BackgroundThe identification of biomarkers of post-traumatic osteoarthritis (PTOA) progression is of clinical importance. The aims of this study were: (1) to assess the abilities of various soluble proinflammatory mediators in plasma to distinguish patients with knee PTOA from controls; (2) to determine the correlations between the mediators in plasma and those mediators in synovial fluid (SF); and (3) to explore the associations of the mediators with radiographic PTOA severity.Materials and methodsThe concentrations of IL-1β, IL-6, IL-18, TNFα, and leptin were measured using ELISA. Nitric oxide was determined as nitrite/nitrate (NOx) using the Griess reaction.ResultsWe included 171 subjects (134 PTOA patients and 37 controls) and excluded patients with rheumatoid arthritis or gout. The ROC curve of plasma NOx had the highest AUC, a specificity of 100%, and a sensitivity of 84.4%. The combination of IL-6 and leptin proved to be the most discriminatory, with an AUC value of 0.933, a specificity of 96.7%, and a sensitivity of 85.7%. The levels of NOx, IL-6, IL-18, and leptin in plasma were significantly correlated with their levels in SF. Leptin levels in both plasma (p = 0.036) and SF (p = 0.041) and the synovial IL-18 level (p = 0.045) were correlated with the Kellgren–Lawrence (KL) grade. Early-stage PTOA (KL 1–2) was associated with a high concentration of IL-1β in plasma before and after (OR 6.235, 95% CI 1.362 to 28.552, p = 0.018) adjusting for age, gender, and BMI.ConclusionsCirculating NOx level and a combination of IL-6 and leptin permitted the strongest discrimination of patients with PTOA from controls. PTOA severity was correlated with leptin levels in plasma and SF and with the synovial IL-18 level. Early PTOA was associated with the circulating level of IL-1β.Level of evidenceIII (case–control study).
e17549 Background: The question of the mechanisms of platinum resistance development in advanced ovarian cancer (OC) remains open. The aim of the study was to reveal the relationship between the proliferative activity of OC cells, the disruption of apoptosis processes and the changes in the activity of transporter proteins that provide the efflux of chemotherapy drugs. Methods: Patients with advanced OC (T3-4N0-3M0-1) of postmenopausal age, sensitive (SPtPs, n = 23) and resistant to platinum drugs (RPtPs, n = 17), operated on after 3-6 cycles of neoadjuvant chemotherapy, were retrospectively studied. The parameters of proliferative activity (ki67), apoptosis disturbances (p53), as well as the expression of BCRP and Pgp transporter proteins were evaluated in OC tissue using immunohistochemistry methods. Statistical analysis was performed using the Mann-Whitney and Pearson tests (χ2), as well as the Spearman's rank correlation coefficient (SC). Results: In total, the dominance of the RPtPs over the SPtPs was noted in terms of intensity of the studied indicators (p < 0.05-0.003), the most significant for Pgp expression. At the same time, moderate and high values of these indicators were observed in SPtPs in 42-61% of cases, which reduced the predictive value of the revealed differences. It was of interest that statistically significant correlations between the indicators in SPtPs differed from those in RPtPs. Thus, the following values of the SC were observed in SPtPs: +0.848 (ki67-p53), -0.675 (ki67-BCRP), -0.575 (p53-BCR). In RPtPs, another intensity and/or direction of these relations were noted: +0.521 (ki 67-p53), +0.500 (ki 67-BCRP), +0.705 (p53-BCR). There were no statistically significant relationships between ki67-Pgp expression in SPtPs and RPtPs. The direction and intensity of the studied relationships could indicate changes in cell regulation in primary OC in SPtPs compared to RPtPs. Thus, in SPtPs, they reflected a significant contribution of apoptotic disturbances to the enhancement of OC cell proliferation, which was limited by the negative feedback mechanism via BCRP activity suppression indicated by the presence of an inverse correlation ki67-BCRP. In RPtPs, this mechanism was apparently already lost, which resulted in a change in the direction of the statistical relationship ki67-BCRP from reverse to direct one. Under these conditions, the positive contribution of apoptosis disruption to the proliferative activity of OC cells could obviously be supplemented by a synergistic increase in the activity of the BCRP transporter protein, which removes platinum drugs from OC cells. Conclusions: Patients with advanced OC may develop platinum resistance due to discoordination of proliferation, apoptosis, and regulation of the activity of the BCRP transporter protein.
Статья имеет проблемный, постановочный характер. На современном этапе, помимо объективных факторов, затрудняющих создание адекватных экспериментальных моделей человеческого онкогенеза, имеет место значительное отставание отечественной науки в разработке данного направления. Это снижает доступность для российских специалистов гуманизированных иммунодефицитных животных, соответствующих уровню исследовательских задач. В работе на основе анализа сведений литературы обсуждаются подходы, которые могут расширить варианты использования широкодоступной иммунодефицитной животной модели-мышей BALB/c nude. Рассматривается возможность использования мезенхимальных стволовых клеток человека, не отторгаемых мышами BALB/c nudе, для локальной гуманизации иммунодефицитных животных и улучшения структурно-функциональных характеристик ксенографтов. Анализируется возможность получения ксенографтов человеческих глиобластом, поддерживаемых в организме иммунокомпетентных мышей BALB/c после серийных пассажей органотипических сфероидов опухоли в головном мозге мышей BALB/c nude. Ключевые слова: ксенографты злокачественных опухолей человека, мыши BALB/c nude, методы гуманизации, мезенхимальные стволовые клетки, иммунокомпетентные животные, сибсы
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