https://hdl.handle.net/20.500.14178/903 Fri, 17 Apr 2026 22:27:55 GMT 2026-04-17T22:27:55Z https://hdl.handle.net/20.500.14178/3699 Determinants of Implantation Success in Pancreatic Cancer Patient-Derived Xenografts: Role of Matrigel Application, Histological Subtype, and Time Management Gayibov, Emin; Sychra, Tomáš; Spálenková, Alžběta; Šeborová, Karolína; Koucká, Kamila; Tesařová, Tereza; Kočí, Kamila; Vícha, Matěj; Szabó, Arpád; Václavíková, Radka; Šubrt, Zdeněk; Souček, Pavel; Oliverius, Martin Pancreatic cancer (PC) is a growing global health concern, highlighting the need for improved preclinical models. Patient-derived xenografts (PDXs) closely replicate tumor biology and serve as a vital link between preclinical and clinical research. This study investigated the key factors influencing the success of PDX implantation in PC. We compared Matrigel-assisted implantation versus Matrigel-free implantation. We also evaluated the impact of histological subtype on implantation success, analyzing pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma (ASPC), and acinar cell carcinoma (ACC). Additionally, we assessed whether the tumor specimen culture-to-implantation period affected both the take rate and tumor growth rate. A significance threshold of p < 0.05 was applied (95% confidence interval), and multivariable regression analysis was conducted to identify independent predictors of implantation success. In both NOD/SCID and NU/NU (nude) strains, Matrigel-assisted PDAC implantations achieved significantly higher take rates (75% vs. 90%) compared to direct implantations (25% vs. 0%) in the second generation (p = 0.02). The ASPC subtype was a significant predictor of success in the NOD/SCID strain (p = 0.04). The culture-to-implantation period did not affect take rates. The nude strain significantly prolonged ACC engraftment (p = 0.02). In direct ACC implantations, earlier generations (F1-F5) required shorter engraftment growth duration (p < 0.0001). For ASPC, later generations demonstrated longer growth duration (p < 0.04). These findings emphasize critical variables in optimizing PC PDX protocols, particularly Matrigel use, mouse strain selection, and consideration of histological and generation-specific effects. Such refinements can optimize PDX efficiency and translational relevance. Wed, 01 Jan 2025 00:00:00 GMT https://hdl.handle.net/20.500.14178/3699 2025-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3479 Negative prognostic significance of primary cilia and cytoplasmic β-catenin expression in non-small cell lung cancer Rosová, Blanka; Filipová, Alžběta; Hadzi Nikolov, Dimitar; Drösslerová, Marie; Matěj, Radoslav; Rozsypalová, Aneta; Richter, Igor; Melichar, Bohuslav; Mahel, Rostislav; Štěpánová, Radka; Lohynská, Radka; Dvořák, Josef The objective of this study was to investigate the prognostic significance of the frequency of primary cilia (PC) and β-catenin expression in 218 patients (pts) with non-small cell lung cancer (NSCLC), including 125 pts with adenocarcinoma and 93 pts with squamous cell carcinoma. In the whole group of 218 pts with NSCLC, overall survival (OS) was significantly inferior among pts with present PC than without PC (p=0.024) and with higher cytoplasmic β-catenin expression (25-75%) than with lower cytoplasmic β-catenin expression (<25%) (p=0.008). In the univariate Cox proportional hazard model, the hazard ratio was 1.653 in pts with present PC (p=0.026) and 1.851 in pts with higher cytoplasmic β-catenin (25-75%) (p=0.009). Multivariate testing of the whole group of 218 pts with NSCLC showed that the presence of PC was associated with a worse prognosis (p=0.018). In the subgroup of 125 pts with adenocarcinoma, OS was significantly improved in pts with higher membranous β-catenin expression (>=50%) than in pts with lower expression (<50%) (p=0.0300) and OS was significantly inferior in pts with higher cytoplasmic β-catenin expression (25-75%) than in pts with lower expression (<25%) (p=0.0004). Multivariate testing of the subgroup of pts with adenocarcinoma showed that cytoplasmic β-catenin (p<0.001) and pleural invasion (p=0.017) were associated with worse prognosis. The present results indicate a negative prognostic significance of PC and cytoplasmic β-catenin expression in NSCLC and a negative prognostic significance of cytoplasmic β-catenin expression in adenocarcinoma. Mon, 01 Jan 2024 00:00:00 GMT https://hdl.handle.net/20.500.14178/3479 2024-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3403 Acute and Short-Term Hemodynamic and Echocardiography Changes During and After Left Atrial Appendage Closure Heřman, Dalibor; Peichl, Petr; Hozman, Marek; Janek, Bronislav; Kníže, Tomáš; Víchová, Teodora; Línková, Hana; Veselá, Jana; Karch, Jakub; Valošková, Naďa; Borisincová, Eva; Osmančík, Pavel Background: The left atrial appendage (LAA) plays an important role as a reservoir and has endocrine functions. This study aimed to assess the acute hemodynamic effects associated with LAA closure (LAAC) and ensuing structural changes 3 months after closure. Methods: Two centers enrolled patients for LAAC from January 2022 to July 2024. Invasive hemodynamic measurements of left atrial pressure (LAP) were taken after the transseptal puncture and postdevice deployment (both before and after isometric exercise). The heart failure (HF) biomarkers (NT-proBNP, NT-proANP, and GDF-15) were assessed before and 3 months after LAAC. The echocardiographic parameters were assessed before and 6 months after LAAC. Results: Sixty-two patients participated (age 75.7 +- 8.2 years, 45 (72.6%) males, CHA<inf>2</inf>DS<inf>2</inf>VASc 4.1 +- 1.3). Both rest and postexercise LAP values increased after device implantation (rest: 14.9 +- 7.1 before vs. 17.6 +- 7.9 mm Hg after, p < 0.001; postexercise: 18.7 +- 8.6 before vs. 21.8 +- 9.5 mm Hg after, p < 0.001). The administration of larger volumes of fluid during the procedure was significantly correlated with a higher increase in resting LAP following device implantation. On the other hand, exercise-induced changes in postprocedural LAP (i.e., the difference between postexercise vs. rest) were negatively associated with the amount of fluid administered during the procedure. Three months postprocedure, we observed no changes in HF biomarkers. Six months postprocedure, we observed no changes in LA and LV echocardiographic parameters. Conclusions: LAAC caused an acute increase in both rest and exercise LAP. The amount of procedural fluid is one of the most important parameters associated with LAP changes. Wed, 01 Jan 2025 00:00:00 GMT https://hdl.handle.net/20.500.14178/3403 2025-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3314 Long-term adaptation of lymphoma cell lines to hypoxia is mediated by diverse molecular mechanisms that are targetable with specific inhibitors Daumová, Lenka; Manakov, Dmitry; Petrák, Jiří; Sovilj, Dana; Běhounek, Matěj; Andera, Ladislav; Vít, Ondřej; Součková, Olga; Havránek, Ondřej; Dolníková, Alexandra; Renešová, Nicol; Tušková, Liliana; Winkowska, Lucie; Bettazová, Nardjas; Kupcová, Kristýna; Hubálek Kalbáčová, Marie; Sikorová, Miriama; Trněný, Marek; Klener, Pavel A large body of evidence suggests that hypoxia drives aggressive molecular features of malignant cells irrespective of cancer type. Non-Hodgkin lymphomas (NHL) are the most common hematologic malignancies characterized by frequent involvement of diverse hypoxic microenvironments. We studied the impact of long-term deep hypoxia (1% O2) on the biology of lymphoma cells. Only 2 out of 6 tested cell lines (Ramos, and HBL2) survived >= 4 weeks under hypoxia. The hypoxia-adapted (HA)b Ramos and HBL2 cells had a decreased proliferation rate accompanied by significant suppression of both oxidative phosphorylation and glycolytic pathways. Transcriptome and proteome analyses revealed marked downregulation of genes and proteins of the mitochondrial respiration complexes I and IV, and mitochondrial ribosomal proteins. Despite the observed suppression of glycolysis, the proteome analysis of both HA cell lines showed upregulation of several proteins involved in the regulation of glucose utilization including the active catalytic component of prolyl-4-hydroxylase P4HA1, an important druggable oncogene. HA cell lines demonstrated increased transcription of key regulators of auto-/mitophagy, e.g., neuritin, BCL2 interacting protein 3 (BNIP3), BNIP3-like protein, and BNIP3 pseudogene. Adaptation to hypoxia was further associated with deregulation of apoptosis, namely upregulation of BCL2L1/BCL-XL, overexpression of BCL2L11/BIM, increased binding of BIM to BCL-XL, and significantly increased sensitivity of both HA cell lines to A1155463, a BCL-XL inhibitor. Finally, in both HA cell lines AKT kinase was hyperphosphorylated and the cells showed increased sensitivity to copanlisib, a pan-PI3K inhibitor. In conclusion, our data report on several shared mechanisms of lymphoma cell adaptation to long-term hypoxia including: 1. Upregulation of proteins responsible for glucose utilization, 2. Degradation of mitochondrial proteins for potential mitochondrial recycling (by mitophagy), and 3. Increased dependence on BCL-XL and PI3K-AKT signaling for survival. In translation, inhibition of glycolysis, BCL-XL, or PI3K-AKT cascade may result in targeted elimination of HA lymphoma cells. Wed, 01 Jan 2025 00:00:00 GMT https://hdl.handle.net/20.500.14178/3314 2025-01-01T00:00:00Z