Objective: To evaluate inflammation-and oxidative stress-related (OxS) background in former athletes in relation to overweight and abdominal obesity status. Design: Cross-sectional data from ongoing follow-up study. Subjects: A total of 60 middle-aged former athletes (46.677.5 years; 181.177.2 cm; 88.1712.9 kg) and 54 age-matched controls (48.177.3 years; 181.476.2 cm; 89.7714.4 kg). Measurements: Anthropometric characteristics, serum lipoproteins (CHOL, HDL-C, LDL-C, TG), oxidized LDL (oxLDL), diene conjugates (DC) and high-sensitive C-reactive protein (hsCRP). Information about the physical activity and other lifestyle variables were collected by the questionnaire. Results: Ex-athletes were characterized by significantly higher physical activity characteristics and lower CHOL and oxLDL in comparison with controls. Correlation analysis among ex-athletes revealed negative associations between all measured overweight data (body mass index, fat percentage, waist to hip circumferences and waist circumference (WC)), and current physical activity. Current physical activity was significantly related to OxS and inflammatory characteristics (oxLDL, DC and hsCRP) among the ex-athletes, but not among the control group. The most expressed positive correlations were found between WC, hsCRP, triglycerides (TG), DC and oxLDL in both study groups. Conclusion: Our study results suggest that there exists an independent (adjusted for potential confounders) association between overweight, abdominal obesity, and atherogenic inflammatory and oxidative stress markers in ex-athletes as well as in age-matched controls. Major findings of our study show that WC is the best correlate of hsCRP, oxLDL, DC and TG levels.
The importance of elevated homocysteine (Hcy) as a risk marker for cardiovascular disease is continuously under debate. Lifestyle factors may increase the total Hcy (tHcy) level of the plasma, but there are no consistent findings relating to Hcy, physical activity, and cardiorespiratory fitness. Cross-sectional measurement from an ongoing follow-up study was performed on 77 former male athletes and 33 sedentary controls (age range 35-62 years). Lifestyle parameters (current physical activity patterns, smoking, etc.), anthropometric and blood pressure data, and data about tHcy, reduced, and oxidized glutathione (GSH, GSSG, respectively) in blood, lipoproteins, and maximal oxygen consumption (VO(2max)) were collected. Our study results showed that the subgroup of physically active ex-athletes (n=52) had a significantly lower tHcy level and glutathione redox ratio (GSSG:GSH) in comparison with the subgroup of sedentary ex-athletes (n=25). tHcy level was inversely related to cardiorespiratory fitness (VO(2max)/kg). Dietary and smoking habits were not significantly associated with the tHcy level in our study group. In conclusion, the research findings indicate that both current physical activity and cardiorespiratory fitness are significantly inversely associated with an elevated homocysteine level in middle-aged former athletes.
Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.
Ovarian cancer (OC) is difficult to treat and has a high mortality rate. There is a strong need for new therapies, but OC is often not the main indication for drug development activities. Hence, here we explored systematic drug repurposing based on clues from ex-vivo testing of human OC patient cells. We established patient-derived cancer cell (PDCs) cultures using ascites or tumor tissue from serous OC patients and applied them to ex vivo Drug Sensitivity and Resistance Testing (DSRT) with a panel of 528 approved and investigational oncology drugs. The representativity of the PDCs was confirmed by genomic and phenotypic profiling in comparison to the original tumor sample. Both 2D and 3D culture conditions were applied and compared for their drug responses. 9 PDCs and 11 high-grade serous OC cell lines were examined. High grade serous OC (HGSOC, 6 cases) with TP53 mutation and CCNE1, CCNE1/KRAS or MYC/KRAS amplifications showed highly resistant drug response profiles, which reflects the clinical challenges in treating this OC subtype. Some HGSOC PDCs showed vulnerability to SMAC mimetics, inhibitors of Apoptosis Protein Antagonists, (e.g. birinapant) and to prexasertib, a checkpoint kinase 1 and 2 inhibitor. In contrast, low-grade serous OC (LGSOC, 3 cases) showed subtype-specific sensitivity to several kinase inhibitors, including EGFR/Her2, MEK, mTOR and PI3K inhibitors. In a metastatic LGSOC patient, RNA-sequencing revealed a CLU-NRG1 fusion gene, which creates an autocrine activation loop of the ErbB family of receptor kinases. DSRT assay confirmed a strong sensitivity of the PDCs ex-vivo to dual-kinase inhibitors, including afatinib. Based on these data, the patient has received approved kinase inhibitors, including afatinib monotherapy followed by a combination of herceptin and pertuzumab. This strategy has managed to keep the disease in control for over 3 years as measured by clinical criteria, including imaging and serum CA125 antigen levels. In conclusion, systems precision cancer medicine with PDCs could provide a valuable approach to reveal patient-specific drug efficacies that can be translated to the clinic in real-time. Citation Format: Astrid Murumägi, Daniela Ungureanu, Suleiman Khan, Akira Hirasawa, Mariliina Arjama, Katja Välimäki, Piia Mikkonen, Wilhelmiina Niininen, Ashwini Kumar, Samuli Eldfors, Teijo Pellinen, Vilja Pietiäinen, Andrus Mägi, Riitta Koivisto-Korander, Johanna Tapper, Mikko Loukovaara, Tero Aittokallio, Ralf Bützow, Olli Kallioniemi. Clinical implementation of precision systems oncology in the treatment of ovarian cancer based on ex-vivo drug testing and molecular profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2945.
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