Background— Allogeneic mesenchymal stem cells (MSCs) were immunoprivileged early after cardiac implantation and improved heart function in preclinical and clinical studies. However, long-term preclinical studies demonstrated that allogeneic MSCs lost their immunoprivilege and were rejected in the injured myocardium, resulting in recurrent ventricular dysfunction. This study identifies some of the mechanisms responsible for the immune switch in MSCs and suggests a new treatment to maintain immunoprivilege and preserve heart function. Methods and Results— Rat MSC immunoprivilege was mediated by prostaglandin E2 (PGE2)–induced secretion of 2 critical chemokines, CCL12 and CCL5. These chemokines stimulated the chemoattraction of T cells toward MSCs, suppressed cytotoxic T-cell proliferation, and induced the production of T regulatory cells. MSCs treated with 5-azacytidine for 24 hours differentiated into myogenic cells after 2 weeks, which was associated with decreased PGE2 and chemokine production and the loss of immunoprivilege. Treatment of differentiated MSCs with PGE2 restored chemokine levels and preserved MSC immunoprivilege. In a rat myocardial infarction model, allogeneic MSCs (3×10 6 cells/rat) were injected into the infarct region with or without a biodegradable hydrogel that slowly released PGE2. Five weeks later, the transplanted MSCs expressed myogenic lineage markers and were rejected in the control group, but in the PGE2-treated group, the transplanted cells survived and heart function improved. Conclusions— Allogeneic MSCs maintained immunoprivilege by PGE2-induced secretion of chemokines CCL12 and CCL5. Differentiation of MSCs decreased PGE2 levels, and immunoprivilege was lost. Maintaining PGE2 levels preserved immunoprivilege after differentiation, prevented rejection of implanted MSCs, and restored cardiac function.

The combined evaluation of FDG uptake, CEA level, smoking status and tumor margins may be helpful in predicting EGFR mutation status in patients with pulmonary adenocarcinoma, especially when the tumor sample is inadequate for genetic analysis or genetic testing is not available. Further large-scale prospective studies are needed to validate these results.

Radioactive iodide uptake (RAIU)

NIS expression is tightly modulated during the transition of intercalated to striated ducts and striated to excretory ducts in salivary ductal cells. NIS expression in salivary glands is decreased during inflammation and tumor formation. Further investigation may identify molecular targets and/or pharmacologic agents that allow selective inhibition of NIS expression/activity in salivary glands during radioactive iodine treatment.

Radioiodine-concentrating activity in thyroid tissues has allowed the use of radioiodine as a diagnostic and therapeutic agent for patients with thyroid disorders such as well-differentiated thyroid cancer. However, some extrathyroidal tissues also take up radioiodine, contributing to unwanted side effects of radioiodine therapy. Now that the molecule that mediates radioiodine uptake, the sodium iodide symporter (NIS), has been cloned and characterized, it may be possible to develop novel strategies to differentially modulate NIS expression and/or activity, enhancing it in target tissues and impeding it in others. In addition to restoring NIS expression/activity to ensure sufficient radioiodine uptake for the diagnosis and treatment of advanced thyroid cancers, we envision that it may be possible to selectively increase or confer NIS expression/activity in tumors of nonthyroidal tissues to facilitate the use of radioiodine in their diagnosis and treatment. We also consider the molecular basis of thyroid and nonthyroid disorders that may be complicated by NIS deregulation. Finally, we explore the use of NIS as an imaging reporter gene to monitor the expression profile of the transgene in transgenic mouse animal models and in patients undergoing gene therapy clinical trials.

The Na þ /I À symporter (NIS) is a membrane glycoprotein that facilitates the uptake of iodine into thyroid follicular cells. Recently, we and others have demonstrated the feasibility of imaging subcutaneous xenografts expressing exogenous NIS, suggesting that NIS may serve as an imaging reporter gene to monitor vector delivery and therapeutic gene expression. In this study, we established NIS-expressing pulmonary tumors in nude mice to investigate the minimal tumor size required for in vivo detection of pulmonary tumors by single photon emission computed tomography (SPECT) with pinhole collimation. In order to define the anatomic location of NIS-expressing tumor nodules detectable by SPECT, we performed simultaneous, dual-isotope imaging. We injected 1 mCi 99m Tc-MAA via tail vein to image pulmonary perfusion and injected 1 mCi Na 125 I intraperitoneally to image NIS-expressing tumors. Fused images showed that 99m Tc-MAA perfusion defects correlated with NIS-mediated 125 I uptake. Post-mortem analysis revealed that tumors 3 mm in diameter could be detected by SPECT with pinhole collimation. These studies demonstrate the feasibility of SPECT to detect pulmonary tumors expressing exogenous NIS in mice.

NIS expression by a proportion of cells in a population was sufficient to confer radionuclide-concentrating function in subcutaneous and metastatic MATLyLu tumors. Ablation of residual normal and neoplastic prostate tissues by radioiodide after prostate-restricted NIS gene transfer might be a novel adjuvant therapy to prostatectomy for the treatment of advanced prostate cancer.

The sodium iodide symporter (NIS) mediates iodide uptake into thyrocytes and is the molecular basis of thyroid radioiodine therapy. We previously have shown that NIS gene transfer into the F98 rat gliomas facilitated tumor imaging and increased survival by radioiodine. In this study, we show that: (1) the therapeutic effectiveness of 131 I in prolonging the survival time of rats bearing F98/hNIS gliomas is dose-and treatment-time-dependent; (2) the number of remaining NISexpressing tumor cells decreased greatly in RG2/hNIS gliomas post 131 I treatment and was inversely related to survival time; (3) 8 mCi each of 125 I/ 131 I is as effective as 16 mCi 131 I alone, despite a smaller tumor absorbed dose; (4) 188 ReO 4 , a potent b À emitter, is more efficient than 131 I to enhance the survival of rats bearing F98/hNIS gliomas. These studies demonstrate the importance of radiopharmaceutical selection, dose, and timing of treatment to optimize the therapeutic effectiveness of NIS-targeted radionuclide therapy following gene transfer into gliomas.