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Abstract: Multimodal treatment approaches, such as radio-immunotherapy, necessitate regimen optimization and the investigation of the interactions of different modalities. The aim of this study was two-fold. Firstly, to select the most effective combination of irradiation and the previously developed tumor cell-based vaccine and then to provide insight into the immune response to the selected combinatorial treatment. The study was performed in immunologically different murine tumor models: B16F10 melanoma and CT26 colorectal carcinoma. The most effective combinatorial treatment was selected by comparing three different IR regimens and three different vaccination regimens. We determined the local immune response by investigating immune cell infiltration at the vaccination site and in tumors. Lastly, we determined the systemic immune response by investigating the amount of tumor-specific effector lymphocytes in draining lymph nodes. The selected most effective combinatorial treatment was 5× 5 Gy in combination with concomitant single-dose vaccination (B16F10) or with concomitant multi-dose vaccination (CT26). The combinatorial treatment successfully elicited a local immune response at the vaccination site and in tumors in both tumor models. It also resulted in the highest amount of tumor-specific effector lymphocytes in draining lymph nodes in the B16F10, but not in the CT26 tumor-bearing mice. However, the amount of tumor-specific effector lymphocytes was intrinsically higher in the CT26 than in the B16F10 tumor model. Upon the selection of the most effective combinatorial treatment, we demonstrated that the vaccine elicits an immune response and contributes to the antitumor efficacy of tumor irradiation. However, this interaction is multi-faceted and appears to be dependent on the tumor immunogenicity.
Keywords: experimental oncology, multimodal treatment, radio-imunotherapy
Published in DiRROS: 14.09.2022; Views: 549; Downloads: 286
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Abstract: 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.
Keywords: interleukin 12, gene electrotransfer, antibiotic resistance, plasmids
Published in DiRROS: 07.09.2022; Views: 502; Downloads: 296
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Keywords: tujerodne drevesne vrste, Alpe, invazivne drevesne vrste
Published in DiRROS: 12.08.2022; Views: 1228; Downloads: 396
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Abstract: Analizirali smo živi arhiv metasekvoje (Metasequoia glyptostroboides Hu et Cheng) na obrečnem rastišču ob Savi pri Ljubljani. Osnovan je bil v letih 1993 in 1994 s sadikami, vzgojenimi iz originalnih semen z območja na Kitajskem, kjer je bila vrsta opisana (klasično nahajališče oz. locus classicus). Drevesa v nasadu so bila prvič izmerjena spomladi leta 2000 in nato še leta 2006, spomladi v letu 2020 pa smo meritve ponovili. V starosti 30 let je povprečno drevo merilo v višino 20,7 m, povprečni premer koreninskega vratu na višini debla 0,1 m je znašal 72,3 cm, povprečni premer debla na prsni višini pa 51,4 cm. Ugotovili smo, da je pogostnost reproduktivnih organov, torej storžev in moških cvetov, povezana s premerom in višino drevesa. Užlebljenost debla je zelo variabilna in povezana s premerom, zelo variabilno je tudi zmanjšanje premera z višino. Povezave med omenjenimi znaki in lego drevesa v nasadu nismo ugotovili. Svetloba oziroma lega v nasadu ni edini dejavnik, ki vpliva na lastnosti posameznega drevesa, vzrok je tudi genetska variabilnost med drevesi.
Keywords: Metasequoia glyptostroboides, semenski nasad, rast, kakovost, Slovenija
Published in DiRROS: 11.08.2022; Views: 693; Downloads: 189
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Abstract: European beech (Fagus sylvatica L.) adapts to local growing conditions to enhance its performance. In response to variations in climatic conditions, beech trees adjust leaf phenology, cambial phenology, and wood formation patterns, which result in different treering widths (TRWs) and wood anatomy. Chronologies of tree ring width and vessel features [i.e., mean vessel area (MVA), vessel density (VD), and relative conductive area (RCTA)] were produced for the 1960%2016 period for three sites that differ in climatic regimes and spring leaf phenology (two early- and one late-flushing populations). These data were used to investigate long-term relationships between climatic conditions and anatomical features of four quarters of tree-rings at annual and intra-annual scales. In addition, we investigated how TRW and vessel features adjust in response to extreme weather events (i.e., summer drought). We found significant differences in TRW, VD, and RCTA among the selected sites. Precipitation and maximum temperature before and during the growing season were the most important climatic factors affecting TRW and vessel characteristics. We confirmed differences in climate-growth relationships between the selected sites, late flushing beech population at Idrija showing the least pronounced response to climate. MVA was the only vessel trait that showed no relationship with TRW or other vessel features. The relationship between MVA and climatic factors evaluated at intra-annual scale indicated that vessel area in the first quarter of tree-ring were mainly influenced by climatic conditions in the previous growing season, while vessel area in the second to fourth quarters of tree ring width was mainly influenced by maximum temperature and precipitation in the current growing season. When comparing wet and dry years, beech from all sites showed a similar response, with reduced TRW and changes in intra-annual variation in vessel area. Our findings suggest that changes in temperature and precipitation regimes as predicted by most climate change scenarios will affect tree-ring increments and wood structure in beech, yet the response between sites or populations may differ.
Keywords: Fagus sylvatica, wood anatomy, tracheograms, dendrochronology, intra specific plasticity
Published in DiRROS: 22.07.2022; Views: 529; Downloads: 370
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