1061. Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region : a first-in-human clinical trial protocolAleš Grošelj, Maša Omerzel, Tanja Jesenko, Maja Čemažar, Boštjan Markelc, Primož Strojan, Gregor Serša, 2022, izvirni znanstveni članek Povzetek: Immune therapies are currently under intensive investigation providing in many cases excellent re-sponses in different tumors. Other possible approach for immunotherapy is a targeted intratumoral delivery of inter-leukin 12 (IL-12), a cytokine with anti-tumor effectiveness. Due to its immunomodulatory action, it can be used as an imunostimulating component to in situ vaccinating effect of local ablative therapies. We have developed a phIL12 plasmid devoid of antibiotic resistance marker with a transgene for human IL-12 p70 protein. The plasmid can be delivered intratumorally by gene electrotransfer (GET). Patients and methods. Here we present a first-in-human clinical trial protocol for phIL12 GET (ISRCTN15479959, ClinicalTrials NCT05077033). The study is aimed at evaluating the safety and tolerability of phIL12 GET in treatment of basal cell carcinomas in patients with operable tumors in the head and neck region. The study is designed as an ex-ploratory, dose escalating study with the aim to determine the safety and tolerability of the treatment and to identify the dose of plasmid phIL12 that is safe and elicits its biological activity. Conclusions. The results of this trail protocol will therefore provide the basis for the use of phIL12 GET as an adjuvant treatment to local ablative therapies, to potentially increase their local and elicit a systemic response.
Ključne besede: skin tumors, gene electrotransfer, interleukin 12, clinical trial
Objavljeno v DiRROS: 24.07.2024; Ogledov: 277; Prenosov: 116
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1062. Sunitinib potentiates the cytotoxic effect of electrochemotherapy in pancreatic carcinoma cellsMaša Omerzel, Tanja Jesenko, Boštjan Markelc, Anja Cerovšek, Gregor Serša, Maja Čemažar, 2022, izvirni znanstveni članek Povzetek: One of the new treatment options for unresectable locally advanced pancreatic cancer is electro-chemotherapy (ECT), a local ablative therapy that potentiates the entry of chemotherapeutic drugs into the cells, by the application of an electric field to the tumor. Its feasibility and safety were demonstrated in preclinical and clinical studies; however, there is a lack of preclinical studies assessing the actions of different drugs used in ECT, their mechanisms and interactions with other target drugs that are used in clinical practice. Materials and methods. The aim of the study was to determine the cytotoxicity of two chemotherapeutic drugs usually used in ECT (bleomycin and cisplatin) in the BxPC-3 human pancreatic carcinoma cell line and evaluate the interactions of ECT with the targeted drug sunitinib. First, the cytotoxicity of ECT using both chemotherapeutics was determined. In the next part, the interactions of ECT and sunitinib were evaluated through determination of combined cytotoxicity, sunitinib targets and kinetics of cell death.Results. The results demonstrate that ECT is effective in pancreatic cancer cell line, especially when bleomycin is used, with the onset of cell death in the first hours after the treatment, reaching a plateau at 20 hours after the treat-ment. Furthermore, we provide the rationale for combining ECT with bleomycin and the targeted drug sunitinib to potentiate cytotoxicity. The combined treatment of sunitinib and ECT was synergistic for bleomycin only at the high-est used concentration of bleomycin 0.14 μM, whereas with lower doses of bleomycin, this effect was not observed. The interaction of ECT and treatment with sunitinib was confirmed by course of the cell death, also indicating on synergism
Ključne besede: electrochemotherapy, pancreas, sunitinib, pancreatic cancer
Objavljeno v DiRROS: 24.07.2024; Ogledov: 265; Prenosov: 158
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1063. Expression of DNA-damage response and repair genes after exposure to DNA-damaging agents in isogenic head and neck cells with altered radiosensitivityVesna Todorović, Blaž Grošelj, Maja Čemažar, Ajda Prevc, Martina Nikšić Žakelj, Primož Strojan, Gregor Serša, 2022, izvirni znanstveni članek Povzetek: Background: Increased radioresistance due to previous irradiation or radiosensitivity due to human papilloma virus (HPV) infection can be observed in head and neck squamous cell carcinoma (HNSCC). The DNA-damage response of cells after exposure to DNA-damaging agents plays a crucial role in determining the fate of exposed cells. Tightly regulated and interconnected signaling networks are activated to detect, signal the presence of and repair the DNA damage. Novel therapies targeting the DNA-damage response are emerging; however, an improved understanding of the complex signaling networks involved in tumor radioresistance and radiosensitivity is needed. Materials and methods: In this study, we exposed isogenic human HNSCC cell lines with altered radiosensitivity to DNA-damaging agents: radiation, cisplatin and bleomycin. We investigated transcriptional alterations in the DNA-damage response by using a pathway-focused panel and reverse-transcription quantitative PCR. Results: In general, the isogenic cell lines with altered radiosensitivity significantly differed from one another in the expression of genes involved in the DNA-damage response. The radiosensitive (HPV-positive) cells showed overall decreases in the expression levels of the studied genes. In parental cells, upregulation of DNA-damage signaling and repair genes was observed following exposure to DNA-damaging agents, especially radiation. In contrast, radioresistant cells exhibited a distinct pattern of gene downregulation after exposure to cisplatin, whereas the levels in parental cells were unchanged. Exposure of radioresistant cells to bleomycin did not significantly affect the expression of DNA-damage signaling and repair genes. Conclusions: Our analysis identified several possible targets: NBN, XRCC3, ATR, GADD45A and XPA. These putative targets should be studied and potentially exploited for sensibilization to ionizing radiation and/or cisplatin in HNSCC. The use of predesigned panels of DNA-damage signaling and repair genes proved to offer a convenient and quick approach to identify possible therapeutic targets.
Ključne besede: DNA-damaging agents, gene expression, head and neck cancer, squamous cell carcinoma
Objavljeno v DiRROS: 24.07.2024; Ogledov: 464; Prenosov: 161
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1064. D.1.1.1 Barriers and needs for inclusion of girls and young women : joint reportPolona Hafner, Katarina Flajšman, Nike Krajnc, Mateja Karničnik, Tatjana Pavlič, Ema Šumenjak, Tina Goznik, Špela Pezdevšek Malovrh, Zala Uhan, Andrea Skiba, 2024, končno poročilo o rezultatih raziskav Ključne besede: gender equality, Europe
Objavljeno v DiRROS: 24.07.2024; Ogledov: 289; Prenosov: 167
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1065. Image reconstruction using small-voxel size improves small lesion detection for positron emission tomographySebastijan Rep, Petra Tomše, Luka Jensterle, Leon Jarabek, Katja Zaletel, Luka Ležaič, 2022, izvirni znanstveni članek Povzetek: Background. PET/CT imaging is widely used in oncology and provides both metabolic and anatomic information. Because of the relatively poor spatial resolution of PET, the detection of small lesions is limited. The low spatial resolution introduces the partial-volume effect (PVE) which negatively affects images both qualitatively and quantitatively. The aim of the study was to investigate the effect of small-voxel (2 mm in-line pixel size) vs. standard-voxel (4 mm in-line pixel size) reconstruction on lesion detection and image quality in a range of activity ratios. Materials and methods. The National Electrical Manufacturers Association (NEMA) body phantom and the Micro Hollow-Sphere phantom spheres were filled with a solution of [18F]fluorodeoxyglucose ([18F]FDG) in sphere-to-background ratios of 2:1, 3:1, 4:1 and 8:1. In all images reconstructed with 2 mm and 4 mm in-line pixel size the visual lesion delineation, contrast recovery coefficient (CRC) and contrast-to-noise ratio (CNR) were evaluated. Results. For smaller (≤ 13 mm) phantom spheres, significantly higher CRC and CNR using small-voxel reconstructions were found, also improving visual lesion delineation. CRC did not differ significantly for larger (≥ 17 mm) spheres using 2 mm and 4 mm in-line pixel size, but CNR was significantly lower; however, lower CNR did not affect visual lesion delineation. Conclusions. Small-voxel reconstruction consistently improves precise small lesion delineation, lesion contrast and image quality.
Ključne besede: PET/CT, voxel size, contrast recovery coefficient, contrast-to-noise ratio
Objavljeno v DiRROS: 24.07.2024; Ogledov: 292; Prenosov: 188
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1068. Spatial and temporal recruitment of the neurovascular unit during development of the mouse blood-retinal barrierAnne-Eva van der Wijk, Ilse M.C. Vogels, Henk A. van Veen, Cornelis J. F. van Noorden, Reinier O. Schlingemann, Ingeborg Klaassen, 2018, izvirni znanstveni članek Povzetek: The inner blood-retinal barrier (BRB) is made up by the neurovascular unit, consisting of endothelial cells, pericytes and glial cells. The BRB maintains homeostasis of the neural retina, but in pathological eye conditions the neurovascular unit is often disrupted, causing BRB loss. Here, we investigated in detail temporal and spatial recruitment of the neurovascular unit in the neonatal mouse retina from postnatal day (P)3 to P25 employing immunohistochemical staining of vascular endothelium (isolectin B4), pericytes (α-SMA and NG2) and astrocytes (GFAP). In addition, we investigated gene expression of polarized astrocytic end-feet markers aquaporin-4 and laminin α2 chain with qPCR. We observed GFAP-positive cells migrating ahead of the retinal vasculature during the first postnatal week, suggesting that the retinal vasculature follows an astrocytic meshwork. From P9 onwards, astrocytes acquired a mature phenotype, with a more stellate shape and increased expression of aquaporin-4. NG2-positive cells and tip cells co-localized at P5 and invaded the retina together as a vascular sprouting front. In summary, these data suggest that recruitment of the cell types of the neurovascular unit is a prerequisite for proper retinal vascularization and BRB formation.
Ključne besede: endothelial cells, astrocytes, pericytes, retinal development
Objavljeno v DiRROS: 24.07.2024; Ogledov: 273; Prenosov: 234
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1069. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivityMohammed Khurshed, Niels Aarnoudse, Renske Hulsbos, Vashendriya V. V. Hira, Hanneke WM van Laarhoven, Johanna W Wilmink, Remco J. Molenaar, Cornelis J. F. van Noorden, 2018, izvirni znanstveni članek Povzetek: Isocitrate dehydrogenase (IDH1)-1 is mutated in various types of human cancer, and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells. Mutated IDH1 (IDH1MUT) enzymes consume NADPH to produce D-2-hydroxyglutarate (D-2HG) resulting in the decreased re ducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current study was to investigate the mechanism behind the chemosensitivity of the widely used anticancer agent cisplatin in IDH1MUT cancer cells. Oxidative stress, DNA damage, and mitochondrial dysfunction caused by cisplatin treatment were monitored in IDH1MUT HCT116 colorectal cancer cells and U251 glioma cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double-strand breaks (DSBS), and cell death in IDH1MUT cancer cells, as compared with IDH1 wild-type (IDH1WT) cells. Mechanistic investigations revealed that cisplatin treatment dose dependently reduced oxidative respiration in IDH1MUT cells, which was accompanied by disturbed mitochondrial proteostasis, indicative of impaired mitochondrial activity. These effects were abolished by the IDH1MUT inhibitor AGI-5198 and were restored by treatment with D-2HG. Thus, our study shows that altered oxidative stress responses and a vulnerable oxidative metabolism underlie the sensitivity of IDH1MUT cancer cells to cisplatin.—Khurshed, M., Aarnoudse, N., Hulsbos, R., Hira, V. V. V., van Laarhoven, H. W. M., Wilmink, J. W., Molenaar, R. J., van Noorden, C. J. F. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity. 32, 6344–6352 (2018). www.fasebj.org
Ključne besede: isocitrate dehydrogenase, chemosensitivity, cis-diamminedichloroplatinum, 2-hydroxyglutarate
Objavljeno v DiRROS: 24.07.2024; Ogledov: 240; Prenosov: 240
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1070. IGF2 and IGF1R identified as novel tip cell genes in primary microvascular endothelial cell monolayersMarchien G. Dallinga, Bahar Yetkin-Arik, Richelle P. Kayser, Ilse M.C. Vogels, Patrycja Nowak-Sliwinska, Arjan W. Griffioen, Cornelis J. F. van Noorden, Ingeborg Klaassen, Reinier O. Schlingemann, 2018, izvirni znanstveni članek Povzetek: Tip cells, the leading cells of angiogenic sprouts, were identified in cultures of human umbilical vein endothelial cells (HUVECs) by using CD34 as a marker. Here, we show that tip cells are also present in primary human microvascular endothelial cells (hMVECs), a more relevant endothelial cell type for angiogenesis. By means of flow cytometry, immunocytochemistry, and qPCR, it is shown that endothelial cell cultures contain a dynamic population of CD34+ cells with many hallmarks of tip cells, including filopodia-like extensions, elevated mRNA levels of known tip cell genes, and responsiveness to stimulation with VEGF and inhibition by DLL4. Furthermore, we demonstrate that our in vitro tip cell model can be exploited to investigate cellular and molecular mechanisms in tip cells and to discover novel targets for anti-angiogenesis therapy in patients. Small interfering RNA (siRNA) was used to knockdown gene expression of the known tip cell genes angiopoietin 2 (ANGPT2) and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), which resulted in similar effects on tip cells and sprouting as compared to inhibition of tip cells in vivo. Finally, we identified two novel tip cell-specific genes in CD34+ tip cells in vitro: insulin-like growth factor 2 (IGF2) and IGF-1-receptor (IGF1R). Knockdown of these genes resulted in a significant decrease in the fraction of tip cells and in the extent of sprouting in vitro and in vivo. In conclusion, this study shows that by using our in vitro tip cell model, two novel essential tip cells genes are identified.
Ključne besede: Angiogenesis, tip cells, CD34, IGF2, endothelial cells, cultured cells, endothelial growth factors
Objavljeno v DiRROS: 24.07.2024; Ogledov: 275; Prenosov: 198
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