Search

Glioblastom je najpogostejši možganski tumor pri odraslih z zelo slabo prognozo preživetja bolnikov. Ta je posledica odpornosti glioblastoma na standardno zdravljenje, ki vključuje radioterapijo in kemoterapijo. Z namenom načrtovanja učinkovitejših pristopov zdravljenja preučujemo biološke mehanizme odpornosti glioblastoma na radioterapijo s poudarkom na mikrookolju tumorja in rakavih matičnih celicah. V predkliničnih raziskavah uporabljamo napredne in personalizirane celične modele, ki posnemajo mikrookolje tumorja v bolnikih in z večjo natančnostjo napovedo odziv bolnika na zdravljenje. Hkrati so takšni modeli pomembni za testiranje novih pristopov za zdravljenje kot je imunoterapija.

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Understanding GBM pathobiology and discovering novel therapeutic targets are critical to finding efficient treatments. Upregulation of the lysosomal cysteine carboxypeptidase cathepsin X has been linked to immune dysfunction and neurodegenerative diseases, but its role in cancer and particularly in GBM progression in patients is unknown. In this study, cathepsin X expression and activity were found to be upregulated in human GBM tissues compared to low-grade gliomas and nontumor brain tissues. Cathepsin X was localized in GBM cells as well as in tumor-associated macrophages and microglia. Subsequently, potent irreversible (AMS36) and reversible (Z7) selective cathepsin X inhibitors were tested in vitro. Selective cathepsin X inhibitors decreased the viability of patientderived GBM cells as well as macrophages and microglia that were cultured in conditioned media of GBM cells. We next examined the expression pattern of neuron-specific enzyme γ-enolase, which is the target of cathepsin X. We found that there was a correlation between high proteolytic activity of cathepsin X and C-terminal cleavage of γ-enolase and that cathepsin X and γ-enolase were colocalized in GBM tissues, preferentially in GBM-associated macrophages and microglia. Taken together, our results on patient-derived material suggest that cathepsin X is involved in GBM progression and is a potential target for therapeutic approaches against GBM.

Supplemental material, DS_10.1369_0022155419878416 for Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies by Vashendriya V.V. Hira, Barbara Breznik, Miloš Vittori, Annique Loncq de Jong, Jernej Mlakar, Roelof-Jan Oostra, Mohammed Khurshed, Remco J. Molenaar, Tamara Lah and Cornelis J.F. Van Noorden in Journal of Histochemistry & Cytochemistry

Diplomsko delo predstavlja pregled glavnih overitvenih pristopov za osebno uporabo. Najprej smo opisali osnovne koncepte overjanja ter obravnavali tri glavne načine overjanja: kaj nekdo ve, kaj nekdo je in kaj nekdo ima. Predstavili smo tudi prednosti in slabosti teh metod in raziskali, katera je najbolj primerna za osebno rabo. Posebej smo se osredotočili na prepoznavanje obrazov, kjer smo tudi opisali različne vrste algoritmov, ki jih sistemi uporabljajo. Na koncu pa smo implementirali metodo prepoznavanja obrazov s pomočjo algoritma Eigenobraz. The thesis presents an overview of the main authentication systems for personal use. At first, we have intruduced the basic concepts of authentication and adressed that there are three main methods of authentication: what one knows, what one is and what one has. We have identified the advantages and disadvantages of these methods and researched which one would be the most suitable for personal use. In particular, we had focused on facial recognition, where we also described the various types of algorithms used by the systems. At the end, we have implemented method for face recognition with the help of algorithm Eigenface.

Background: In past ten years imatinib (IM) has greatly improved the prognosis of patients with chronic myeloid leukemia (CML). However, 30 % of patients still fail to achieve treatment goals or cannot maintain them later. In the last three years, Imatinib plasma concentration (IPC) has been mentioned as a possible influence on treatment success. Therefore, for the first time in Slovenia, we searched for possible connection between IPC and treatment success defined as a major molecular response (MMR) until 18 months of treatement. Patients and methods: We included 75 patients with CML who had been receiving IM at that time of the study and were diagnosed in a chronic or accelerated phase of CML. Blood samples for IPC determination were sent to areference laboratory in Bordeaux. We set up a method of IPC determination in Slovenia. Results: Association between IPC and MMR achievement until 18 months of tretment was not statistically significant in patients receiving 400 mg of imatinib (p = 0.30). Age and time from the second to last dose of IM were not associated with IPC (p = 0.47 and 0.80, respectively), while gender and dose were (p for both < 0.01). Conclusions: There was no clear correlation between IPC and MMR achievement until 18months of treatment. We conclude that IPC determination would be rational in patents who fail to meet the generally accepted criteria for treatment success, in patients who experience severe side effects of IM, or patients receiving drugs that cause a pharmacokinetic interference with IM. Izhodišča: V zadnjih desetih letih je imatinib (IM) močno izboljšal napoved izida bolezni pri bolnikih s kronično mieloično levkemijo (KML). Toda 30 % bolnikov še vedno ne doseže želenih ciljev zdravljenja ali pa se po določenem času od njih ponovno oddalji. V zadnjih treh letih v literaturi kot možni dejavnik uspešnosti oz. neuspešnost zdravljenja KML omenjajo koncentracijo IM v plazmi (KIP). Zato smo prvič v Sloveniji analizirali povezavo KIP z uspešnostjo zdravljenja KML in jo opredelili kot glavni molekularni odgovor (MMR) do 18. meseca zdravljenja. Bolniki in metode: Vključili smo 75 bolnikov s KML, ki so se v proučevanem obdobju zdravili z IM in so imeli ob diagnozi kronično oziroma pospešeno obdobje KML. Vzorce krvi za določanje KIP smo pošiljali v referenčni laboratorij v Bordeauxu. Vzpostavili smo metodo določanja KIP v Sloveniji. Rezultati: KIP pri bolnikih, ki so prejemali 400 mgIM ni bila statistično značilno povezana z doseganjem MMR do 18. meseca zdravljenja (p = 0,30). Starost in čas od predzadnjega odmerka IM nista bila statistično značilno povezana s plazemsko koncentracijo IM (p = 0,47 oz. 0,80). Spol in odmerek sta bila statistično značilno povezana s koncentracijo (za oba p < 0,01). Zaključki: Jasne povezave med KIP in doseganjem MMR do 18. meseca zdravljenja nismo dokazali.Menimo, da bi bilo določanje koncentracije smiselno pri bolnikih, ki ne dosegajo splošno sprejetih meril za uspešen potek zdravljenja, pri bolnikih, ki imajo močno izražene stranske učinke IM in pri bolnikih, ki ob jemanju IM prejemajo druga zdravila s klinično pomembnimi farmakokinetičnimi interakcijami.

Graphical Abstract Highlights d Derivation of human neocortical and spinal cord neuroepithelial stem (NES) cells d Zika virus (ZIKV) infects NES cells and radial glia, impairing mitosis and survival d ZIKV induces mitochondrial sequestration of centrosomal phospho-TBK1 d Nucleoside analogs inhibit ZIKV replication, protecting NES cells from cell death In Brief Onorati et al. establish neuroepithelial stem (NES) cells as a model for studying human neurodevelopment and ZIKV-induced microcephaly. Together with analyses in human brain slices and microcephalic human fetal tissue, they find that ZIKV predominantly infects NES and radial glial cells, reveal a pivotal role for pTBK1, and find that nucleoside analogs inhibit ZIKV replication, protecting NES cells from cell death.