https://hdl.handle.net/20.500.14178/901 Fri, 17 Apr 2026 17:22:46 GMT 2026-04-17T17:22:46Z https://hdl.handle.net/20.500.14178/3733 Unraveling the telomere-mitochondrial axis in colorectal cancer: Results from a prospectively followed cohort Gil-Korilis, Adrián; Ergui-Arbizu, Jorge; Hanák, Petr; Danešová, Natálie; Tomášová, Kristýna; Valíčková, Anna; Horák, Josef; Gentiluomo, Manuel; Levý, Miroslav; Křivonosková, Soňa; Král, Jan; Jungwirth, Jiří; Vodičková, Ľudmila; Vymetálková, Veronika; Azqueta, Amaya; Campa, Daniele; Vodička, Pavel; Vodenková, Soňa Background Telomere shortening and mitochondrial dysfunction are well-known independent contributors to many diseases, but emerging evidence suggests a reciprocal relationship between the two processes. The role of the so-called telomere-mitochondrial axis in colorectal cancer (CRC) remains largely unknown. Methods This prospective cohort study screened CRC patients who underwent surgery, from whom peripheral blood, intestinal mucosa, and tumor samples were collected. Colonoscopically confirmed cancer- and adenoma-free healthy individuals were screened as controls, from whom peripheral blood and intestinal mucosa samples were obtained. Relative mitochondrial DNA copy number (mtDNA-CN) and relative telomere length (RTL) were measured in all samples by real-time quantitative polymerase chain reaction and were further compared and correlated considering clinical data. Relative mtDNA-CN was quantified using both TaqMan probes and SYBR Green to compare both methods. Finally, multivariable analyses were conducted to investigate the association between both biomarkers and the risk of tumor recurrence and mortality. Results A total of 166 CRC patients and 61 healthy individuals were included in the study. In TNM stage I patients, relative mtDNA-CN and RTL were negatively correlated with each other in intestinal mucosa (ρ = -0.77, p < 0.0001), tumor tissue (ρ = -0.41, p = 0.032), and the tumor-to-intestinal mucosa ratio (ρ = -0.39, p = 0.046). However, these associations disappeared with increasing TNM stage, suggesting a dysregulation of the telomere-mitochondrial axis in advanced disease. Higher relative mtDNA-CN in blood was associated with a lower risk of disease recurrence even after adjusting for multiple covariates (HR = 0.43, 95% CI 0.20-0.97, p = 0.041), highlighting its potential use as a prognostic tool. The quantification of mtDNA-CN performed by both methods -TaqMan probes and SYBR Green- was shown to be positively correlated (p < 0.01). Relative mtDNA-CN and RTL were found to be tissue-dependent in both CRC patients and healthy controls. Conclusions This study provides a novel contribution to the understanding of the almost unexplored telomere-mitochondrial axis in CRC, highlighting its potential role in disease progression and prognosis. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3733 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3728 Comparative effectiveness of anti-CD20 therapies and S1P receptor modulators in late-onset multiple sclerosis: real-world evidence from the MSBase registry Surcinelli, Andrea; Kalincik, Tomas; Roos, Izanne; D'amico, Emanuele; Lechner-Scott, Jeannette; Ozakbas, Serkan; Hradilek, Pavel; Horáková, Dana; Vachová, Marta; Panzera, Ivan; Ruzza, Stefano; Piscaglia, Maria Grazia; Gerlach, Oliver; Meca-Lallana, Jose Eustasio; Valero-Lopez, Gabriel; Kermode, Allan G.; Fabis-Pedrini, Marzena J.; Prevost, Julie; Ampapa, Radek; Hodgkinson, Suzanne; Grand'maison, Francois; Khoury, Samia J.; John, Nevin A.; Peterka, Marek; Houskova, Jana; Recmanova, Eva; Rous, Zuzana; Shaygannejad, Vahid; Alroughani, Raed; Kuhle, Jens; Jakob, Gregor Brecl; Grammond, Pierre; Patti, Francesco; Van Der Walt, Anneke; Butzkueven, Helmut; Foschi, Matteo Background: Late-onset multiple sclerosis (LOMS), defined by symptom onset after age 50, is increasingly recognised as a distinct clinical entity. Evidence comparing disease-modifying therapies (DMTs) in this subgroup remains limited. Objectives: To compare clinical outcomes of anti-CD20 monoclonal antibodies and sphingosine-1-phosphate receptor modulators (S1PRMs) in LOMS. Design: Multicentre, observational cohort study based on real-world data from an international multiple sclerosis registry. Methods: We analysed data from the MSBase registry, including relapsing-remitting LOMS patients treated with anti-CD20 therapies (ocrelizumab, ofatumumab, rituximab) or S1PRMs (fingolimod, ozanimod, siponimod, ponesimod) for >= 6 months. Primary outcomes were annualised relapse rate (ARR), Expanded Disability Status Scale (EDSS) change, confirmed disability worsening (CDW), progression independent of relapse activity (PIRA), and PIRA without MRI activity (PIRMA). Analyses used inverse probability of treatment weighting (IPTW). Causal forest and best linear projector (BLP) models explored effect modification. Results: After weighting, 347 patients (median age 53.7 years; 69% female; median follow-up 6.9 years) were included. No significant differences were found for ARR, EDSS change, CDW, PIRA, or PIRMA. Exploratory analyses suggested greater anti-CD20 benefit in patients with earlier onset (<= 55 years), shorter disease duration (<= 2 years from diagnosis), and lower disability (EDSS < 3). Conclusions: In this real-world LOMS cohort, no statistically significant differences were observed between anti-CD20 and S1PRM therapies. Exploratory analyses suggested anti-CD20 may be associated with better outcomes in selected subgroups; these findings are hypothesis-generating. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3728 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3720 Does motherhood increase the risk of developing subsequent malignant neoplasms after childhood cancer treatment? Blagodárná, Sarah; Hošek, Petr; Jelínková, Kristýna; Korbelová, Lucie; Eckschlager, Tomáš; Lischke, Robert; Šrámková, Lucie; Kruseová, Jarmila BACKGROUND: Most young women who have survived childhood cancer express a desire to have children. Many of them are concerned about the potential adverse impact of pregnancy on their health, which has been affected by prior cancer treatment. The aim of this study was to determine whether motherhood increases the risk of developing subsequent malignant neoplasms. METHODS: The study cohort consisted of 942 female childhood cancer survivors, median age at first cancer diagnosis 10.84 years (IQR 4.29-14.92), who had been treated at the Department of Pediatric Hematology and Oncology, Motol University Hospital, Prague, between 1965 and 2018. In this group, 363 women gave birth to 559 children. RESULTS: Seventy-three female childhood cancer survivors developed 80 subsequent malignant neoplasms. Of these, 40 subsequent malignant neoplasms occurred in women who had children. The median time from the end of primary cancer treatment to first subsequent malignant neoplasm development was 19.93 years (IQR 14.55-26.56). A comprehensive analysis revealed no difference in the risk of subsequent malignant neoplasms between mothers and "non-mothers". Only older age of the cancer survivors in follow-up and previous radiotherapy (p = 0.0133) were significant risk factors for subsequent malignant neoplasm development. CONCLUSIONS: This study revealed that motherhood does not increase the risk of subsequent malignant neoplasms. We confirmed a statistically significant increased risk of subsequent malignant neoplasms only for previous treatment modality, the length of follow-up and the age of the female childhood cancer survivors. These results are important for improving the quality of life of young cured women who are worried about a planned pregnancy. PLAIN LANGUAGE SUMMARY: This study evaluated the long-term cancer risk among women treated for cancer during childhood, with particular focus on those who later gave birth. Among 942 participants, 363 had post-treatment pregnancies. Results indicate that childbearing does not increase the risk of subsequent malignant neoplasms in this population. Instead, elevated risk for subsequent malignant neoplasms was associated with older age at follow-up and prior exposure to radiotherapy. These findings provide evidence that pregnancy is safe for female childhood cancer survivors and support informed reproductive decision-making. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3720 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3719 Discovery of Novel Murine PML Isoforms Anderová, Karolína; Horníková, Lenka; Šroller, Vojtěch; Rjabčenko, Boris; Pánek, Dalibor; Andrikopoulos, Prokopios; Zahradník, Jiří; Forstová, Jitka; Huerfano Meneses, Sandra Promyelocytic leukemia protein (PML) orchestrates the formation of PML nuclear bodies (PML NBs), membraneless organelles with diverse regulatory roles. Despite their importance, the specific functions of individual PML splicing variants remain unclear, particularly in murine models. Here we study the repertoire of murine PML isoforms expressed in mouse tissues and cells. We demonstrate that in addition to canonical mPML1-3, mice express five predicted variants (mPMLX1, mPMLX2, mPMLX4-X6) and a novel isoform, mPMLX7, distinguished by unique RBCC domain splicing. All isoforms exhibit distinct turnover kinetics at endogenous PML NBs. In PML-knockout cells, all isoforms except mPMLX7 form NBs de novo and are degraded upon arsenic exposure. Molecular dynamics simulations suggest mPMLX7 adopts a stable conformation; furthermore, this isoform is enriched in the nucleoplasm, suggesting a specialized function. Altogether, this isoform-resolved PML system provides a relevant model for dissecting the wide spectrum of PML-associated processes. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3719 2026-01-01T00:00:00Z