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1662. Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα : dynophore-derived discoveryBarbara Herlah, Matej Janežič, Iza Ogris, Simona Golič Grdadolnik, Katja Kološa, Sonja Žabkar, Bojana Žegura, Andrej Perdih, 2024, original scientific article Abstract: The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.
Keywords: topoisomerase II, catalytic inhibitors, chemotherapy, DNA damage, cancer
Published in DiRROS: 03.06.2024; Views: 566; Downloads: 327
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1663. Implant-prosthetic rehabilitation after radiation treatment in head and neck cancer patients : a case-series report of outcomeJasna Cotič, Jure Jamšek, Milan Kuhar, Nataša Ihan Hren, Andrej Kansky, Mutlu Özcan, Peter Jevnikar, 2017, original scientific article Abstract: Background. Slovenia has a high burden of head and neck cancer. Patients are mostly treated with surgery followed by radiation therapy. Advanced surgical and prosthodontic techniques have expanded the rehabilitation options. The aim of the study was to review the outcome of implant-prosthetic treatment after radiation therapy. Patients and methods. Twenty irradiated head and neck cancer patients who received a removable implantsupported denture at the University Medical Centre Ljubljana were included in the study. Kaplan-Meier survival analysis, Cox proportional hazard models and logistic regression were used to assess the implant survival and success rate. Results. Twenty patients had 100 implants inserted. The estimated implant survival rate was 96% after 1 year and 87% after 5 years. Failures were mostly observed before loading (91.2%). Implants inserted in the transplanted bone were significantly more likely to fail. Out of 89 implants supporting the dentures, 79 implants (88.7%) were successful, meaning that they were functionally loaded and exhibited no pain, radiolucency or progressive bone loss. Prosthetic treatment was significantly less successful in older patients. The attachment system and the number of implants did not have a statistically significant influence on the success rate. Conclusions. Implant-supported dentures have been shown to be a reliable treatment modality after head and neck cancer surgery and radiation therapy. Possible early failures should be communicated with the patients.
Keywords: head and neck cancer, radiation therapy, dental implants
Published in DiRROS: 03.06.2024; Views: 349; Downloads: 144
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1664. Long-term outcomes of high dose treatment and autologous stem cell transplantation in follicular and mantle cell lymphomas : a single centre experienceLučka Boltežar, Karlo Pintarić, Jože Pretnar, Maja Pohar Perme, Barbara Jezeršek Novaković, 2017, original scientific article Abstract: Background. Advanced follicular lymphoma (FL) and mantle cell lymphoma (MCL) are incurable diseases with conventional treatment. The high dose treatment (HDT) with autologous stem cell transplantation (ASCT), however, offers a certain proportion of these patients the prospect of a prolonged disease-free and overall survival. The aim of this study was to investigate the event free survival (EFS) and overall survival (OS) in patients with FL and MCL treated with ASCT. Patients and methods. Seventeen patients with FL and 29 patients with MCL were included, 15 of them were trans- planted to consolidate the response to second line treatment and 24 to consolidate their first remission, respectively. All were conditioned with total body irradiation (TBI) and high dose cyclophosphamide between 2006 and 2014 and all were transplanted with peripheral blood stem cells. Results. The estimated 5-year OS for FL was 87.8% (95% confidence interval [CI] 59.5%-96.8%) and for MCL 79.3% (95% CI 56.1%-91.1%), respectively. The estimated 5-year EFS for FL was 76.0% (95% CI 48.0%-90.3%) and for MCL 69.8% (95% CI 45.5%-84.8%), respectively. There were no secondary hematological malignancies observed in either group. Conclusions. Based on above results, the ASCT with TBI is a good treatment option in terms of long-term survival for patients with follicular and mantle cell lymphoma demonstrating a relatively low rate of late toxicities and secondary malignancies.
Keywords: follicular lymphoma, mantle cell lymphoma, autologous stem cell transplantation
Published in DiRROS: 03.06.2024; Views: 330; Downloads: 210
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1665. Incidence of positive peritoneal cytology in patients with endometrial carcinoma after hysteroscopy vs. dilatation and curettageAndraž Dovnik, Bojana Crnobrnja, Branka Žegura Andrić, Iztok Takač, Maja Pakiž, 2017, original scientific article Abstract: Background. The aim of the study was to compare the frequency of positive peritoneal washings in endometrial cancer patients after either hysteroscopy (HSC) or dilatation and curettage (D&C). Patients and methods. We performed a retrospective analysis of 227 patients who underwent either HSC (N = 144) or D&C (N = 83) and were diagnosed with endometrial carcinoma at the University Medical Centre Maribor between January 2008 and December 2014. The incidence of positive peritoneal cytology was evaluated in each group. Results. There was no overall difference in the incidence of positive peritoneal washings after HSC or D&C (HSC = 13.2%; D&C = 12.0%; p = 0.803). However, a detailed analysis of stage I disease revealed significantly higher rates of positive peritoneal washings in the HSC group (HSC = 12.8%; D&C = 3.4%; p = 0.046). Among these patients, there was no difference between both groups considering histologic type (chi-square = 0.059; p = 0.807), tumour differentiation (chi-square = 3.709; p = 0.156), the time between diagnosis and operation (t = 0.930; p = 0.357), and myometrial invasion (chi-square = 5.073; p = 0.079). Conclusions. Although the diagnostic procedure did not influence the overall incidence of positive peritoneal washings, HSC was associated with a significantly higher rate of positive peritoneal cytology in stage I endometrial carcinoma compared to D&C.
Published in DiRROS: 03.06.2024; Views: 421; Downloads: 232
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1666. Prognostic significance of uPA/PAI-1 level, HER2 status, and traditional histologic factors for survival in node-negative breast cancer patientsNina Fokter Dovnik, Iztok Takač, 2017, original scientific article Abstract: Background. The association of HER2 status with urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) levels raises the question whether uPA/PAI-1 level carries additional clinically relevant prognostic information independently from HER2 status. The aim of our study was to compare the prognostic value of uPA/PAI-1 level, HER2 status, and traditional prognostic factors for survival in node-negative breast cancer patients. Patients and methods. A retrospective analysis of 858 node-negative breast cancer patients treated in Maribor University Clinical Center, Slovenia, in the years 2000-2009 was performed. Data were obtained from patient medical records. The median follow-up time was 100 months. Univariate and multivariate analyses of disease-free (DFS) and overall survival (OS) were performed using the Cox regression and the Cox proportional hazards model. Results. In univariate analysis, age, tumor size, grade, lymphovascular invasion, HER2 status and UPA/PAI-1 level were associated with DFS, and age, tumor size, grade, and uPA/PAI-1 level were associated with OS. In the multivariate model, the most important determinants of DFS were age, estrogen receptor status and uPA/PAI-1 level, and the most important factors for OS were patient age and tumor grade. The HR for death from any cause in the multivariate model was 1.98 (95% CI 0.83-4.76) for patients with high uPA and/or PAI-1 compared to patients with both values low. Conclusions. uPA/PAI-1 level clearly carries an independent prognostic value regardless of HER2 status in node-negative breast cancer and could be used in addition to HER2 and other markers to guide clinical decisions in this setting.
Published in DiRROS: 03.06.2024; Views: 300; Downloads: 204
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1667. Insulin-like growth factor 1 receptor expression in advanced non-small-cell lung cancer and its impact on overall survivalMojca Humar, Izidor Kern, Gregor Vlačić, Vedran Hadžić, Tanja Čufer, 2017, original scientific article Keywords: insulin-like growth factor 1 receptor, type 2 diabetes mellitus, advanced non-small-cell lung cancer, overall survival
Published in DiRROS: 03.06.2024; Views: 355; Downloads: 240
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1668. Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma : introducing a haplotype based approachBarbara Faganel Kotnik, Janez Jazbec, Petra Bohanec Grabar, Christina Rodriguez-Antona, Vita Dolžan, 2017, original scientific article Keywords: acute lymphoblastic leukaemia, genetic polymorphism, haplotype, methotrexate
Published in DiRROS: 31.05.2024; Views: 323; Downloads: 236
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1669. PD-L1 expression in squamous-cell carcinoma and adenocarcinoma of the lungUrška Janžič, Izidor Kern, Andrej Janžič, Luka Čavka, Tanja Čufer, 2017, original scientific article Abstract: With introduction of immunotherapy (IT) into the treatment of advanced non-small-cell lung cancer (NSCLC), a need for predictive biomarker became apparent. Programmed death ligand 1 (PD-L1) protein expression is most widely explored predictive marker for response to IT. We assessed PD-L1 expression in tumor cells (TC) and immune cells (IC) of squamous-cell carcinoma (SCC) and adenocarcinoma (AC) patients. We obtained 54 surgically resected tumor specimens and assessed PD-L1 expression by immunohistochemistry after staining them with antibody SP142 (Ventana, USA). Clinicopathological characteristics were acquired from the hospital registry database. Results were analyzed according to cut-off values of % 5% and % 10% of PD-L1 expression on either TC or IC. 29 (54%) samples were AC and 25 (46%) were SCC. PD-L1 expression was significantly higher in TC of SCC compared to AC at both cut-off values (52% vs. 17%, p = 0.016 and 52% vs. 14%, p = 0.007, respectively) no difference in PD-L1 expression in IC of SCC and AC was found. In AC alone, PD-L1 expression was significantly higher in IC compared to TC at both cut-off values (72% vs. 17%, p < 0.001 and 41% vs. 14%, p = 0.008, respectively), while no significant difference between IC and TC PD-L1 expression was revealed in SCC. Our results suggest a significantly higher PD-L1 expression in TC of SCC compared to AC, regardless of the cut-off value. PD-L1 expression in IC is high in both histological subtypes of NSCLC, and adds significantly to the overall positivity of AC but not SCC.
Keywords: lung cancer, squamous-cell lung cancer, adenocarcinoma, tumor cells, immune cells, PD-L1 expression
Published in DiRROS: 31.05.2024; Views: 492; Downloads: 367
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1670. A novel mutation in the FOXC2 gene : a heterozygous insertion of adenosine (c.867insA) in a family with lymphoedema of lower limbs without distichiasisTanja Planinšek Ručigaj, Matija Rijavec, Jovan Miljković, Julij Šelb, Peter Korošec, 2017, original scientific article Keywords: primary lymphedema, FOXC2 mutation, distichiasis, lower limbs lymphedema
Published in DiRROS: 31.05.2024; Views: 378; Downloads: 189
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