Adipogenic differentiation of adipose tissue-derived human mesenchymal stem cells: effect of gastric bypass surgery

BACKGROUND: Adipose tissue dysfunction is an important feature of obesity characterized by enlarged adipocytes and marked changes in secretion of cytokines. These changes result in insulin resistance, chronic vascular inflammation, oxidative stress, and activation of the renin–angiotensin system (RAS), eventually leading to type 2 diabetes, obesity-related hypertension, and cardiovascular disease (CVD). Several trials have shown that bariatric surgery significantly reduces these comorbidities. However, there is a gap in knowledge regarding the mechanisms whereby bariatric surgery reduces the burden of CVD in obese individuals. METHOD: Mesenchymal stem cells (MSCs) were isolated from adipose tissue collected from three groups: (1) nonobese control subjects, (2) obese subjects undergoing gastric bypass surgery (GBS), and (3) subjects 1 year or more after GBS. In the study, MSCs were induced to adipogenic differentiation, and RAS-related gene expressions were determined by quantitative polymerase chain reaction. The effect of angiotensin II (Ang II) on adipogenic differentiation of MSCs also was investigated. RESULTS: Angiotensinogen mRNA levels in MSCs and differentiated adipocytes were significantly higher in the obese group than in the nonobese control subjects. Renin mRNA levels were significantly higher in the obese group MSCs than in the nonobese and post-GBS groups. Angiotensin–converting enzyme mRNA levels were significantly lower in the MSCs derived from the post-GBS group than in the obese and nonobese control subjects. Serum Ang II levels were significantly lower in the post-GBS group (52.1 ± 4.2 pg/ml) than in the nonobese (85.4 ± 12.4 pg/ml) and obese (84.7 ± 10.0 pg/ml) groups. Ang II treatment inhibited adipogenesis of MSCs in a dose-dependent manner. The inhibitory effect of Ang II was mainly abolished by PD123319, a receptor 2 blocker. CONCLUSIONS: The adipogenesis of MSCs is inhibited by Ang II treatment. Obese individuals are characterized by an upregulation of the RAS-related gene expressions in adipose tissue. This upregulation resolves in post-GBS subjects

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer : meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.Peer reviewe