Iskanje po repozitoriju

A+ | A- | | SLO | ENG

Povzetek: Tumor irradiation combined with adjuvant treatments, either vascular targeted or immunomodulatory, is under intense investigation. Gene electrotransfer of therapeutic genes is one of these approaches. The aim of this study was to determine, whether gene electrotransfer of plasmid encoding shRNA for silencing endoglin, with vascular targeted effectiveness, can radiosensitize melanoma B16F10 tumors. Materials and methods. The murine melanoma B16F10 tumors, growing on the back of C57Bl/6 mice, were treated by triple gene electrotransfer and irradiation. The antitumor effect was evaluated by determination of tumor growth delay and proportion of tumor free mice. Furthermore, histological analysis of tumors (necrosis, apoptosis, proliferation, vascularization, presence of hypoxia and infiltration of immune cells,) was used to evaluate the therapeutic mechanisms. Results. Gene electrotransfer of plasmid silencing endoglin predominantly indicated vascular targeted effects of the therapy, since significant tumor growth delay and 44% of tumor free mice were obtained. In addition, irradiation had minor effects on radioresistant melanoma, with 11% of mice tumor free. The combined treatment resulted in excellent effectiveness with 88% of mice tumor free, with more than half resistant to secondary tumor challenge, which was observed also with the plasmid devoid of the therapeutic gene. Histological analysis of tumors in the combined treatment group, demonstrated similar mode of action of the gene electrotransfer of plasmid encoding shRNA for silencing endoglin and devoid of it, both through the induction of an immune response. Conclusions. The results of this study indicate that irradiation can in radioresistant melanoma tumors, by release of tumor associated antigens, serve as activator of the immune response, besides directly affecting tumor cells and vasculature. The primed antitumor immune response can be further boosted by gene electrotransfer of plasmid, regardless of presence of the therapeutic gene, which was confirmed by the high radiosensitization, resulting in prolonged tumor growth delay and 89% of tumor free mice that were up to 63% resistant to secondary challenge of tumor. In addition, gene electrotransfer of therapeutic plasmid for silencing endoglin has also a direct effect on tumor vasculature and tumors cells; however in combination with radiotherapy this effect was masked by pronounced immune response.
Ključne besede: gene therapy, electrotransfer, plasmid, irradiation, immune response, melanoma
Objavljeno v DiRROS: 24.05.2024; Ogledov: 90; Prenosov: 61
Celotno besedilo (1,13 MB)

Povzetek: Background. Electrochemotherapy is a tumour ablation modality, based on electroporation of the cell membrane, allowing non-permeant anticancer drugs to enter the cell, thus augmenting their cytotoxicity by orders of magnitude. In preclinical studies, bleomycin and cisplatin proved to be the most suitable for clinical use. Intravenous administration of cisplatin for electrochemotherapy is still not widely accepted in the clinics, presumably due to its lower antitumor effectiveness, but adjuvant therapy by immunomodulatory or vascular-targeting agents could provide a way for its potentiation. Hence, the aim of the present study was to explore the possibility of adjuvant tumour necrosis factor % (TNF-%) therapy to potentiate antitumor effectiveness of electrochemotherapy with intravenous cisplatin administration in murine sarcoma. Materials and methods. In vivo study was designed to evaluate the effect of TNF-% applied before or after the electrochemotherapy and to evaluate the effect of adjuvant TNF-% on electrochemotherapy with different cisplatin doses. Results. A synergistic interaction between TNF-% and electrochemotherapy was observed. Administration of TNF-% before the electrochemotherapy resulted in longer tumour growth delay and increased tumour curability, and was significantly more effective than TNF-% administration after the electrochemotherapy. Tumour analysis revealed increased platinum content in tumours, TNF-% induced blood vessel damage and increased tumour necrosis after combination of TNF-% and electrochemotherapy, indicating an anti-vascular action of TNF-%. In addition, immunomodulatory effect might have contributed to curability rate of the tumours. Conclusion. Adjuvant intratumoural TNF-% therapy synergistically contributes to electrochemotherapy with intravenous cisplatin administration. Due to its potentiation at all doses of cisplatin, the combined treatment is predicted to be effective also in tumours, where the drug concentration is suboptimal or in bigger tumours, where electrochemotherapy with intravenous cisplatin is not expected to be sufficiently effective.
Ključne besede: electrochemotherapy, TNF, adjuvant immunotherapy, cisplatin
Objavljeno v DiRROS: 17.04.2024; Ogledov: 179; Prenosov: 33
Celotno besedilo (978,26 KB)

Povzetek: In this paper, we present the mechanisms of premature fracture of modular neck stems in two case studies: (I) when the neck and stem are both made of the same Ti6Al4V alloy, and (II) when the neck and stem are made from two different alloys, CoCrMo and Ti6Al4V alloy. Our study integrates two orthopedic patients who have undergone primary uncemented THA for usual indications in two orthopedic centers (Community Health Centre and University Medical Centre). Both centers are part of the national public health care system. Both surgeries were performed by two skilled orthopedic surgeons with more than 10 years of experience in THA. The survivorship of the modular neck of cast CoCrMo alloy was 24 months. The survivorship of the modular neck from Ti6Al4V alloy was 84 months. Multivariate analyses were performed to assess the differences in the fretting, corrosion, and fatigue of the two prematurely failed modular neck stems: stereo light microscopy (SLM), scanning electron microscopy (SEM), X-ray energy-dispersive spectroscopy (EDS), and electron backscatter diffraction (EBSD). Patient demographic information, including sex, age, body mass index, survivorship of implants, and reason for the revision, was collected from medical records. We found that fretting and fatigue occurred on both neck-stem retrievals due to additional galvanic corrosion, but the CoCrMo/Ti6Al4V alloy system suffered more corrosion due to additional galvanic corrosion and fractured earlier than the Ti6Al4V/Ti6Al4V metal alloy system. Both metallic alloy systems used in this application are known to be highly corrosion-resistant, but the bio-tribo-corrosion processes need to be understood in detail and characterized so that appropriate improvements in design and materials can be made.
Ključne besede: total hip arthroplasty, modular neck, Ti6Al4V alloy, CoCrMo alloy, corrosion
Objavljeno v DiRROS: 07.02.2024; Ogledov: 276; Prenosov: 147
Celotno besedilo (5,12 MB)
Gradivo ima več datotek! Več...

Ključne besede: Ti6Al7Nb implant alloy cementless hip endoprostheses, roughness, Al2O3 grit blasting, surface and subsurface implant contamination, cytotoxicity, aseptic loosening, infection, osseointegration
Objavljeno v DiRROS: 01.02.2024; Ogledov: 225; Prenosov: 83
Celotno besedilo (16,21 MB)
Gradivo ima več datotek! Več...

Ključne besede: onkologija, bolniki, nasveti
Objavljeno v DiRROS: 22.11.2023; Ogledov: 419; Prenosov: 142
Celotno besedilo (798,13 KB)