IL-33 administration is associated with facilitation of Th type-2 (Th2) responses and cardioprotective properties in rodent models. However, in heart transplantation, the mechanism by which IL-33, signaling through ST2L, the membrane-bound form of ST2, promotes transplant survival is unclear. We report that IL-33 administration, while facilitating Th2 responses, also increases immunoregulatory myeloid cells and CD4+ Foxp3+ regulatory T cells (Treg) in mice. IL-33 expands functional myeloid-derived suppressor cells (MDSC), -CD11b+ cells that exhibit intermediate (int) levels of Gr-1 and potent T cell suppressive function. Furthermore, IL-33 administration causes a St2-dependent expansion of suppressive CD4+ Foxp3+ Treg, including a ST2L+ population. IL-33 monotherapy following fully allogeneic mouse heart transplantation resulted in significant graft prolongation, associated with increased Th2-type responses and decreased systemic CD8+ IFN-γ+ cells. Also, despite reducing overall CD3+ cell infiltration of the graft, IL-33 administration markedly increased intragraft Foxp3+ cells. Whereas control graft recipients displayed increases in systemic CD11b+ Gr-1hi cells, IL-33-treated recipients exhibited increased CD11b+ Gr-1int cells. Enhanced ST2 expression was observed in the myocardium and endothelium of rejecting allografts, however the therapeutic effect of IL-33 required recipient St2 expression and was dependent on Treg. These findings reveal a new immunoregulatory property of IL-33. Specifically, in addition to supporting Th2 responses, IL-33 facilitates regulatory cells, particularly functional CD4+ Foxp3+ Treg that underlie IL-33-mediated cardiac allograft survival.

99m Tc-3PRGD2 is a new SPECT tracer targeting integrin a V b 3 receptor for detecting tumors, imaging angiogenesis, and evaluating tumor response to therapy. A multicenter study was designed to investigate the efficacy of 99m Tc-3PRGD2 for the evaluation of patients with lung cancer. Methods: Seventy patients (51 men, 19 women; mean age 6 SD, 63 6 9 y) with a suspected lung lesion and for whom definite pathologic diagnosis was finally obtained (malignant, n 5 58; benign, n 5 12) were recruited from 6 centers. Whole-body planar scanning and chest SPECT were performed at 1 and 4 h, respectively, after intravenous injection of 11.1 MBq/kg (0.3 mCi/kg) of 99m Tc-3PRGD2. The images were read in consensus by 6 experienced nuclear medicine physicians masked to the source, history, and pathologic diagnosis. The tumor-to-background (T/B) ratios were calculated for semiquantitative analysis. A Student t test was used for statistical analysis, and a P value less than 0.05 was considered significant. Results: With low 99m Tc-3PRGD2 background in the lungs and mediastinum, most lung malignancies were prominent on the 1-h images (T/B ratio, 1.65 6 0.47 for the planar imaging and 2.78 6 1.52 for SPECT). The T/B ratios were significantly lower in the benign lesions (P , 0.05). The sensitivity was 88% for semiquantitative analysis and could reach 93%-97% in visual analysis when considering the volume effect, necrosis, and metastasis. However, the specificity was only 58%-67%. Most lymph node and bone metastases could also be detected. Conclusion: 99m Tc-3PRGD2 imaging at 1 h is sensitive for the detection of lung cancer, meriting further investigation of 99m Tc-3PRGD2 as a novel clinical tracer for integrin receptor imaging. Si nce integrins were revealed as an important family of transmembrane receptors about 30 y ago, they have been widely studied and are found to play essential roles in angiogenesis and tumor metastasis because they are mainly involved in the cell-cell and cell-matrix interactions (1). Integrin a V b 3 is an important member of this receptor family and expressed preferentially on various types of tumor cells and the activated endothelial cells of tumor angiogenesis but not at all or very little on the quiescent vessel cells and other normal cells (2,3). Therefore, the integrin a V b 3 receptor is becoming a valuable target for diagnosis and treatment of malignant tumors (4,5).The tripeptide sequence of arginine-glycine-aspartic acid (RGD) can specifically bind to the integrin a V b 3 receptor (6,7). Accordingly, a variety of radiolabeled RGD-based peptides have been developed for noninvasive imaging of integrin a v b 3 expression via PET or . Among all the RGD radiotracers studied, 2 PET agents, 18 F-galacto-RGD and 18 F-AH111585, have been well investigated in clinical trials. The results demonstrated that both radiotracers allowed the specific imaging of various types of tumors, and the tumor uptake correlated well with the expression of integrin a v b 3 in both animal models and patients (9-14). The 99m Tc...

There is evidence that H2R blockade improves ischemia/reperfusion (I/R) injury, but the underlying cellular mechanisms remain unclear. Histamine is known to increase vascular permeability and induce apoptosis, and these effects are closely associated with endothelial and mitochondrial dysfunction, respectively. Here, we investigated whether activation of the histamine H2 receptor (H2R) exacerbates myocardial I/R injury by increasing mitochondrial and endothelial permeability. Serum histamine levels were measured in patients with coronary heart disease, while the influence of H2R activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells, and myocardial I/R injury in mice. The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls. In neonatal rat cardiomyocytes, histamine dose-dependently reduced viability and induced apoptosis. Mitochondrial permeability and the levels of p-ERK1/2, Bax, p-DAPK2, and caspase 3 were increased by H2R agonists. In cultured human umbilical vein endothelial cells (HUVECs), H2R activation increased p-ERK1/2 and p-moesin levels and also enhanced permeability of HUVEC monolayer. All of these effects were abolished by the H2R blocker famotidine or the ERK inhibitor U0126. After I/R injury or permanent ischemia, the infarct size was reduced by famotidine and increased by an H2R agonist in wild-type mice. In H2R KO mice, the infarct size was smaller; myocardial p-ERK1/2, p-DAPK2, and mitochondrial Bax were downregulated. These findings indicate that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability.

Some new radiotracers might add useful information and improve diagnostic confidence of 18 F-FDG imaging in tumors. A multicenter clinical trial was designed to investigate the diagnostic performance of dual-tracer ( 18 F-FDG and 39-deoxy-39-18 F-fluorothymidine [ 18 F-FLT]) PET/CT in pulmonary nodules. Methods: Fifty-five patients underwent dual-tracer imaging in 6 imaging centers using the same models of equipment and standardized protocols. The images were interpreted by a collective group of readers who were unaware of the clinical data. The diagnostic performance using either tracer alone or dual-tracers together, with or without CT, was compared. The histological diagnosis or clinical findings in a 12-mo follow-up period served as the standard of truth. Results: In 16 patients with malignant tumor, 16 with tuberculosis, and 23 with other benign lesions, the sensitivity and specificity of 18 F-FDG and 18 F-FLT were 87.5% and 58.97% and 68.75% and 76.92%, respectively. The combination of dual-tracer PET/CT improved the sensitivity and specificity up to 100% and 89.74%. The 3 subgroups of patients could be best separated when the 18 F-FLT/ 18 F-FDG standardized uptake value ratio of 0.4-0.90 was used as the threshold. Conclusion: By reflecting different biologic features, the dualtracer PET/CT using 18 F-FDG and 18 F-FLT favorably affected the diagnosis of lung nodules.

Low‐intensity ultrasound‐microbubble (LIUS‐MB) treatment is a promising antivascular therapy for tumors. We sought to determine whether LIUS‐MB treatment with an appropriate ultrasound pressure could achieve substantial and persistent cessation of tumor perfusion without having significant effects on normal tissue. Further, we investigated the mechanisms underlying this treatment. Murine S‐180 sarcomas, thigh muscles, and skin tissue from 60 tumor‐bearing mice were subjected to sham therapy, an ultrasound application combined with microbubbles in four different ultrasound pressures (0.5, 1.5, 3.0, 5.0 MPa), or ultrasound at 5.0 MPa alone. Subsequently, contrast‐enhanced ultrasonic imaging and histological studies were performed. Tumor microvessels, tumor cell necrosis, apoptosis, tumor growth, and survival were evaluated in 85 mice after treatment with the selected ultrasound pressure. We found that twenty‐four hours after LIUS‐MB treatment at 3.0 MPa, blood perfusion and microvessel density of the tumor had substantially decreased by 84 ± 8% and 84%, respectively (p < 0.01). Similar reductions were not observed in the muscle or skin. Additionally, an extreme reduction in the number of immature vessels was observed in the tumor (reduced by 90%, p < 0.01), while the decrease in mature vessels was not significant. Further, LIUS‐MB treatment at 3.0 MPa promoted tumor cell necrosis and apoptosis, delayed tumor growth, and increased the survival rate of tumor‐bearing mice (p < 0.01). These findings indicate that LIUS‐MB treatment with an appropriate ultrasound pressure could selectively and persistently reduce tumor perfusion by depleting the neovasculature. Therefore, LIUS‐MB treatment offers great promise for clinical applications in antivascular therapy for solid tumors.

With the rapid development of cancer-targeted nanotechnology, a variety of nanoparticle-based drug delivery systems have clinically been employed in cancer therapy. However, multidrug resistance significantly impacts the therapeutic efficacy. Physical non-drug therapy has emerged as a new and promising strategy. This study aimed to determine whether novel folate-nanobubbles (F-NBs), combined with therapeutic ultrasound (US), could act as a safe and effective physical targeted cancer therapy. Using folate-conjugated N-palmitoyl chitosan (F-PLCS), we developed novel F-NBs and characterised their physicochemical properties, internalization mechanism, targeting ability, therapeutic effects, and killing mechanism. The results showed that the novel F-NBs selectively accumulated in FR-positive endothelial cells and tumour cells via FR coupled with clathrin- and caveolin-mediated endocytosis in vitro and in vivo. In addition, the F-NBs killed target cells by an intracellular explosion under US irradiation. Hoechst/PI staining demonstrated that apoptosis and necrosis accounted for a large proportion of cell death in vivo. F-NBs combined with US therapy significantly inhibited tumour growth and improved the overall survival of tumour-bearing mice. Under US irradiation, the novel F-NBs selectively killed FR-positive tumour cells in vitro and in vivo via intracellular explosion and therefore is a promising alternative for targeted cancer treatment.

Supplemental Digital Content is available in the text

No abstract