• Publication type
• Meeting Abstract MeSH

Úvod: Luxační zlomeniny distálního bérce jsou indikovány k operačnímu řešení. Pokud kvalita měkkých tkání a kůže neumožňuje primární suturu rány, jedná se o závažný problém, který musí operatér řešit. V našem případě jsme po repozici a fixaci skeletu byli schopni provést suturu fascie s reziduálním velkým defektem kůže a podkoží. Rozhodli jsme se pro využití kombinace aplikace Amniodermu a podtlakové terapie. Metodika: Autoři popisují postup léčby akutní rány u mladého morbidně obézního pacienta s poraněním hlezna po dopravní nehodě. Diskuze: Uzávěr operační rány v terénu otoku a hematomu představuje častý problém, se kterým se setkáváme u nemocných po osteosyntéze hlezna. Existuje několik možných způsobů, které lze využít, zcela jistě mezi ně patří i možnost využití podtlakové terapie, jejíž efekt lze umocnit aplikací Amniodermu. Závěr: Přestože se jedná o první využití prezentované techniky, na podkladě našich dalších zkušeností s Amniodermem obecně a častého využití podtlakové terapie z jiných indikací si dovolujeme tvrdit, že se jedná o bezpečnou metodu, která nabízí efektivní řešení složité ultimátní situace.

Introduction: Dislocation fractures of the distal lower leg require surgical treatment. If the quality of the soft tissues and skin does not allow primary suture of the wound, it presents a serious challenge for the surgeon. In our case, after reposition and fixation of the fractures, we were able to perform a fascia suture with a residual large skin and subcutaneous defect. We decided to use a combination of Amnioderm application and negative pressure therapy. Methods: The authors describe the procedure for the treatment of an acute wound in a young, morbidly obese patient with an ankle injury following a traffic accident. Discussion: Closure of the surgical wound in the field of swelling and hematoma is a frequent problem encountered in patients after ankle osteosynthesis. There are several possible approaches, one of which is the use of negative pressure therapy. Its effect can be enhanced by the application of Amnioderm. Conclusion: Although this is the first use of the presented technique, based on our other general experience with Amnioderm and the frequent use of negative pressure wound therapy from other indications, we dare to say that it is a safe method that offers an effective solution to a complex, critical situation.

• Keywords
• Amnioderm,
• MeSH
• Biological Dressings MeSH
• Adult MeSH
• Ankle Fractures * surgery   complications   MeSH
• Wound Healing MeSH
• Humans MeSH
• Obesity, Morbid complications   MeSH
• Ankle Injuries surgery   complications   MeSH
• Negative-Pressure Wound Therapy * MeSH
• Fracture Fixation, Internal MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.

• MeSH
• Drug Resistance, Neoplasm * MeSH
• Docetaxel * pharmacology   therapeutic use   MeSH
• Epithelial-Mesenchymal Transition drug effects   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms * pathology   drug therapy   metabolism   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Glioblastomas are aggressive brain tumors for which effective therapy is still lacking, resulting in dismal survival rates. These tumors display significant phenotypic plasticity, harboring diverse cell populations ranging from tumor core cells to dispersed, highly invasive cells. Neuron navigator 3 (NAV3), a microtubule-associated protein affecting microtubule growth and dynamics, is downregulated in various cancers, including glioblastoma, and has thus been considered a tumor suppressor. In this study, we challenge this designation and unveil distinct expression patterns of NAV3 across different invasion phenotypes. Using glioblastoma cell lines and patient-derived glioma stem-like cell cultures, we disclose an upregulation of NAV3 in invading glioblastoma cells, contrasting with its lower expression in cells residing in tumor spheroid cores. Furthermore, we establish an association between low and high NAV3 expression and the amoeboid and mesenchymal invasive phenotype, respectively, and demonstrate that overexpression of NAV3 directly stimulates glioblastoma invasive behavior in both 2D and 3D environments. Consistently, we observed increased NAV3 expression in cells migrating along blood vessels in mouse xenografts. Overall, our results shed light on the role of NAV3 in glioblastoma invasion, providing insights into this lethal aspect of glioblastoma behavior.

• MeSH
• Phenotype * MeSH
• Glioblastoma * pathology   genetics   metabolism   MeSH
• Neoplasm Invasiveness * genetics   MeSH
• Humans MeSH
• Membrane Proteins MeSH
• Microtubules metabolism   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms * pathology   genetics   metabolism   MeSH
• Cell Movement genetics   physiology   MeSH
• Nerve Tissue Proteins metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: In women with severe aortic stenosis, there are limited data regarding outcome differences following transcatheter (TAVR) vs surgical aortic valve replacement (SAVR). OBJECTIVES: The authors sought to examine outcomes of TAVR vs SAVR in a patient-level pooled analysis of women in the RHEIA and PARTNER 3 trials. METHODS: Patients in both trials were randomly allocated to a balloon-expandable SAPIEN 3/Ultra valve or to surgical bioprostheses. Individual patient data of female participants in the 2 trials were pooled. The primary endpoint was all-cause mortality, all stroke, or rehospitalization at 1 year. RESULTS: A total of 376 women were randomized to TAVR and 336 to SAVR. The mean age was ∼73 years, and the mean Society of Thoracic Surgeons (STS) score was 2.1%. Kaplan-Meier estimates of event rates at 1 year with TAVR vs SAVR were 8.5% vs 16.8% for the composite of all-cause mortality, all stroke, or rehospitalization (absolute difference -8.2%; 95% CI: -13.1% to -3.3%; P < 0.001), 1.1% vs 2.1% (P = 0.27) for all-cause mortality, 2.7% vs 3.9% (P = 0.35) for all stroke, and 5.4% vs 11.9% (P = 0.002) for rehospitalization. The composite endpoint of all-cause death or stroke was similar between the 2 treatment groups: 3.5% vs 5.4% (absolute difference -1.9%; 95% CI: -5.0% to 1.1%; P = 0.21). CONCLUSIONS: Among women with symptomatic severe aortic stenosis, TAVR led to a reduction in the rate of the combined endpoint of all-cause mortality, stroke, or rehospitalization at 1-year follow-up, largely due to a significant reduction in the rate of rehospitalization.

• MeSH
• Aortic Valve * surgery   physiopathology   diagnostic imaging   MeSH
• Aortic Valve Stenosis * mortality   surgery   physiopathology   diagnostic imaging   MeSH
• Bioprosthesis MeSH
• Time Factors MeSH
• Stroke mortality   etiology   therapy   MeSH
• Heart Valve Prosthesis Implantation * adverse effects   mortality   instrumentation   MeSH
• Risk Assessment MeSH
• Humans MeSH
• Prosthesis Design MeSH
• Randomized Controlled Trials as Topic MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sex Factors MeSH
• Heart Valve Prosthesis MeSH
• Severity of Illness Index MeSH
• Transcatheter Aortic Valve Replacement * adverse effects   mortality   instrumentation   MeSH
• Treatment Outcome MeSH
• Patient Readmission MeSH
• Check Tag
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy.

• MeSH
• Hypoglycemic Agents * pharmacology   MeSH
• Humans MeSH
• Metabolic Reprogramming MeSH
• Mitochondria metabolism   drug effects   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms * metabolism   drug therapy   pathology   MeSH
• Pioglitazone * pharmacology   MeSH
• Cell Movement drug effects   MeSH
• PPAR gamma * agonists   metabolism   MeSH
• Cell Proliferation drug effects   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in multiple carcinomas. For example, up to 20% of breast cancer cases are classified as HER2 positive (HER2+). Treatment of this condition typically involves immunotherapy using monoclonal antibodies, such as trastuzumab or pertuzumab. The precise targeting of monoclonal antibodies to HER2+ tumour lesions can be used as well in radioimmunotherapy to deliver medical radionuclides exactly to the afflicted area and therefore minimize radiation exposure of healthy tissues. In this study, DOTA conjugates of monoclonal antibodies trastuzumab and pertuzumab were prepared and tested in vitro. One of these, 225Ac-DOTA-pertuzumab, was also the subject of an ex vivo biodistribution study with normal as well as HER2+ and HER2- tumour-xenografted mice. This radioconjugate has not been previously described. RESULTS: Three DOTA-conjugates of HER2 targeting monoclonal antibodies, one of trastuzumab and two of pertuzumab, were prepared and radiolabelled with 225Ac in different molar ratios. This procedure led to an optimisation of the preparation and radiolabelling process. The radioconjugates were shown to be highly stable in vitro in both fetal bovine serum and phosphate buffered saline under room temperature and decreased temperature for 10 days. In vitro cell studies with HER2-overexpressing cell-line (SKOV-3) and low HER2-expressing cell line (MDA-MB-231) proved that radioconjugates of both antibodies have high binding specificity and affinity towards HER2 receptors. These findings were confirmed for a novel radioconjugate 225Ac-DOTA-pertuzumab in an ex vivo biodistribution study, where uptake in HER2+ tumour was 50 ± 14% ID/g and HER2- tumour showed uptake comparable with healthy tissues (max. 5.0 ± 1.7% ID/g). The high uptake observed in the spleen can be attributed to the elimination of the antibody, as well as the use of an immunedeficient mouse strain (SCID). CONCLUSIONS: During this study, the optimization of preparation and radiolabelling of HER2 targeting antibodies with 225Ac was accomplished. Furthermore, the radioconjugate 225Ac-DOTA-pertuzumab was prepared and evaluated for the first time. The radioconjugates of both tested antibodies demonstrated excellent qualities in terms of stability and HER2 receptor affinity. Initial ex vivo studies indicated that especially the radioconjugate 225Ac-DOTA-pertuzumab is a very promising candidate for further more detailed in vivo studies.

• Publication type
• Journal Article MeSH

BACKGROUND: The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown. METHODS: TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays. RESULTS: High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth. CONCLUSION: TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.

• MeSH
• Gene Knockdown Techniques MeSH
• Glioma * pathology   genetics   drug therapy   metabolism   MeSH
• Kruppel-Like Factor 4 MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * genetics   pathology   MeSH
• Lomustine * pharmacology   therapeutic use   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms * pathology   genetics   drug therapy   metabolism   MeSH
• Tumor Necrosis Factor Receptor-Associated Peptides and Proteins * genetics   metabolism   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Cell Proliferation MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Cellular Senescence * drug effects   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Long-term evidence about bioprosthetic tricuspid valve replacement is scarce. This study aims to investigate the long-term clinical outcomes of patients who underwent tricuspid valve replacement with bioprostheses. METHODS: This multicentre retrospective study included patients from 10 high-volume centres in 7 different countries, who underwent tricuspid valve replacement with bioprostheses. Echocardiographic and clinical data were reviewed. Long-term outcomes were investigated using Kaplan-Meier estimates, Cox regression, and competing risk analysis. RESULTS: Of 675 patients, isolated tricuspid valve replacement was performed in 358 patients (53%), while 317 (47%) underwent concomitant procedures. Between these 2 groups, patients who underwent combined procedures reported a significantly higher incidence of infection, atrioventricular block, multi-organ failure, longer intensive care unit and hospital stay and higher 30-day mortality over patients who underwent isolated procedure. The overall 30-day mortality occurred in 70 patients (10.4%) [46 (14.6%) combined vs 24 (6.74%) isolated, P = 0.001]. During the follow-up, there was a continuous rate of attrition due to death, with cumulative incidences of death at 5, 10 and 15 years being 27.2%, 46.2% and 60.6%, respectively. In contrast, the risk of reintervention starts to significantly increase after 10 years of follow-up, with cumulative incidences of reintervention being 6.1%, 10.8% and 23.3%, respectively. Freedom from tricuspid valve reintervention, pacemaker implantation, tricuspid valve endocarditis and major thromboembolic events at 15 years were 56.5%, 77.3%, 84.0% and 86.4%, respectively. CONCLUSIONS: Tricuspid valve replacement with bioprostheses is an effective treatment for valvular disease, despite being associated with relatively high early and long-term mortality. However, the risk of structural valve degeneration rises significantly after 10 years.

• MeSH
• Bioprosthesis * adverse effects   MeSH
• Heart Valve Prosthesis Implantation * mortality   adverse effects   methods   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Heart Valve Diseases * surgery   mortality   MeSH
• Postoperative Complications epidemiology   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Heart Valve Prosthesis * adverse effects   MeSH
• Tricuspid Valve * surgery   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.

• MeSH
• Child MeSH
• Adult MeSH
• Glioma * drug therapy   genetics   pathology   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Protein Kinase Inhibitors * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms * drug therapy   genetics   pathology   MeSH
• Child, Preschool MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Pyrazoles * pharmacology   therapeutic use   MeSH
• Pyrroles MeSH
• Receptor, Platelet-Derived Growth Factor alpha * genetics   antagonists & inhibitors   metabolism   MeSH
• Neoplasm Grading MeSH
• Triazines MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH