1. Epithelial-to-mesenchymal transition as the driver of changing carcinoma and glioblastoma microenvironmentBernarda Majc, Tilen Sever, Miki Zarić, Barbara Breznik, Boris Turk, Tamara Lah Turnšek, 2020, review article Abstract: Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process that is part of normal embryogenesis and wound healing, and also has a ubiquitous role in various types of carcinoma and glioblastoma. EMT is activated and regulated by specific microenvironmental endogenous triggers and a complex network of signalling pathways. These mostly include epigenetic events that affect protein translation-controlling factors and proteases, altogether orchestrated by the switching on and off of oncogenes and tumour-suppressor genes in cancer cells. The hallmark of cancer-linked EMT is that the process is incomplete, as it is opposed by the reverse process of mesenchymal-to-epithelial transition, which results in a hybrid epithelial/mesenchymal phenotype that shows notable cell plasticity. This is a characteristic of cancer stem cells (CSCs), and it is of the utmost importance in their niche microenvironment, where it governs CSC migratory and invasive properties, thereby creating metastatic CSCs. These cells have high resistance to therapeutic treatments, in particular in glioblastoma.
Keywords: carcinomas, cancer stem cellsInvasion, proteases, tumour microenvironment
Published in DiRROS: 06.08.2024; Views: 30; Downloads: 50
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2. Brain malignancies : glioblastoma and brain metastasesTamara Lah Turnšek, Metka Novak, Barbara Breznik, 2020, review article Abstract: Brain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor – glioblastoma and metastases from other organs to the brain are lethal leaving the patients with very short time of survival. The brain tissue landscape is very different from any other tissues and the specific microenvironment, comprising stem cells niches and blood-brain barrier, significantly influences the low rate of glioblastoma metastasis out of the brain, but better accommodates brain-invading cancer. In contrast to low frequency (0.5%) of all glioblastoma metastases, 10%–45% of other primary cancers do metastasize to the brain. This review addresses general cellular and molecular pathways that are to some extent similar in both types of metastases, involving circulating tumor cells (CTCs) with cancer stem cells (CSCs) characteristics, and metastatic niches. The invasion is a dynamic process involving reversible epithelial-to-mesenchymal (EMT) cell process, creating a transient gradient state that is inter-connected with epigenetic plasticity of the metastasizing (m)CSCs. These cells can switch between stationary, low proliferating/dormant state to a migratory, mesenchymal-like state. Settling in their respective niches as dormant CSCs in the secondary organ is a common feature in all types of metastases. In glioblastoma metastasis, the malignant mGSC cells express markers of mesenchymal GSC subtype (MES-GSC), such as CD44 and YK-40 and their major obstacle seems to be propagating in the in various organs’ microenvironments, different from the niches that home GSCs in the primary glioblastoma. Focusing on one stromal component in the glioblastoma niches, the mesenchymal stem cells (MSCs), we report herein on their differential effects on glioblastoma cells, highly depending on their genetic subtype. On the other hand, in brain metastases, the major hindrance to metastatic progression of mCSCs seem to be crossing the blood-brain-barrier. Novel therapeutic approaches for brain metastases from various cancer types are advancing slowly, and the general trends involve targeting metastatic sub-clones and selective determinants of their niches. The update on the four most common brain metastases from lung, breast, melanoma and colorectal carcinoma is presented.
Keywords: glioblastoma, cancer stem cells, invasion, metastasis, tumor microenvironment
Published in DiRROS: 06.08.2024; Views: 47; Downloads: 76
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3. Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapyBahar Yetkin-Arik, Arnoud W. Kastelein, Ingeborg Klaassen, Charlotte H. J. R. Jansen, Yani P. Latul, Miloš Vittori, Aydan Biri, Korhan Kahraman, Arjan W. Griffioen, Frederic Amant, Christianne A. R. Lok, Reinier O. Schlingemann, Cornelis J. F. van Noorden, 2021, review article Abstract: Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.
Keywords: angiogenesis, anti-angiogenic therapy, endothelial cells, endothelial cell metabolism, gynecological cancer, non-tip cells, tip cells, tumor microenvironment, vascular disrupting agents
Published in DiRROS: 05.08.2024; Views: 32; Downloads: 55
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4. TRIM28 and [beta]-actin identified via nanobody-based reverse proteomics approach as possible human glioblastoma biomarkersIvana Jovchevska, Neja Šamec, Nina Kočevar Britovšek, Daniela Cesselli, Neža Podergajs, Clara Limbaeck Stanic, Michael P. Myers, Serge Muyldermans, Gholamreza Hassanzadeh Ghassabeh, Helena Motaln, Maria Elisabetta Ruaro, Evgenia Bourkoula, Tamara Lah Turnšek, Radovan Komel, 2014, original scientific article Abstract: Malignant gliomas are among the rarest brain tumours, and they have the worst prognosis. Grade IV astrocytoma, known as glioblastoma multiforme (GBM), is a highly lethal disease where the standard therapies of surgery, followed by radiation and chemotherapy, cannot significantly prolong the life expectancy of the patients. Tumour recurrence shows more aggressive form compared to the primary tumour, and results in patient survival from 12 to 15 months only. Although still controversial, the cancer stem cell hypothesis postulates that cancer stem cells are responsible for early relapse of the disease after surgical intervention due to their high resistance to therapy. Alternative strategies for GBM therapy are thus urgently needed. Nanobodies are single-domain antigen-binding fragments of heavy-chain antibodies, and together with classical antibodies, they are part of the camelid immune system. Nanobodies are small and stable, and they share a high degree of sequence identity to the human heavy chain variable domain, and these characteristics offer them advantages over classical antibodies or antibody fragments. We first immunised an alpaca with a human GBM stem-like cell line prepared from primary GBM cultures. Next, a nanobody library was constructed in a phage-display vector. Using nanobody phage-display technology, we selected specific GBM stem-like cell binders through a number of affinity selections, using whole cell protein extracts and membrane protein-enriched extracts from eight different GBM patients, and membrane protein-enriched extracts from two established GBM stem-like cell lines (NCH644 and NCH421K cells). After the enrichment, periplasmic extract ELISA was used to screen for specific clones. These nanobody clones were recloned into the pHEN6 vector, expressed in Escherichia coli WK6, and purified using immobilised metal affinity chromatography and size-exclusion chromatography. Specific nanobody:antigen pairs were obtained and mass spectrometry analysis revealed two proteins, TRIM28 and β-actin, that were up-regulated in the GBM stem-like cells compared to the controls.
Keywords: malignant gliomas, cancer stem cells, nanobodies
Published in DiRROS: 02.08.2024; Views: 89; Downloads: 69
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5. BioMinerJoachim Selbig, Kristina Gruden, Michal Or-Guil, Christian Schichor, Chris Bauer, Karol Stec, Alexander Glintschert, Johannes Schuchhardt, 2015, original scientific article Abstract: Personalized medicine is promising a revolution for medicine and human biology in the 21st century. The scientific foundation for this revolution is accomplished by analyzing biological high-throughput data sets from genomics, transcriptomics, proteomics, and metabolomics. Currently, access to these data has been limited to either rather simple Web-based tools, which do not grant much insight or analysis by trained specialists, without firsthand involvement of the physician. Here, we present the novel Web-based tool “BioMiner,” which was developed within the scope of an international and interdisciplinary project (SYSTHER†) and gives access to a variety of high-throughput data sets. It provides the user with convenient tools to analyze complex cross-omics data sets and grants enhanced visualization abilities. BioMiner incorporates transcriptomic and cross-omics high-throughput data sets, with a focus on cancer. A public instance of BioMiner along with the database is available at http://systherDB.microdiscovery.de/, login and password: “systher”; a tutorial detailing the usage of BioMiner can be found in the Supplementary File.
Keywords: data mining, multiomics data integration, biomarker detection, pathway visualization, personalized medicine, cancer
Published in DiRROS: 26.07.2024; Views: 104; Downloads: 89
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6. Phase angle as a prognostic indicator of surgical outcomes in patients with gastrointestinal cancerJana Gulin, Ester Ipavic, Denis Mlakar-Mastnak, Erik Brecelj, Ibrahim Edhemović, Nada Rotovnik-Kozjek, 2023, original scientific article Keywords: phase angle, colorectal cancer, postoperative complications, malnutrition
Published in DiRROS: 26.07.2024; Views: 252; Downloads: 30
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7. Post-radiation xerostomia therapy with allogeneic mesenchymal stromal stem cells in patients with head and neck cancer : study protocol for phase I clinical trialPrimož Strojan, Gaber Plavc, Marko Kokalj, Goran Mitrović, Olga Blatnik, Luka Ležaič, Aljaž Sočan, Aljoša Bavec, Nataša Tešić, Katrina Pretnar-Hartman, Urban Švajger, 2023, original scientific article Abstract: Background: Xerostomia is a common side effect of radiotherapy in patients with head and neck tumors that negatively affects quality of life. There is no known effective standard treatment for xerostomia. Here, we present the study protocol used to evaluate the safety and preliminary efficacy of allogeneic mesenchymal stromal stem cells (MSCs) derived from umbilical cord tissue. Methods: Ten oropharyngeal cancer patients with post-radiation xerostomia and no evidence of disease recurrence 2 or more years after (chemo)irradiation (intervention group) and 10 healthy volunteers (control group) will be enrolled in this nonrandomized, open-label, phase I exploratory study. MSCs from umbilical cord tissue will be inserted under ultrasound guidance into both parotid glands and both submandibular glands of the patients. Toxicity of the procedure will be assessed according to CTCAE v5.0 criteria at days 0, 1, 5, 28, and 120. Efficacy will be assessed by measuring salivary flow and analyzing its composition, scintigraphic evaluation of MSC grafting, retention, and migration, and questionnaires measuring subjective xerostomia and quality of life. In addition, the radiological, functional, and morphological characteristics of the salivary tissue will be assessed before, at 4 weeks, and at 4 months after the procedure. In the control group subjects, only salivary flow rate and salivary composition will be determined. Discussion: The use of allogeneic MSCs from umbilical cord tissue represents an innovative approach for the treatment of xerostomia after radiation. Due to the noninvasive collection procedure, flexibility of cryobanking, and biological advantages, xerostomia therapy using allogeneic MSCs from umbilical cord tissue may have an advantage over other similar therapies.
Keywords: oropharyngeal cancer, xerostomia, mesenchymal stromal stem cells
Published in DiRROS: 26.07.2024; Views: 252; Downloads: 106
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9. Local control and survival after stereotactic body radiation therapy of early-stage lung cancer patients in SloveniaKarmen Stanič, Jasna But-Hadžić, Jan Žagar, Martina Vrankar, 2023, original scientific article Abstract: Background. Stereotactic body radiation therapy (SBRT) precisely and non-invasively delivers ablative radiationdose to tumors in early-stage lung cancer patients who are not candidates for surgery or refuse it. The aim of researchwas to evaluate local control, overall survival (OS), local progression free survival (LPFS), distant metastases free survival(DMFS), disease free survival (DFS) and toxicity in early-stage lung cancer patients treated with SBRT in a single tertiarycancer centre.Patients and methods. We retrospectively evaluated medical records and radiation treatment plan parametersof 228 tumors irradiated in 206 early-stage lung cancer patients between 2016 and 2021 at the Institute of OncologyLjubljana.Results. After 25 months of median follow up, 68 of 206 (33%) patients died. Median OS was 46 months (CI 36 −56),1-year, 2-year and 3-year OS were 87%, 74% and 62% and 5-year OS was 31%. A total of 45 disease progressions havebeen identified in 41 patients. Local progress only was noticed in 5 (2%) patients, systemic progress in 32 (16%) andcombined systemic and local in 4 (2%) patients. Local control rate (LCR) at 1 year was 98%, at 2 and 3 years 96%and 95% at 5 years. The 1-, 2- and 3-year LPFS were 98%, 96% and 94%, respectively and 5-year LPFS was 82%. One,2-, 3- and 5-year DFS w ere 89%, 81%, 72% and 49%, respectively. Among 28 toxicities recorded only one was Grade4 (pneumonitis), all others were Grade 1 or 2. No differences in LCR, LPFS, DFS were found in univariate analysis com-paring patient, tumor, and treatment characteristics. For OS the only statistically significant difference was found inpatients with more than 3 comorbidities compared to those with less comorbidities.Conclusions. Early lung cancer treated with SBRT at single tertiary cancer centre showed that LCR, LPFS, DFS, DMFSand OS were comparable to published studies. Patients with many comorbidities had significantly worse overallsurvival compared to those with less comorbidities. No other significant differences by patient, tumor, or treatmentcharacteristics were found for DMFS, LPFS, and DFS. Toxicity data confirmed that treatment was well tolerated.
Keywords: stereotactic body radiotherapy, early-stage lung cancer, lung cancer
Published in DiRROS: 25.07.2024; Views: 119; Downloads: 54
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10. Breast cancer risk assessment and risk distribution in 3,491 Slovenian women invited for screening at the age of 50 : a population-based cross-sectional studyKatja Jarm, Vesna Zadnik, Mojca Birk, Miloš Vrhovec, Kristijana Hertl, Žan Klaneček, Andrej Studen, Cveto Šval, Mateja Krajc, 2023, original scientific article Abstract: Background. The evidence shows that risk-based strategy could be implemented to avoid unnecessary harm in mammography screening for breast cancer (BC) using age-only criterium. Our study aimed at identifying the uptake of Slovenian women to the BC risk assessment invitation and assessing the number of screening mammographies in case of risk-based screening.Patients and methods. A cross-sectional population-based study enrolled 11,898 women at the age of 50, invited to BC screening. The data on BC risk factors, including breast density from the first 3,491 study responders was col-lected and BC risk was assessed using the Tyrer-Cuzick algorithm (version 8) to classify women into risk groups (low, population, moderately increased, and high risk group). The number of screening mammographies according to risk stratification was simulated. Results. 57% (6,785) of women returned BC risk questionnaires. When stratifying 3,491 women into risk groups, 34.0% were assessed with low, 62.2% with population, 3.4% with moderately increased, and 0.4% with high 10-year BC risk. In the case of potential personalised screening, the number of screening mammographies would drop by 38.6% com-pared to the current screening policy. Conclusions. The study uptake showed the feasibility of risk assessment when inviting women to regular BC screen-ing. 3.8% of Slovenian women were recognised with higher than population 10-year BC risk. According to Slovenian BC guidelines they may be screened more often. Overall, personalised screening would decrease the number of screening mammographies in Slovenia. This information is to be considered when planning the pilot and assessing the feasibility of implementing population risk-based screening.
Keywords: breast cancer screening, personalised screening, risk assessment, mammography
Published in DiRROS: 25.07.2024; Views: 99; Downloads: 121
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