko v krvni obtok. Ker plazmidna DNA ne prehaja celične membrane, so potrebni dostavni sistemi, virusni ali nevirusni. V naših študijah uporabljamo predvsem nevirusni dostavni sistem – elektroporacijo. Interlevkin 12 (IL-12) je eden od zanimivih citokinov, za katerega je znano protitumorsko delovanje s spodbujanjem imunskega odziva in antiangiogenim delovanjem. Namen projekta SmartGene.si je bil pripraviti plazmid z zapisom za interlevkin 12 (plazmid phIL12) in pripraviti vse potrebno za njegovo klinično testiranje za zdravljenje kožnih tumorjev. V konzorciju smo združili moči s partnerji z akademskega in industrijskega področja. Treba je bilo pripraviti plazmid za uporabo v humani onkologiji po zahtevah Evropske agencije za zdravila (EMA). Za prijavo klinične študije na Javno agencijo za zdravila in medicinske pripomočke (JAZMP) smo morali izvesti tudi vse neklinične raziskave o varnosti in učinkovitosti zdravila. Nato je bilo treba razviti postopek priprave zdravila, zagotoviti primerne prostore za pripravo in izvedbo postopka priprave zdravila. V treh letih smo dosegli vse te zastavljene cilje in dobili dovoljenje za izvajanje klinične študije na kožnih tumorjih, ki ga je izdala JAZMP na osnovi pozitivnega mnenja Komisije Republike Slovenije za medicinsko etiko. Zdaj poteka klinična študija faze I preizkušanja plazmida phIL12 na kožnih tumorjih glave in vratu z namenom preveriti varnost in sprejemljivost genskega elektroprenosa plazmida v tumorje. Cilj študije je prav tako določiti primeren odmerek zdravila, ki bi ga v nadaljnji klinični študiji uporabili kot adjuvantno zdravljenje k ablativnim terapijam, kot sta radioterapija ali elektrokemoterapija.
Ključne besede: genska terapija, interlevkin-12, plazmidna DNA, elektroprenos genov, rak kože
Objavljeno v DiRROS: 01.07.2022; Ogledov: 1162; Prenosov: 233
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24. Carboxypeptidase cathepsin X defines a multifunctional role of gamma-enolase in cancerTjaša Vižin, Anja Pišlar, Ib Jarle Christensen, Hans Jørgen Nielsen, Pika Meško-Brguljan, Janko Kos, 2022, izvirni znanstveni članek Povzetek: Gamma-enolase enzymatic activity is involved in glycolysis, a prevalent process in cancer cell metabolism. Additionally, gamma-enolase has a pro-survival function, exhibited through the active site at the C-terminal end of the molecule. This activity is regulated by cysteine peptidase cathepsin X, which cleaves two amino acids at C-terminal end of gamma-enolase. In clinical practice, the determination of gamma-enolase as a tumour marker does not differ between total, uncleaved and C-terminally cleaved forms. However, levels of uncleaved gamma-enolase alone may provide additional clinical information. In this study we analysed cathepsin X, C- terminally uncleaved and total gamma-enolase in tumour cell lines and sera from 255 patients with colorectal cancer (CRC) by western blot, immunoprecipitation, enzymatic activity, ELISAs and ECLIA. Results show that uncleaved gamma-enolase, rather than total gamma- enolase, exhibits different levels in cells, being the highest in those, derived from metastatic sites or highly invasive tumours. Gamma-enolase is secreted into the extracellular space predominantly as an uncleaved form and levels were congruent to those within the cells. Furthermore, levels of uncleaved gamma-enolase in cells are inversely related to cathepsin X protein level and its enzymatic activity. Uncleaved gamma-enolase is also predominant form in sera of patients with CRC. Both forms exhibit similar stage dependent distribution, with slightly elevated levels in stage IV patients. Higher levels of total gamma-enolase are significantly related to shorter survival in patients with metastatic CRC. Results support evidence of additional pro-survival function of gamma-enolase in cancer. Future studies should focus on analysis of uncleaved gamma-enolase in tumour samples, which may provide additional relations to clinical indicators of disease progression.
Ključne besede: cancer, cathepsin X, cell survival, gamma-enolase, prognosis
Objavljeno v DiRROS: 06.04.2022; Ogledov: 786; Prenosov: 450
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25. Priporočila za obravnavo bolnikov z malignimi limfomiBarbara Jezeršek Novaković, Gorana Gašljević, Biljana Grčar-Kuzmanov, Monika Jagodic, Tanja Južnič Šetina, Veronika Kloboves-Prevodnik, Gregor Kos, Milica Miljković, Jana Pahole Goličnik, Samo Rožman, Urška Rugelj, Marija Skoblar Vidmar, Uroš Smrdel, Danijela Štrbac, Miha Toplak, Lorna Zadravec-Zaletel, Mateja Dolenc-Voljč, 2021, strokovna monografija Ključne besede: maligni limfomi, smernice, novotvorbe
Objavljeno v DiRROS: 17.03.2022; Ogledov: 702; Prenosov: 379
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26. Poročilo o poteku študije za uvajanje tekočinske tehnologije v SlovenijiVeronika Kloboves-Prevodnik, Mojca Florjančič, Tine Jerman, Jerneja Kos, Urška Ivanuš, 2021, objavljeni znanstveni prispevek na konferenci Ključne besede: epidemija, presejalni programi, rak materničnega vratu, citopatologija
Objavljeno v DiRROS: 16.03.2022; Ogledov: 567; Prenosov: 303
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27. Klinična pot celostne rehabilitacije bolnikov z rakom dojkeNikola Bešić, Simona Borštnar, Andreja Gornjec, Teja Kovačec Hermann, Vesna Homar, Denis Mlakar-Mastnak, Nataša Kos, Nada Rotovnik-Kozjek, Mateja Kurir-Borovčić, Tanja Marinko, Andreja Cirila Škufca Smrdel, Branka Stražišar, Tanja Španić, Lorna Zadravec-Zaletel, 2020, končno poročilo o rezultatih raziskav Ključne besede: rak dojke, bolniki, zdravljenje, klinične poti
Objavljeno v DiRROS: 14.03.2022; Ogledov: 715; Prenosov: 356
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28. Priporočila za obravnavo bolnikov z malignimi limfomiBarbara Jezeršek Novaković, Lučka Boltežar, Gorana Gašljević, Biljana Grčar-Kuzmanov, Monika Jagodic, Tanja Južnič Šetina, Veronika Kloboves-Prevodnik, Gregor Kos, Milica Miljković, Jana Pahole Goličnik, Samo Rožman, Urška Rugelj, Marija Skoblar Vidmar, Uroš Smrdel, Danijela Štrbac, Miha Toplak, Lorna Zadravec-Zaletel, Mateja Dolenc-Voljč, 2022, strokovna monografija Ključne besede: maligni limfomi, smernice, novotvorbe
Objavljeno v DiRROS: 14.03.2022; Ogledov: 784; Prenosov: 432
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29. Klinična pot celostne rehabilitacije bolnikov z rakom dojkeNikola Bešić, Simona Borštnar, Vesna Homar, Denis Mlakar-Mastnak, Zlatka Mavrič, Anamarija Mozetič, Jana Knific, Nataša Kos, Nina Kovačević, Nada Rotovnik-Kozjek, Nena Kopčavar Guček, Mateja Kurir-Borovčić, Tanja Marinko, Ana Pekle-Golež, Irena Rahne Otorepec, Gabrijela Simetinger, Andreja Cirila Škufca Smrdel, Branka Stražišar, Tanja Španić, Lorna Zadravec-Zaletel, 2021, končno poročilo o rezultatih raziskav Ključne besede: rak dojke, bolniki, celostna rehabilitacija, klinične poti
Objavljeno v DiRROS: 14.03.2022; Ogledov: 780; Prenosov: 369
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30. Programske smernice Državnega programa ZORAUrška Ivanuš, Edita Arh, Sonja Bebar, Branko Cvjetičanin, Dušan Deisinger, Mojca Florjančič, Aljoša Frelih, Urška Gašper, Biljana Grčar-Kuzmanov, Nina Jančar, Tine Jerman, Kaja Kališnik, Silvestra Kašnik-Čas, Veronika Kloboves-Prevodnik, Borut Kobal, Amela Duratović Konjević, Jerneja Kos, Gabrijela Kupljen, Mateja Lasič Pecev, Mateja Marčec, Leon Meglič, Sebastjan Merlo, Marko Mlinarič, Nataša Nolde, Irena Oblak, Maja Pakiž, Boštjan Pirš, Ana Pogačnik, Maja Primic-Žakelj, Alenka Repše-Fokter, Luka Roškar, Uršula Salobir Gajšek, Špela Sitar, Špela Smrkolj, Vivijana Snoj, Margareta Strojan Fležar, Tadeja Štrumbelj, Iztok Takač, Renata Toff-Jovan, Tomaž Tušek, Andreja Uštar, 2022, strokovna monografija Ključne besede: predrakave spremembe, zgodnja diagnostika, presejanje, presejalni programi, nacionalni programi, postopki, elektronske knjige
Objavljeno v DiRROS: 10.03.2022; Ogledov: 774; Prenosov: 391
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