Yun Xi

Brown Adipose Tissue Activation Is Inversely Related to Central Obesity and Metabolic Parameters in Adult Human

Background Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in affecting obesity. However, the supporting evidence on the relationship between BAT and central obesity and metabolic profile in large population based studies is sparse. Methodology/Principal Findings We studied 4011 (2688 males and 1323 females) tumor-free Chinese adults aged 18-89 for BAT activities, visceral/subcutaneous fat areas (VFA/SFA), waist circumferences (WC) and metabolic parameters. We found that the prevalence of BAT was around 2.7% in our study participants, with a significant sexual difference (5.5% in the females vs. 1.3% in the males; p<0.0001). BAT detection was increased in low temperature and declined in elderly subjects. The BAT positive subjects had lower BMI (P<0.0001), less SFA (P<0.01), VFA (P<0.0001), WC (P<0.0001), lower fasting glucose and triglyceride levels (both P<0.01) and increased HDL cholesterol concentrations (P<0.0001), compared with the BAT negative subjects. Robust logistic regression revealed that after adjustment for covariates (including age, sex, BMI, VFA, SFA and WC), age and BMI in the males (0.92 [95%CI, 0.88-0.96] and 0.84 [95% CI, 0.75-0.96], both P ≤0.008) while age and VFA in the females (0.87 [95%CI, 0.83-0.91] and 0.98 [95%CI, 0.97-0.99], respectively, P<0.05) were independently associated with detectable BAT. Conclusions/Significance Our data suggest that decreased amount of active BAT might be associated with accumulation of visceral fat content and unfavorable metabolic outcomes.

Theranostic Studies of Human Sodium Iodide Symporter Imaging and Therapy Using 188Re: A Human Glioma Study in Mice

Objective To investigate the role of 188Re in human sodium iodide symporter (hNIS) theranostic gene-mediated human glioma imaging and therapy in model mice. Methods The human glioma cell line U87 was transfected with recombinant lentivirus encoding the hNIS gene under the control of cytomegalovirus promoter (U87-hNIS). The uptake and efflux of 188Re were determined after incubating the cells with 188Re. 188Re uptake experiments in the presence of various concentrations of sodium perchlorate were carried out. In vitro cell killing tests with 188Re were performed. U87-hNIS mediated 188Re distribution, imaging and therapy in nude mice were also tested. Results U87-hNIS cell line was successfully established. The uptake of 188Re in U87-hNIS cells increased up to 26-fold compared to control cells, but was released rapidly with a half-life of approximately 4 minutes. Sodium perchlorate reduced hNIS-mediated 188Re uptake to levels of control cell lines. U87-hNIS cells were selectively killed following exposure to 188Re, with a survival of 21.4%, while control cells had a survival of 92.1%. Unlike in vitro studies, U87-hNIS tumor showed a markedly increased 188Re retention even 48 hours after 188Re injection. In the therapy study, there was a significant difference in tumor size between U87-hNIS mice (317±67 mm3) and control mice (861±153 mm3) treated with 188Re for 4 weeks (P<0.01). Conclusion The results indicate that inserting the hNIS gene into U87 cells is sufficient to induce specific 188Re uptake, which has a cell killing effect both in vitro and in vivo. Moreover, our study, based on the function of hNIS as a theranostic gene allowing noninvasive imaging of hNIS expression by 188Re scintigraphy, provides detailed characterization of in vivo vector biodistribution and level, localization, essential prerequisites for precise planning and monitoring of clinical gene therapy that aims to individualize gene therapy concept.

18F-fluoro-2-deoxy-D-glucose retention index as a prognostic parameter in patients with pancreatic cancer.

ObjectivesThe objective of this study was to determine the most effective way to use dual-phase 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET/computed tomography (CT) semiquantitative indices to predict prognosis in patients with pancreatic cancer and to guide treatment. Study designPrognostic parameters were retrospectively analyzed in 40 patients with histologically proven pancreatic cancer who received 18F-FDG PET/CT at Ruijin Hospital. Maximum standardized uptake values (SUVs) were determined at 1 h (SUV1) and 2 h (SUV2) after 18F-FDG injection. The retention index (RI) was defined as the percentage change between SUV1 and SUV2. ResultsRI less than 17% was explored as having a significant independent correlation with prolonged patient survival (P<0.05). Patients with tumor resection and RI less than 17% survived significantly longer than those with or without tumor resection and RI of 17% or higher (P<0.05). Neither SUV1, nor SUV2 showed any prognostic significance, but they did show a positive correlation with tumor diameter (P1<0.01; P2<0.05); RI had a strong positive correlation with tumor, node, and metastasis stage (P<0.01). Two factors were found to be associated with RI, including pancreatitis (P<0.05) and diabetes (P<0.01). ConclusionRI served as the most accurate parameter to predict disease prognosis in pancreatic cancer and to identify patients who could benefit from surgery. However, pancreatitis and diabetes had a potential impact on RI, reflecting the influence of tumor pathophysiological changes on the metabolism of glucose in pancreatic tumor cells. Therefore, further comprehensive analyses are required.

Feasibility of lentiviral‑mediated sodium iodide symporter gene delivery for the efficient monitoring of bone marrow‑derived mesenchymal stem cell transplantation and survival

The aim of the present study was to explore the feasibility of lentiviral-mediated sodium iodide symporter (NIS) gene delivery for monitoring bone marrow-derived mesenchymal stem cell (BMSC) transplantation into the infarcted myocardium. For this purpose, we constructed a lentiviral vector (Lv-EF1α-NIS-IRES-EGFP) expressing NIS and enhanced green fluorescent protein (EGFP), and introduced it into BMSCs at different multiplicities of infection (MOI). The expression of EGFP was observed under a fluorescence microscope. Iodine uptake and the inhibition of iodine uptake by sodium perchlorate (NaClO4) in the Lv-EF1α-NIS-IRES-EGFP‑treated BMSCs were dynamically monitored in vitro. The Lv-EF1α-NIS-IRES-EGFP‑treated BMSCs were transplanted into the infarcted myocardium of Sprague-Dawley rats, and 99mTc99g (Tc, technetium; 99m indicates that technetium is at its excited stage; 99g indicates the atomic weight of technetium) micro-single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging was performed in vivo 1 week following transplantation. The isolated BMSCs successfully differentiated into adipocytes and osteoblasts. The BMSCs were positive for the cell surface markers, CD105, CD29 and CD90, and negative for CD14, CD34 and CD45. Lv-EF1α-NIS-IRES-EGFP was efficiently transfected into the BMSCs. RT-qPCR and western blot analysis confirmed that the BMSCs expressed high protein and mRNA levels of NIS by day 7 following infection, and NIS expression remained at a consistent level from day 14 to 21. In the Lv-EF1α-NIS-IRES-EGFP‑treated BMSCs, the accumulation of iodine-125 (125I) was observed in vitro and was successfully monitored by 99mTc99g micro-SPECT/CT imaging at 1 week following transplantation. These results suggest that lentiviral vectors are powerful vehicles for studying gene delivery in BMSCs. It is feasible to use lentiviral vectors to deliver an NIS gene for the non-invasive monitoring of BMSC transplantation and survival in the infarcted myocardium in vivo.

Human sodium iodide transporter gene-mediated imaging and therapy of mouse glioma, comparison between 188Re and 131I

Novel treatment options are urgently required for patients with glioma who are not effectively treated through standard therapy. Human sodium iodide symporter (hNIS) is a molecular target of certain tumors types. Compared with 131I, 188Re possesses a higher energy and shorter half-life; therefore, the effects of 188Re and 131I were compared in hNIS-mediated gene imaging and therapy in the present study. Recombinant human brain glioma cell line U87 was transfected with a recombinant lentiviral vector containing hNIS (U87-hNIS). U87-0 cell line transfected with blank lentivirus was prepared as a control. In vitro, the 188Re and 131I uptake of U87-hNIS cells were 21.3-times and 25.9-times that of the control groups, however the excretion rate of the two nuclides was very rapid, and the half-life was only ~4 min. Sodium perchlorate inhibited hNIS-mediated 188Re and 131I uptake to levels observed in the control groups. 188Re and 131I were able to kill U87-hNIS cells selectively, with a survival of only 21.6 and 36.2%, respectively. U87-hNIS nude mice appeared to accumulate 188Re, with a ratio of radioactivity counts between tumor and non-tumor sites of ~13.5 compared with 10.3 of 131I 1 h after radionuclide injection. In contrast with in vitro studies, U87-hNIS cells demonstrated a notable increase in 188Re retention in vivo, even 24 h after 188Re injection. U87-hNIS cells also exhibited increased 131I retention in vivo; however, as the time increased, 131I was rapidly released with the tumor no longer able to be imaged 24 h after 131I injection. Following treatment, U87-hNIS tumors experienced a volume reduction of 24.1%, whereas U87-0 cells demonstrated an increase of 28.8%. 188Re and 131I were revealed to be effective at decreasing tumor volume compared with the control. However, 188Re was significantly more potent compared with 131I (P<0.01). The present study indicated that the U87-hNIS cell line is sufficient to induce specific 188Re and 131I uptake, which may kill cells in vitro and in vivo. 188Re exhibited an increased retention time in vivo compared with 131I, which facilitates the imaging and therapy of U87-hNIS tumors.

131I therapy mediated by sodium/iodide symporter combined with kringle 5 has a synergistic therapeutic effect on glioma

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor; the prognosis of patients with GBM remains poor. The sodium/iodide symporter (NIS) can be used to absorb several isotopes, such as 131I for nuclear medicine imaging and radionuclide therapy. Previously, we found that the early growth response-1 (Egr1) promoter had an 131I radiation positive feedback effect on the NIS gene. Kringle 5 (K5), a kringle domain of plasminogen, induced endothelial cell apoptosis. We investigated the effect of K5 combined with the 131I radiation positive feedback effect (Egr1-NIS) for treating malignant U87 glioma cells using a lentiviral vector. We successfully constructed a stable U87 glioma cell line, U87-K5-Egr1-NIS. The radio-inducible Egr1 promoter induced an 131I radiation positive feedback effect absorbed by NIS. Mediated by 131I, K5 increased glioma cell apoptosis; 131I radiation also increased endothelial cell sensitivity to K5-induced apoptosis. The combined therapy had a synergistic effect on the antitumor efficacy of glioma treatment, not only increasing tumor cell apoptosis but also significantly inhibiting tumor cell proliferation and reducing capillary density in U87 glioma tissues.