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The bone SPECT/CT allows for precise anatomic delineation of bone activity, which can be valuable for diagnosis of nonmalignant bone diseases. We report an extremely rare case of sphenoid sinus aspergillosis, observed on bone SPECT/CT imaging, as an isolated disease in an immunocompetent individual. A 58-year-old woman with a history of plantar fasciitis was assessed for infection in the tarsal bones. Planar bone scan image revealed incidental focal lesion in skull base, which was considered to be the left sphenoid sinusitis by the bone SPECT/CT scan.

Effective pain and symptom management is a crucial part of the care of those with life-threatening illnesses and their family members. Nurses in all settings have a vital role in providing this essential care. A recent summit held on May 12, 2017, "Nurses Leading Change and Transforming Palliative Care," convened by the Hospice and Palliative Nurses Association and attended by leaders of 26 nursing organizations strongly endorsed the importance of nursing's role in pain and symptom management and developed an agenda to advance these efforts. The agreed-upon goals of pain and symptom treatment include care that is effective (as defined by the patient), efficient (delivered in a timely manner), and safe (reduced risk of respiratory depression, prevention and early management of adverse effects, as well as attention to methods to prevent diversion such as safe storage and disposal). Through an iterative process, desired patient outcomes and nursing actions were outlined to support effective pain and symptom management in primary palliative care. These recommendations were categorized as education, clinical care, research, and regulatory concerns. This article reports on the outcomes of this summit related to pain and symptom management.

Radioactive-iodine (RAI) therapy is typically unprevailing as anaplastic thyroid cancer (ATC) management, owing to the decrease in the endogenous sodium iodide symporter (NIS) expression. Therefore, new strategies for NIS re-induction are required to improve the efficacy of RAI therapy in ATC. In this study, we developed a novel high-throughput NIS enhancer screening platform using a dual reporter gene system to identify a potent tyrosine kinase inhibitor (TKI) and selected a new hit compound, K905-0266 TKI. The effects of K905-0266 TKI treatment was validated as RAI accumulation, changes in signalling pathway related to thyroid pathogenesis, and cytotoxicity of RAI depending on re-induction of endogenous NIS expression in ATC. Furthermore, we evaluated enhancement of NIS promoter and therapeutic efficacy of RAI in ATC tumour xenograft mice. After K905-0266 TKI treatment, the expression of endogenous NIS was significantly increased, while phosphorylated-ERK was decreased. In addition, the thyroid-metabolising protein expressions were upregulated and increased of RAI accumulation and its therapeutic effects in ATC. Moreover, K905-0266 TKI increased therapeutic efficacy of RAI in ATC tumour in vivo . In conclusion, we successfully established a novel high-throughput NIS enhancer screening platform to excavate a NIS enhancer and identified K905-0266 TKI among TKI candidates and it's proven to increase the endogenous NIS expression and therapeutic efficacy of RAI in ATC. These findings suggest that a novel high-throughput NIS enhancer screening platform is useful for selecting of NIS promoter enhancers. In addition, K905-0266 TKI can be used to re-induce endogenous NIS expression and recover RAI therapy in ATC., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests.

Exosomes are endogenous nanocarriers that can deliver biological information between cells. They are secreted by all cell types, including immune cells such as natural killer (NK) cells. However, mammalian cells release low quantities of exosomes, and the purification of exosomes is difficult. Here, nanovesicles were developed by extrusion of NK cells through filters with progressively smaller pore sizes to obtain exosome mimetics (NK-EM). The anti-tumour effect of the NK-EM was confirmed in vitro and in vivo. The morphological features of the NK-EM were revealed by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. In vitro, the cytotoxicity of the NK-EM to cancer cells (glioblastoma, breast carcinoma, anaplastic thyroid cancer and hepatic carcinoma) was assessed using bioluminescence imaging (BLI) and CCK-8 assay. For in vivo study, a xenograft glioblastoma mouse model was established. The anti-tumour activity of NK-EM was confirmed in vivo by the significant decreases of BLI, size and weight (all p < .001) of the tumour compared with the control group. Moreover, NK-EM cytotoxicity for glioblastoma cells that related with decreased levels of the cell survival markers p-ERK and p-AKT, and increased levels of apoptosis protein markers cleaved-caspase 3, cytochrome-c and cleaved-PARP was confirmed. All those results suggest that NK-EM exert stronger killing effects to cancer cells compared with the traditional NK-Exo, at the same time, the tumour targeting ability of the NK-EM was obtained in vivo. Therefore, NK-EM might be a promising immunotherapeutic agent for treatment of cancer.

Pluripotent stem cells can potentially be used in clinical applications as a model for studying disease progress. This tracking of disease-causing events in cells requires constant assessment of the quality of stem cells. Existing approaches are inadequate for robust and automated differentiation of stem cell colonies. In this study, we developed a new model of vector-based convolutional neural network (V-CNN) with respect to extracted features of the induced pluripotent stem cell (iPSC) colony for distinguishing colony characteristics. A transfer function from the feature vectors to the virtual image was generated at the front of the CNN in order for classification of feature vectors of healthy and unhealthy colonies. The robustness of the proposed V-CNN model in distinguishing colonies was compared with that of the competitive support vector machine (SVM) classifier based on morphological, textural, and combined features. Additionally, five-fold cross-validation was used to investigate the performance of the V-CNN model. The precision, recall, and F-measure values of the V-CNN model were comparatively higher than those of the SVM classifier, with a range of 87-93%, indicating fewer false positives and false negative rates. Furthermore, for determining the quality of colonies, the V-CNN model showed higher accuracy values based on morphological (95.5%), textural (91.0%), and combined (93.2%) features than those estimated with the SVM classifier (86.7, 83.3, and 83.4%, respectively). Similarly, the accuracy of the feature sets using five-fold cross-validation was above 90% for the V-CNN model, whereas that yielded by the SVM model was in the range of 75-77%. We thus concluded that the proposed V-CNN model outperforms the conventional SVM classifier, which strongly suggests that it as a reliable framework for robust colony classification of iPSCs. It can also serve as a cost-effective quality recognition tool during culture and other experimental procedures.

Background: Recently, 18 F-tetrafluoroborate (TFB) was used as a substrate for the human sodium/iodide symporter (hNIS) reporter gene. This study evaluated the feasibility of performing molecular-genetic imaging by using the new radiotracer ( 18 F-TFB) for the hNIS gene, to track dendritic cell (DC) migration in live mice. A murine dendritic cell line (DC2.4) co-expressing the hNIS and effluc genes (DC/NF) was established. To confirm the functional cellular expression of both effluc and NIS in the inoculated DC/NF cells by bio-medical imaging, combined bioluminescence imaging (BLI) and 18 F-TFB positron emission tomography/computed tomography (PET/CT) imaging was performed after intramuscular injection with parental DCs and DC/NF cells. For DC-tracking, parental DCs or DC/NF cells were injected in the left or right mouse footpad, respectively, and 18 F-TFB PET/CT and BLI were performed to monitor these cells in live mice., Results: In vivo PET/CT and BLI showed a clear signal in DC/NF injection sites but not in parental DC injection sites. The signal intensity in DC/NF cells was correlated with time. In vivo 18 F-TFB PET/CT imaging showed higher radiotracer activity in the draining popliteal lymph nodes (DPLNs) in DC/NF injection sites than those in DC injection sites on day 2. BLI also showed DC/NF cell migration to the DPLNs on day 2 after the injection., Conclusions: Migration of DCs to the lymph nodes was successfully monitored using 18 F-TFB PET/CT imaging of the NIS gene and optical imaging of the effluc gene in live mice. These data support the feasibility of using 18 F-TFB as a substrate for hNIS reporter gene imaging to track the migration of DCs to the lymph nodes in live animals. The use of 18 F-TFB may facilitate enhanced PET imaging of the hNIS reporter gene in small animals and humans in future studies.

In vivo biodistribution and fate of extracellular vesicles (EVs) are still largely unknown and require reliable in vivo tracking techniques. In this study, in vivo bioluminescence imaging (BLI) using Renilla luciferase (Rluc) was developed and applied to monitoring of EVs derived from thyroid cancer (CAL-62 cells) and breast cancer (MDA-MB-231) in nude mice after intravenous administration and was compared with a dye-based labeling method for EV derived from CAL-62 cells. The EVs were successfully labeled with Rluc and visualized by BLI in mice. In vivo distribution of the EVs, as measured by BLI, was consistent with the results of ex vivo organ analysis. EV-CAL-62/Rluc showed strong signals at lung followed by liver, spleen & kidney ( P < 0.05). EV-MDA-MB-231/Rluc showed strong signals at liver followed by lung, spleen & kidney ( P < 0.05). EV-CAL-62/Rluc and EV-MDA-MB-231/Rluc stayed in animal till day 9 and 3, respectively; showed a differential distribution. Spontaneous EV-CAL-62/Rluc shown distributed mostly to lung followed by liver, spleen & kidney. The new BLI system used to show spontaneous distribution of EV-CAL-62/Rluc in subcutaneous CAL-62/Rluc bearing mice. Dye (DiR)-labeled EV-CAL-62/Rluc showed a different distribution in vivo & ex vivo compared to EV-CAL-62/Rluc. Fluorescent signals were predominately detected in the liver ( P < 0.05) and spleen ( P < 0.05) regions. The bioluminescent EVs developed in this study may be used for monitoring of EVs in vivo . This novel reporter-imaging approach to visualization of EVs in real time is expected to pave the way for monitoring of EVs in EV-based treatments., Competing Interests: CONFLICTS OF INTEREST The authors declare that no competing interests exist.

Hair loss is a common medical problem. In this study, we investigated the proliferation, migration, and growth factor expression of human dermal papilla (DP) cells in the presence or absence of treatment with mesenchymal stem cell extracellular vesicles (MSC-EVs). In addition, we tested the efficacy of MSC-EV treatment on hair growth in an animal model. MSC-EV treatment increased DP cell proliferation and migration, and elevated the levels of Bcl-2, phosphorylated Akt and ERK. In addition; DP cells treated with MSC-EVs displayed increased expression and secretion of VEGF and IGF-1. Intradermal injection of MSC-EVs into C57BL/6 mice promoted the conversion from telogen to anagen and increased expression of wnt3a, wnt5a and versican was demonstrated. The first time our results suggest that MSC-EVs have a potential to activate DP cells, prolonged survival, induce growth factor activation in vitro, and promotes hair growth in vivo.

Background: The aim of this study was to evaluate the prognostic implication of asphericity (ASP); spatial irregularity; of pretherapeutic F 2-deoxy-2-fluoro-D-glucose (F FDG) tumor uptake in patients with invasive ductal carcinoma (IDC) of the breast., Methods: One hundred thirty-one female IDC patients (mean age = 48.1 ± 10.4 years), with pathological tumor size greater than 2 cm were retrospectively evaluated using F FDG positron emission tomography/computed tomography (PET/CT). ASP of F FDG distribution was calculated on the basis of the deviation of the tumor shape from spherical symmetry. Progression-free survival (PFS) was predicted on the basis of the univariate and multivariate analyses of the measured clinicopathologic factors and metabolic PET parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)]., Results: The PFS rate among the 131 patients was 90.1%. The mean follow-up time was 50 months for the entire study cohort and 26 months for the patients with recurrent disease. It is evident from the univariate analysis that N stage, hormonal receptor (Estrogen, ER/Progesterone, PR) status, MTV (≤4.2 mL), and ASP (≤15.1%) affected the PFS. Hazard ratios (HRs) estimated from the multivariate Cox regression analysis show that N stage (HR = 17.6), ASP (HR = 11.9), and hormonal receptor status (HR = 6.9) were independent prognostic factors in predicting PFS. In the subgroup of patients with lymph node metastasis, ASP (HR = 10.9) and hormonal receptor status (HR = 9.1) were independent prognostic factors for PFS., Conclusion: ASP of F FDG uptake is an independent predictor of outcome in IDC patients, and can be used for prognostic stratification.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are potential therapies for various diseases, but their angiogenic mechanisms of therapeutic efficacy remain unclear. Here, we describe how MSC-EVs, activates VEGF receptors and downstream angiogenesis pathways. Mouse MSC-EVs were isolated from cell culture medium and characterized using transmission electron microscopy, nanoparticle analysis, and western blotting. In vitro migration, proliferation, and tube formation assays using endothelial cells were used to assess the angiogenic potential of MSC-EVs, and revealed higher levels of cellular migration, proliferation, and tube formation after treatment. qRT-PCR and western blotting (WB) revealed higher protein and mRNA expression of the angiogenic genes VEGFR1 and VEGFR2 in mouse SVEC-4 endothelial cells after MSC-EVs treatment. Additionally, other vital pro-angiogenic pathways (SRC, AKT, and ERK) were activated by in vitro MSC-EV treatment. WB and qRT-PCR revealed enriched presence of VEGF protein and miR-210-3p in MSC-EV. The hindlimb ischemia mouse model was established and MSC-EVs with or without Matrigel (EV-MSC+Gel) were injected into the ischemic area and blood reperfusion was monitored using molecular imaging techniques. The in vivo administration of MSC-EVs increased both blood reperfusion and the formation of new blood vessels in the ischemic limb, with the addition of matrigel enhancing this effect further by releasing EVs slowly. MSC-EVs enhance angiogenesis in ischemic limbs, most likely via the overexpression of VEGFR1 and VEGFR2 in endothelial cells. These findings reveal a novel mechanism of activating receptors by MSC-EVs influence the angiogenesis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We optimized the protocol for thyroid ablation in living mice using radioactive iodine (RAI) and a low-iodine diet (LID). To examine the effect of LID on thyroid ablation, mice were randomly divided into 4 groups: Vehicle, 131 I 2.775 MBq, 131 I 5.55 MBq, and LID +  131 I 2.775 MBq. The LID group was fed a LID for up to 7 days and then mice in the 131 I 2.775, 131 I 5.55, and LID +  131 I 2.775 MBq groups were intravenously administrated with 131 I, respectively. Scintigraphy imaging with 99m Tc pertechnetate was performed once in 2 weeks for 4 weeks. After establishment of athyroid mice, control or athyroid mice were injected with human anaplastic thyroid cancer cells co-expressing sodium iodine symporter and enhanced firefly luciferase (ARO/NF) to evaluate RAI uptake. Scintigraphy imaging with 99m Tc pertechnetate was performed with ARO/NF tumor-bearing mice. Scintigraphy imaging showed decreased thyroid uptake in the LID +  131 I 2.775 MBq group compared to other groups. Scintigraphy images showed that tumor uptake was statically higher in athyroid mice than in control mice. These data suggest that these optimized conditions for thyroid ablation could be helpful to establish an in vivo mouse model.

Although most differentiated thyroid cancers show excellent prognosis, treating radioiodine refractory differentiated thyroid cancer (RR-DTC) is challenging. Various therapies, including chemotherapy, radiotherapy, and targeted therapy, have been applied for RR-DTC but show limited effectiveness. Redifferentiation followed by radioiodine therapy is a promising alternative therapy for RR-DTC. Retinoic acids, histone deacetylase inhibitors, and peroxisome proliferator-activated receptor-gamma agonists are classically used as redifferentiation agents, and recent targeted molecules are also used for this purpose. Appropriate selection of redifferentiation agents for each patient, using current knowledge about genetic and biological characteristics of thyroid cancer, might increase the efficacy of redifferentiation treatment. In this review, we will discuss the mechanisms of these redifferentiation agents, results of recent clinical trials, and promising preclinical results.

Objective: The aim of this study was to assess I-131 biokinetics in thyroid cancer and remnant tissue in patients with differentiated thyroid cancer using whole-body scan (WBS) and SPECT images acquired after I-131 therapy. The influence of thyroid stimulating hormone (TSH) stimulation method on the kinetics was also evaluated., Methods: A total of 57 patients who received I-131 therapy (2.96-7.4 GBq) were retrospectively included. TSH stimulation was achieved by recombinant human thyrotropin (rhTSH) or by thyroid hormone withdrawal (THW). Each patient received three sequential WBSs on days 1, 2, and 4 (or 5) after I-131 administration. All lesions were classified either as thyroid remnant (ThyR) or as metastatic lymph nodes (mLN) after considering the SPECT/CT images acquired during the last WBS. The lesion-based retention rate and absorbed dose of ThyR and mLN were calculated using a commercial dosimetric toolkit combined with the OLINDA software., Results: The retention rate and the effective half-time of mLN were lower than that of ThyR (p < 0.001, p = 0.003). In addition, the retention rate and the effective half-time of ThyR in the rhTSH group were higher than those in the THW group (p < 0.001, p < 0.001). The differences in the retention rate and the effective half-time of mLN were not statistically significant between the THW group and rhTSH group (p = 0.549, p = 0.571)., Conclusions: Radioiodine therapy using rhTSH delivered an at least similar radiation dose to target lesions compared to using THW in thyroid remnants and metastatic lymph nodes.

Molecular imaging is a relatively new discipline that allows visualization, characterization, and measurement of the biological processes in living subjects, including humans, at a cellular and molecular level. The interaction between cancer cells and natural killer (NK) cells is complex and incompletely understood. Despite our limited knowledge, progress in the search for immune cell therapies against cancer could be significantly improved by dynamic and non-invasive visualization and tracking of immune cells and by visualization of the response of cancer cells to therapies in preclinical and clinical studies. Molecular imaging is an essential tool for these studies, and a multimodal molecular imaging approach can be applied to monitor immune cells in vivo , for instance, to visualize therapeutic effects. In this review, we discuss the usefulness of NK cells in cancer therapies and the preclinical and clinical usefulness of molecular imaging in NK cell-based therapies. Furthermore, we discuss different molecular imaging modalities for use with NK cell-based therapies, and their preclinical and clinical applications in animal and human subjects. Molecular imaging has contributed to the development of NK cell-based therapies against cancers in animal models and to the refinement of current cell-based cancer immunotherapies. Developing sensitive and reproducible non-invasive molecular imaging technologies for in vivo NK cell monitoring and for real-time assessment of therapeutic effects will accelerate the development of NK cell therapies.

Molecular imaging allows a noninvasive assessment of biochemical and biological processes in living subjects. Treatment strategies for malignant lymphoma depend on histology and tumor stage. For the last two decades, molecular imaging has been the mainstay diagnostic test for the staging of malignant lymphoma and the assessment of response to treatment. This technology enhances our understanding of disease and drug activity during preclinical and clinical drug development. Here, we review molecular imaging applications in drug development, with an emphasis on oncology. Monitoring and assessing the efficacy of anti-cancer therapies in preclinical or clinical models are essential and the multimodal molecular imaging approach may represent a new stage for pharmacologic development in cancer. Monitoring the progress of lymphoma therapy with imaging modalities will help patients. Identifying and addressing key challenges is essential for successful integration of molecular imaging into the drug development process. In this review, we highlight the general usefulness of molecular imaging in drug development and radionuclide-based reporter genes. Further, we discuss the different molecular imaging modalities for lymphoma therapy and their preclinical and clinical applications., Competing Interests: The authors declare no conflict of interest.

Objective: Natural killer (NK) cells represent the third largest population of lymphocytes, and they play an important role in immune surveillance against tumors. The lungs are a common metastatic site for anaplastic thyroid cancer (ATC), and metastasis is one of the most frequent causes of mortality in this type of cancer. In the current study, we evaluated the effects of NK cell-based immunotherapy for pulmonary metastasis of ATC and determined how it affects the effector molecules of NK cells., Methods: Human NK cells (NK-92MI) were retrovirally transduced to express the effluc gene. Human ATC cells (CAL-62) were transduced with the effluc and Rluc genes. The cytotoxicity of NK cells against CAL-62 cells was assessed using the CytoTox 96 ® Non-Radioactive Cytotoxicity Assay system. Pulmonary metastases of ATC were developed by i.v. injection of CAL-62, and metastasis growth was monitored using bioluminescence imaging (BLI). To treat the metastases, five million NK-92MI cells were injected twice into the caudal vein of nude mice. To assess the targetability of NK cells to ATC tumors, NK-92MI cells expressing the effluc gene (NK/F) were administered through the tail vein of nude mice with a pulmonary metastasis or tumor xenograft. BLI was subsequently performed at 1, 3, 24, and 48 h., Results: NK/F and CAL-62 cells expressing the effluc or Rluc gene (CAL-62/F, CAL-62/R) were successfully established. Expression of the effluc and Rluc genes in NK/F, CAL-62/F, and CAL-62/R cells was verified by RT-polymerase chain reaction, western blotting, and luciferase assay. After coculture of NK-92MI and CAL-62/F cells for 24 h, the BLI signal intensity of CAL-62/F cells proportionally decreased with the number of cocultured NK cells. An ATC pulmonary metastasis mouse model was successfully generated, and NK cells significantly inhibited the growth of the metastasis ( p  < 0.01). The NK/F cells exhibited targetability to the pulmonary metastasis and tumor xenograft in the mouse model., Conclusion: The results of present study suggest that NK cells are able to target ATC tumors and that NK cell-based immunotherapy may serve as an effective therapeutic approach for pulmonary metastases of ATC.

Anaplastic thyroid cancer (ATC) is the most aggressive malignancy of the thyroid, during which undifferentiated tumors arise from the thyroid follicular epithelium. ATC has a very poor prognosis due to its aggressive behavior and poor response to conventional therapies. Gene-directed enzyme/prodrug therapy using genetically engineered mesenchymal stromal cells (MSC) is a promising therapeutic strategy. The doxycycline (DOX)-controlled Tet inducible system is the most widely utilized regulatory system and could be a useful tool for therapeutic gene-based therapies. For example, use a synthetic "tetracycline-on" switch system to control the expression of the therapeutic gene thymidine kinase, which converts prodrugs to active drugs. The aim of this study was to develop therapeutic MSCs, harboring an inducible suicide gene, and to validate therapeutic gene expression using optical molecular imaging of ATC. We designed the Tet-On system using a retroviral vector expressing herpes simplex virus thymidine kinase (HSV1-sr39TK) with dual reporters (eGFP-Fluc2). Mouse bone marrow-derived mesenchymal stromal cells (BM-MSC) were transduced using this system with (MSC-Tet-TK/Fluc2) or without (MSC-TK/Fluc) the Tet-On system. Transduced cells were screened and characterized. Engineered MSCs were co-cultured with ATC (CAL62/Rluc) cells in the presence of the prodrug ganciclovir (GCV) and stimulated with DOX. The efficiency of cell killing monitored by assessing Rluc (CAL62/Rluc) and Fluc (MSC-Tet-TK/Fluc and MSC-TK/Fluc) activities using IVIS imaging. Fluc activity increased in MSC-Tet-TK/Fluc cells in a dose dependent manner following DOX treatment (R2 = 0.95), whereas no signal was observed in untreated cells. eGFP could also be visualized after induction with DOX, and the HSV1-TK protein could be detected by western blotting. In MSC-TK/Fluc cells, the Fluc activity increased with increasing cell number (R2 = 0.98), and eGFP could be visualized by fluorescence microscopy. The Fluc activity and cell viability of MSC-Tet-TK/Fluc and MSC-TK/Fluc cells decreased significantly following GCV treatment. A bystander effect of the therapeutic cells confirmed in co-cultures of CAL62 cells, an anaplastic thyroid cancer cell line, with either MSC-Tet-TK/Fluc cells or MSC-TK/Fluc cells. The Rluc activity in MSC-Tet-TK/Fluc co-cultures, derived from the CAL62/Rluc cells, decreased significantly with GCV treatment of DOX treated cultures, whereas no significant changes were observed in untreated cultures. In addition, the Fluc activity of MSC-Tet-TK/Fluc cells also decreased significantly with DOX treatment whereas no signal was present in untreated cultures. A bystander effect also be demonstrated in co-cultures with MSC-TK/Fluc cells and CAL62/Rluc; both the Rluc activity and the Fluc activity were significantly decreased following GCV treatment. We have successfully developed a Tet-On system of gene-directed enzyme/prodrug delivery using MSCs. We confirmed the therapeutic bystander effect in CAL62/Rluc cells with respect to MSC-Tet-TK/Fluc and MSC-TK/Fluc cells after GCV treatment with and without DOX. Our results confirm the therapeutic efficiency of a suicide gene, with or without the Tet-On system, for ATC therapy. In addition, our findings provide an innovative therapeutic approach for using the Tet-On system to eradicate tumors by simple, repeated administration of MSC-Tet-TK/Fluc cells with DOX and GCV.

Objective: Exosomes are nanovesicles that are released from normal and tumor cells and are detectable in cell culture supernatant and human biological fluids. Although previous studies have explored exosomes released from cancer cells, little is understood regarding the functions of exosomes released by normal cells. Natural killer (NK) cells display rapid immunity to metastatic or hematological malignancies, and efforts have been undertaken to clinically exploit the antitumor properties of NK cells. However, the characteristics and functions of exosomes derived from NK cells remain unknown. In this study, we explored NK cell-derived exosome-mediated antitumor effects against aggressive melanoma in vitro and in vivo . Methods: B16F10 cells were transfected with enhanced firefly luciferase (effluc) and thy1.1 genes, and thy1.1-positive cells were immunoselected using microbeads. The resulting B16F10/effluc cells were characterized using reverse transcriptase polymerase chain reaction (RT-PCR), western blotting, and luciferase activity assays. Exosomes derived from NK-92MI cells (NK-92 Exo) were isolated by ultracentrifugation and density gradient ultracentrifugation. NK-92 Exo were characterized by transmission electron microscopy and western blotting. We also performed an enzyme-linked immunosorbent assay to measure cytokines retained in NK-92 Exo cells. The in vitro cytotoxicity of NK-92 Exo against the cancer cells was determined using a bioluminescence imaging system (BLI) and CCK-8 assays. To investigate the possible side effects of NK-92 Exo on healthy cells, we also performed the BLI and CCK-8 assays using the human kidney Phoenix™-Ampho cell line. Flow cytometry and western blotting confirmed that NK-92 Exo induced apoptosis in the B16F10/effluc cells. In vivo , we used a B16F10/effluc cell xenograft model to detect the immunotherapeutic effect of NK-92 Exo. We injected NK-92 Exo into tumors, and tumor growth progression was monitored using the IVIS Lumina imaging system and ultrasound imaging. Tumor mass was monitored after in vivo experiments. Results: RT-PCR and western blotting confirmed effluc gene expression and protein levels in B16F10/effluc cells. B16F10/effluc activity was found to increase with increasing cell numbers, using BLI assay. For NK-92 Exo characterization, western blotting was performed on both ultracentrifuged and density gradient-isolated exosomes. The results confirmed that NK cell-derived exosomes express two typical exosome proteins, namely CD63 and ALIX. We demonstrated by western blot analysis that NK-92 Exo presented two functional NK proteins, namely perforin and FasL. Moreover, we confirmed the membrane expression of FasL. The enzyme-linked immunosorbent assay results indicated that NK-92 Exo can secrete tumor necrosis factor (TNF)-α, which affected the cell proliferation signaling pathway. The antitumor effect of NK-92 Exo against B16F10/effluc cells in vitro was confirmed by BLI ( p < 0.001) and CCK-8 assays ( p < 0.001). Furthermore, in normal healthy cells, even after 24 h of co-culture, NK-92 Exo did not exhibit significant side effects. In the in vivo experiments, tumors in the vehicle control group were significantly increased, compared with those in the NK-92 Exo-treated group ( p < 0.05). Conclusion: The results of the current study suggest that exosomes derived from NK cells exert cytotoxic effects on melanoma cells and thus warrant further development as a potential immunotherapeutic strategy for cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Purpose: Although Sjögren's syndrome (SS) is the most common disease causing xerostomia, autoimmune thyroid diseases can also affect the salivary glands. The aim of our study was to estimate the prevalence of thyroid diseases (TD) in subjects with symptoms of xerostomia and evaluate the efficacy of salivary gland scintigraphy (SGS) in the detection of TD in patients with SS and without SS., Methods: We retrospectively reviewed the SGS findings of 173 subjects (men:women, 29:144) with symptoms of xerostomia. Ejection fractions (EF) in the parotid and submandibular glands were calculated. Thyroid disease was diagnosed on the basis of the results of the visual assessment of tracer uptake in the thyroid gland on SGS images as well as serological thyroid function tests., Results: Based on the American-European Criteria, 94 patients were diagnosed with SS. Hashimoto's thyroiditis was diagnosed in 63 patients, subacute thyroiditis in 23, subclinical hypothyroidism in five, and Graves' disease in one. There were significant differences in the EF values of the parotid and submandibular glands between patients with TD and those with undetermined diagnoses., Conclusions: More than half of patients with xerostomia exhibited TD. Thyroid assessment by SGS is feasible, and SGS appears to be useful for the patients with xerostomia caused by TD. SGS may be the first imaging modality capable of evaluating both salivary gland function and thyroid gland status in patients with xerostomia. This strategy would make the requirement for additional workup for thyroid disease.

Here, we sought to monitor bone marrow-derived dendritic cell (BMDC) migration and antitumor effects using a multimodal reporter imaging strategy in living mice. BMDCs were transduced with retroviral vector harboring human sodium iodide symporter (hNIS, nuclear imaging reporter), firefly luc2 (optical imaging reporter), and thy1.1 (surrogate marker of NIS and luc2) genes (BMDC/NF cells). No significant differences in biological functions, including cell proliferation, antigen uptake, phenotype expression, and migration ability, were observed between BMDC and BMDC/NF cells. Combined bioluminescence imaging and I-124 positron emission tomography/computed tomography clearly revealed the migration of BMDC/NF cells to draining popliteal lymph nodes at day 7 postinjection. Interestingly, marked tumor protection was observed in mice immunized with TC-1 lysate-pulsed BMDC/NF cells. Our findings suggested that multimodal reporter gene imaging of NIS and luciferase could provide insights into the biological behaviors of dendritic cells in living organisms and could be a useful tool for the optimization of DC-based immunotherapy protocols., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of highly sensitive, stable, and biocompatible imaging agents allowing visualization of dendritic cell (DC) migration is one of the essential factors for effective DC-based immunotherapy. Here, we used a novel and efficient synthesis approach to develop radioiodine-124-labeled tannic acid gold core-shell nanoparticles ( 124 I-TA-Au@AuNPs) for DC labeling and in vivo tracking of their migration using positron emission tomography (PET). 124 I-TA-Au@AuNPs were produced within 40 min in high yield via straightforward tannic acid-mediated radiolabeling chemistry and incorporation of Au shell, which resulted in high radio-sensitivity and excellent chemical stability of nanoparticles in DCs and living mice. 124 I-TA-Au@AuNPs demonstrated good DC labeling efficiency and did not affect cell biological functions, including proliferation and phenotype marker expression. Importantly, 124 I-TA-Au@AuNPs in an extremely low amount (0.1 mg/kg) were successfully applied to track the migration of DCs to lymphoid organs (draining lymph nodes) in mice.

Background: The purpose of this retrospective study was to assess the diagnostic value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT and the prognostic value of metabolic PET parameters in patients with adenoid cystic carcinoma of the head and neck (ACCHN)., Methods: Forty patients with newly diagnosed ACCHN were enrolled in this study. We investigated the diagnostic value of 18 F-FDG PET/CT for detecting and staging compared to conventional CT. Kaplan-Meier survival analysis for progression-free survival (PFS) was performed with clinicopathological factors and metabolic PET parameters., Results: The 18 F-FDG PET/CT showed comparable sensitivity (92.3%) to conventional CT for lesion detection, and changed staging and management plan in 6 patients (15.0%). Lower PFS rates were associated with advanced T classification, advanced TNM classification, high maximum standardized uptake value (SUVmax; >5.1), and high total lesion glycolysis (>40.1) of the primary tumor., Conclusion: The 18 F-FDG PET/CT can provide additional information for initial staging, and metabolic PET parameters may serve as prognostic factors of ACCHN. © 2016 Wiley Periodicals, Inc. Head Neck 39: 447-455, 2017., (© 2016 Wiley Periodicals, Inc.)

Purpose: Recent studies have suggested that a low dose (LD) of radioiodine (RAI) is sufficient to treat differentiated thyroid cancer (DTC) even in patients with intermediate risk. However, these studies evaluated the efficacy of RAI therapy, irrespective of the results of the whole-body scan (WBS). The aim of the present study was to evaluate the response to LD and high-dose (HD) RAI therapy using two different criteria (with and without WBS results) and the reclassification system according to the revised 2015 guidelines of the American Thyroid Association in Korean intermediate-risk DTC patients. In addition, we evaluated the long-term clinical outcomes of treatment with LD and HD RAI., Materials and Methods: In total, 204 intermediate-risk DTC patients who underwent postoperative RAI therapy at two tertiary referral hospitals from 2003 to 2004 were enrolled in the present retrospective study. One hundred and twenty-four patients were treated with 3.7 and 5.55 GBq (HD) of RAI in one center and 80 patients were treated with 1.11 GBq (LD) in the other center. The success rate of RAI therapy was assessed with or without the inclusion of WBS results in the analysis. In addition, the response to therapy during the first 2 years of follow-up after the initial RAI therapy was categorized according to the reclassification system of 2015 American Thyroid Association guidelines as excellent response, indeterminate response, biochemical incomplete response, or structural incomplete response. Recurrence was defined as a newly detected cytologically or pathologically confirmed lesion., Results: There were no significant differences between the success rates of the HD and LD groups irrespective of the inclusion of WBS results in the analysis (with WBS: 54.84 vs. 45.0%, P=0.23; without WBS: 60.48 vs. 62.5%, P=0.77). The response to HD and LD RAI therapy was excellent in 54.84 and 45.0% of the patients, respectively; indeterminate in 34.68 and 30.0% of the patients, respectively; biochemical incomplete in 4.03 and 13.75% of the patients, respectively; and structural incomplete in 6.45% and in 11.25% of the patients, respectively (P=0.04). In particular, the biochemical or structural incomplete response rate was lower in patients treated with HD than in patients treated with LD (HD, 10.48%; LD, 25.0%, P=0.01). At the last follow-up (HD, median 11 years; LD, median 10 years), patients who achieved an excellent response showed no evidence of disease. After the initial RAI therapy, eight patients in the HD group and 18 patients in the LD group who achieved either indeterminate response or biochemical incomplete response received additional RAI therapy. Seven patients (indeterminate response in five patients; biochemical incomplete response in two patients) in the HD group and seven patients (indeterminate response in five patients; biochemical incomplete response in two patients) in the LD group showed recurrences., Conclusion: LD RAI therapy after thyroidectomy appears to be insufficient in Korean DTC patients with intermediate risk. The patients in the LD group predominantly showed biochemical or structural incomplete response to initial RAI therapy and additional RAI therapy was required.

Improving care at the end of life is a health priority. At least one-third of deaths in the United States occur in the hospital; nearly half of the Americans who die in the hospital will have spent time in the intensive care unit during the last 3 days of life. Critically ill patients and their families identify significant unmet spiritual, environmental, and communication needs. Although the Society of Critical Care Medicine recommends that the spiritual needs of critically ill patients be addressed by the health care team and be incorporated in patients' plans of care, spiritual concerns are infrequently addressed during goals-of-care discussions. The American Association of Critical-Care Nurses' Synergy Model recognizes the central importance of spirituality to the provision of patient-centered care. Furthermore, the model highlights the value of the relationship between the patient and the nurse to a healing environment. The privileged connection between patients and nurses, foundational to the creation of a healing environment, may be understood as a sacred space. Critical care nurses are uniquely positioned to improve end-of-life care by focusing on the spiritual, environmental, and communication needs of their patients through the creation of a third space in the intensive care unit, a sacred space.

Reliable and sensitive imaging tools are required to track macrophage migration and provide a better understating of their biological roles in various diseases. Here, we demonstrate the possibility of radioactive iodide-embedded gold nanoparticles (RIe-AuNPs) as a cell tracker for nuclear medicine imaging. To demonstrate this utility, we monitored macrophage migration to carrageenan-induced sites of acute inflammation in living subjects and visualized the effects of anti-inflammatory agents on this process. Macrophage labeling with RIe-AuNPs did not alter their biological functions such as cell proliferation, phenotype marker expression, or phagocytic activity. In vivo imaging with positron-emission tomography revealed the migration of labeled macrophages to carrageenan-induced inflammation lesions 3 h after transfer, with highest recruitment at 6 h and a slight decline of radioactive signal at 24 h; these findings were highly consistent with the data of a bio-distribution study. Treatment with dexamethasone (an anti-inflammation drug) or GSK5182 (an ERRγ inverse agonist) hindered macrophage recruitment to the inflamed sites. Our findings suggest that a cell tracking strategy utilizing RIe-AuNPs will likely be highly useful in research related to macrophage-related disease and cell-based therapies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: The aim of this study was to predict the survival of patients with hepatocellular carcinoma (HCC) by examining metabolic PET parameters, apparent diffusion coefficients (ADCs), and clinical parameters., Methods: We retrospectively reviewed 52 patients with pathologically confirmed HCC (age, 57.9 ± 10.7 years; 43 men) who underwent MRI and F-FDG PET/CT. The tumor-to-normal liver SUV ratio (TLR), the mean ADC of each tumor, and other clinical data were obtained. Survival analysis was performed., Results: Thirty-two patients died during the follow-up period. There was an inverse correlation between the mean SUV and the mean ADC of a tumor (r = -0.402, P = 0.020). Among HCC patients, disease-specific survival was significantly associated with each of the following factors: high TLR (TLR ≥ 2; hazard ratio [HR], 3.78; P = 0.001), high mean ADC (mean ADC ≥ 1.250 × 10 mm/s; HR, 0.45; P = 0.028), AFP ≥ 400 ng/mL (HR, 3.48; P = 0.001), PIVKA-II ≥ 100mAU/mL (HR, 6.39; P = 0.011), tumor size (HR, 1.13; P < 0.001), number of tumors (HR, 2.16; P = 0.031), tumor stage (HR, 3.08; P < 0.001), and surgery for initial treatment (HR, 0.06; P < 0.001). The results of multivariate analysis show that DSS was significantly associated with each of the following factors: TLR ≥ 2 (HR, 2.46; P = 0.044), PIVKA-II ≥ 100mAU/mL (HR, 5.11; P = 0.037), tumor stage (HR, 3.01; P < 0.001), and surgery for initial treatment (HR, 0.04; P < 0.001)., Conclusions: High TLRs and low mean ADCs were associated with poor outcomes. The TLR was an independent prognostic factor in patients with HCC, but the mean ADC was not. A negative correlation was found between the mean ADC and the mean SUV of a tumor.

CXCR4, the stromal cell-derived factor-1 receptor, plays an important role in the migration of hematopoietic progenitor/stem cells to injured and inflamed areas. Noninvasive cell tracking methods could be useful for monitoring cell fate. Therefore, in this study, we evaluated the efficacy of an intravenous infusion of genetically engineered mesenchymal stem cells (MSCs) overexpressing CXC chemokine receptor 4 (CXCR4) to home to the tumor, by optical imaging. We constructed a retroviral vector containing CXCR with dual reporter genes, eGFP and Fluc2 , under the control of an EF1 α promoter (pBABE-EF1 α -CXCR4-eGFP-IRES-Fluc2). We also developed an eGFP-Fluc2 construct in the Retro-X retroviral vector (Retro-X-eGFP-Fluc2). MSCs were transduced with retroviruses to generate CXCR4-overexpressing MSCs (MSC-CXCR4/Fluc2) and MSCs (MSC/Fluc2). CXCR4 mRNA and protein expression was confirmed by RT-PCR and Western blotting, respectively, and it was higher in MSC-CXCR4/Fluc2 than in naive MSCs. eGFP expression was confirmed by confocal microscopy. The transfected MSC-CXCR4/Fluc2 cells showed higher migratory capacity than naive MSCs observed in Transwell migration assay. The in vivo migration of CXCR4-overexpressing MSCs to MDAMB231/Rluc tumor model by BLI imaging was also confirmed. Intravenous delivery of genetically modified MSCs overexpressing CXCR4 with a Fluc2 reporter gene may be a useful, noninvasive BLI imaging tool for tracking cell fate.

Clinical and preclinical in vivo tracking of extracellular vesicles (EVs) are a crucial tool for the development and optimization of EV-based diagnosis and treatment. EVs have gained interest due to their unique properties that make them excellent candidates for biological applications. Noninvasive in vivo EV tracking has allowed marked progress towards elucidating the mechanisms and functions of EVs in real time in preclinical and clinical studies. In this review, we summarize several molecular imaging methods that deal with EVs derived from different cells, which have allowed investigations of EV biodistribution, as well as their tracking, delivery, and tumor targeting, to determine their physiological functions and to exploit imaging-derived information for EV-based theranostics., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

The inability to monitor the in vivo dynamics of mast cells (MCs) limits the better understanding of its role in cancer progression. Here, we report on noninvasive imaging of MC migration to tumor lesions in mice and evaluation of the effects of migrated MCs on tumor progression through reporter gene-based in vivo optical imaging and glucose metabolism monitoring in cancer with 18 F-fluorodeoxyglucose ( 18 F-FDG) in vitro and in vivo. Murine MCs (MC-9) and Lewis lung cancer cells (LLC) expressing an enhanced firefly luciferase (effluc) gene were established, termed MC-9/effluc and LLC/effluc, respectively. MC-9/effluc cell migration to LLC tumor lesions was initially detected within 1 h post-transfer and distinct bioluminescence imaging signals emitted from MC-9/effluc cells were observed at tumor sites until 96 h. In vivo optical imaging as well as a biodistribution study with 18 F-FDG demonstrated more rapid tumor growth and upregulated glucose uptake potentially associated with MC migration to tumor lesions. These results suggest that the combination of a reporter gene-based optical imaging approach and glucose metabolism status monitoring with 18 F-FDG represents a promising tool to better understand the biological role of MCs in tumor microenvironments and to develop new therapeutic drugs to regulate their involvement in enhanced tumor growth., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This study describes a novel approach to reducing the challenges of highly nonlinear multiclass gene expression values for cancer diagnosis. To build a fruitful system for cancer diagnosis, in this study, we introduced two levels of gene selection such as filtering and embedding for selection of potential genes and the most relevant genes associated with cancer, respectively. The filter procedure was implemented by developing a fuzzy rough set (FR)-based method for redefining the criterion function of f-information (FI) to identify the potential genes without discretizing the continuous gene expression values. The embedded procedure is implemented by means of a water swirl algorithm (WSA), which attempts to optimize the rule set and membership function required to classify samples using a fuzzy-rule-based multiclassification system (FRBMS). Two novel update equations are proposed in WSA, which have better exploration and exploitation abilities while designing a self-learning FRBMS. The efficiency of our new approach was evaluated on 13 multicategory and 9 binary datasets of cancer gene expression. Additionally, the performance of the proposed FRFI-WSA method in designing an FRBMS was compared with existing methods for gene selection and optimization such as genetic algorithm (GA), particle swarm optimization (PSO), and artificial bee colony algorithm (ABC) on all the datasets. In the global cancer map with repeated measurements (GCM&#95;RM) dataset, the FRFI-WSA showed the smallest number of 16 most relevant genes associated with cancer using a minimal number of 26 compact rules with the highest classification accuracy (96.45%). In addition, the statistical validation used in this study revealed that the biological relevance of the most relevant genes associated with cancer and their linguistics detected by the proposed FRFI-WSA approach are better than those in the other methods. The simple interpretable rules with most relevant genes and effectively classified samples suggest that the proposed FRFI-WSA approach is reliable for classification of an individual's cancer gene expression data with high precision and therefore it could be helpful for clinicians as a clinical decision support system., Competing Interests: The authors have declared that no competing interests exist.

Several clinical studies have demonstrated that increased macrophage infiltration into tumors confers metastatic potential and poor prognosis in cancer. Preclinical studies are needed to develop new strategies for countering metastasis. Our study was designed to investigate the impact of pulmonary macrophages on lung metastasis of anaplastic thyroid cancer (ATC). ATC (CAL-62) and macrophage (Raw264.7) were transfected with the effluc (CAL-62/effluc, Raw264.7/effluc). Coculture and migration assays were used to assess the effect of Raw264.7 or THP1 (human macrophage) (or conditioned medium) on the proliferation and/or migration of CAL-62/effluc cells in vitro. The effect of clodro-lipo or PBS-lipo on macrophage depletion was confirmed in vitro and in vivo. CAL-62/effluc cells (1 × 10(6) ) were intravenously injected into nude mice 24 h after clodro-lipo or PBS-lipo administration. Effect of clodro-lipo on the lung metastasis of CAL-62/effluc was assessed by bioluminescence imaging (BLI). Micro computed tomography (micro-CT) and histology. BLI signals of CAL-62/effluc and Raw264.7/effluc increased to cell number. Raw264.7 cells and THP1 cells promoted CAL-62/effluc proliferation, and conditioned medium of Raw264.7 cells promoted CAL-62/effluc migration. Clodro-lipo significantly depleted pulmonary macrophages in vitro and in vivo. Intensity of BLI signals in ATC lung metastasis was weaker in the clodro-lipo group than PBS-lipo control. Micro-CT imaging and hematoxylin/eosin staining revealed smaller tumor masses in the clodro-lipo group than PBS-lipo control. Our findings indicate that pulmonary macrophages have an important role in initiation of lung metastasis of ATC. New therapeutic strategies that preclude initiation of pulmonary metastasis could potentially be developed by targeting pulmonary macrophages., (© 2016 UICC.)

Background: Depression and anxiety disorders are two of the most common mental disorders in the United States. These disorders are prevalent among college students., Objective: The main objective of this study is to compare the effectiveness of two different types of intervention practices (mindfulness vs. yoga) and a noninterventional control group in mitigating the effects of depression and/or anxiety in college students., Method: A sample of 90 students (both genders) over age 18 who had a diagnosis of anxiety and/or depression was recruited from 11,500 undergraduate college students in a mid-size university. The study's design included stratified-randomized controlled repeated measures with three groups: a mindfulness intervention group, a yoga-only intervention group, and a noninterventional group. Participants were randomly assigned to the aforementioned three groups. Participants in the intervention groups received an 8-week training either in mindfulness or yoga. Depressive, anxiety, stress symptoms, self-compassion, and mindfulness were measured at baseline, Week 4, Week 8, and Week 12., Results: Depressive, anxiety, and stress symptoms decreased significantly (p < .01) from baseline to follow-up conditions in both the mindfulness and yoga intervention groups. The changes in mindfulness scores were also significant in both groups. However, the changes in self-compassion scores were significant only in the mindfulness intervention group. No significant changes in the control group were demonstrated., Conclusions: The findings from this study can provide useful information to nurses and other health care providers. This study may have implications for a cost-effective treatment for depression and anxiety., (© The Author(s) 2016.)

Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.

Despite the possibility of combining Toll-like receptor (TLR) ligands as adjuvants to improve vaccine efficacy, it remains unclear which combinations of TLR ligands are effective or what their underlying mechanisms may be. Here, we investigated the mechanism of action of L-pampo, a proprietary adjuvant composed of TLR1/2 and TLR3 ligands. L-pampo dramatically increased humoral immune responses against the tested target antigens, which was correlated with an increase in follicular helper T cells and the maintenance of antigen-specific CD4(+) T cells. During the initial priming phase, in contrast to the induction of type I interferon (IFN) and pro-inflammatory cytokines stimulated by polyI:C, L-pampo showed a greatly diminished induction of type I IFN, but not of other cytokines, and remarkably attenuated IRF3 signaling, which appeared to be critical to L-pampo-mediated adjuvanticity. Collectively, our results demonstrate that the adjuvant L-pampo contributes to the promotion of antigen-specific antibodies and CD4(+) T cell responses via a fine regulation of the TLR1/2 and TLR3 signaling pathways, which may be helpful in the design of improved vaccines.

Although radioiodines are widely used to localize metastatic differentiated thyroid cancer (DTC), TcO4 also can be used because it is a substrate for the sodium-iodide symporter protein. The use of TcO4 has advantages over radioiodine, namely, easy availability, dispensability of iodine restriction, and early imaging time. However, its low sensitivity precludes its practical application. Scintigraphic detectability of DTC using sodium-iodide symporter substrates is related to the serum TSH levels. Here, I report a case with multiple metastatic lesions of DTC that were detected upon TSH-stimulated TcO4 scintigraphy, but not with non-TSH-stimulated scintigraphy using the same tracer.

New imaging probes with high sensitivity and stability are urgently needed to accurately detect sentinel lymph nodes (SLNs) for successful cancer diagnosis. Herein, the use of highly sensitive and stable PEGylated radionuclide-embedded gold nanoparticles (PEG-RIe-AuNPs) is reported for the detection of SLNs by combined positron emission tomography and Cerenkov luminescence imaging (PET/CLI). PEG-RIe-AuNPs show high sensitivity and stability both in vitro and in vivo, and are not toxic to normal ovarian and immune cells. In vivo PET/CLI imaging clearly reveals SLNs as early as 1 h post PEG-RIe-AuNP-injection, with peak signals achieved at 6 h postinjection, which is consistent with the biodistribution results. Taken together, the data provide strong evidence that PEG-RIe-AuNPs are promising as potential lymphatic tracers in biomedical imaging for pre and intraoperative surgical guidance., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mesenchymal stem cells (MSCs) can be used as a therapeutic armor for cancer. Extracellular vesicles (EVs) from MSCs have been evaluated for anticancer effects. In vivo targeting of EVs to the tumor is an essential requirement for successful therapy. Therefore, non-invasive methods of monitoring EVs in animal models are crucial for developing EV-based cancer therapies. The present study to develop bioluminescent EVs using Renilla luciferase (Rluc)-expressing MSCs. The EVs from MSC/Rluc cells (EV-MSC/Rluc) were visualized in a murine lung cancer model. The anticancer effects of EVs on Lewis lung carcinoma (LLC) and other cancer cells were assessed. EV-MSC/Rluc were visualized in vivo in the LLC-efffuc tumor model using optical imaging. The induction of apoptosis was confirmed with Annexin-V and propidium iodide staining. EV-MSC/Rluc and EV-MSCs showed a significant cytotoxic effect against LLC-effluc cells and 4T1; however, no significant effect on CT26, B16F10, TC1 cells. Moreover, EV-MSC/Rluc inhibited LLC tumor growth in vivo. EV-MSC/Rluc-mediated LLC tumor inhibitory mechanism revealed the decreased pERK and increased cleaved caspase 3 and cleaved PARP. We successfully developed luminescent EV-MSC/Rluc that have a therapeutic effect on LLC cells in both in vitro and in vivo. This bioluminescent EV system can be used to optimize EV-based therapy.

The purpose of this article is to explore how effective communication, in the form of engaged feedback, may aid in the self-care of the preceptor and an improved working relationship between preceptor and orientee. The application of the Engaged Feedback Reflective Inventory offers opportunity for both new and seasoned preceptors to discover growth opportunities in the realms of effective communication and self-care. Further research needs to be conducted in order to assess improved outcomes post training.

Purpose of the Report: This study was performed to evaluate the prognostic relevance of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured using F FDG PET/CT in patients with primary cutaneous malignant melanoma (CMM)., Materials and Methods: We conducted a retrospective review (July 2005 to November 2010) of 41 patients with a histological diagnosis of CMM who underwent pretreatment F FDG PET/CT. PET parameters (maximum standardized uptake value [SUVmax], MTV, and TLG) of the primary tumor were measured. Clinical variables such as age, sex, clinical stage, location and thickness of the primary lesion, and existence of ulceration were also assessed. Univariate and multivariate analyses for disease-free survival (DFS) and melanoma-specific survival (MSS) were performed using the Kaplan-Meier method and Cox proportional hazards models., Results: SUVmax and TLG were found to be significantly higher in patients with recurrence than in patients without recurrence (3.98 ± 2.91 vs 1.89 ± 1.35, P = 0.0145; 9.16 ± 8.44 vs 3.72 ± 3.64, P = 0.0249). SUVmax and TLG were also found to be significantly higher in nonsurvivors than in survivors (4.21 ± 3.06 vs 2.00 ± 1.46, P = 0.0260; 10.53 ± 8.83 vs 3.67 ± 3.44, P = 0.0170). The optimal cutoff values for DFS determined using a time-dependent receiver operating characteristic (ROC) curve were 1.8 for SUVmax, 6.07 cm for MTV, and 4.046 for TLG. Sixteen (39%) of the 41 patients experienced recurrence during the follow-up period. In univariate analysis, age (P = 0.0382), male sex (P = 0.0187), ulceration of the primary lesion (P = 0.0001), stage ≥ III (P = 0.0011), SUVmax greater than 1.8 (P = 0.0006), MTV greater than 6.07 cm (P = 0.0136), and TLG greater than 4.046 (P = 0.0010) affected DFS, whereas the other variables (location of the primary lesion and thickness of primary lesion) did not. After adjustment for the effects of the clinical parameters (age, sex, clinical stage, and existence of ulceration), SUVmax, MTV, and TLG were all significant predictors of DFS, and the best predictive factor was SUVmax. Thirteen (32%) of the 41 patients died because of CMM during the follow-up period. The optimal cutoff values for MSS determined using a time-dependent ROC curve were 2.2 for SUVmax, 4.02 cm for MTV, and 4.352 for TLG. In univariate analysis, ulceration of the primary lesion (P = 0.0005), SUVmax greater than 2.2 (P = 0.0001), MTV greater than 4.02 cm (P = 0.0071), and TLG greater than 4.352 (P = 0.0001) affected MSS, whereas the other variables (age, sex, clinical stage, primary lesion site, and thickness of the primary lesion) did not. After adjustment for the effect of the clinical parameter (existence of ulceration), MTV and TLG were significant predictors of MSS, and the best predictive factor of MSS was TLG., Conclusions: Pretreatment MTV and TLG may be useful in stratifying the likelihood of recurrence and melanoma-specific death, and TLG was found to be the best predictive marker for predicting melanoma-specific death.

To assess the role of [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) as a preoperative diagnostic tool in papillary thyroid carcinoma (PTC). From 2011 to 2014, 197 patients with PTC (246 tumor foci in all) underwent FDG-PET. Among these patients, 46 underwent neck dissection for lateral neck metastasis. According to the FDG avidity of the tumor foci or lateral neck metastasis, factors associated with the prognostic value were evaluated by univariate and multivariate logistic regression analyses. Among the 197 patients, 7 (3.6 %) were incidentally found to have non-thyroid origin malignancy. Additionally, 63.0 % (155/246) of PTC foci showed FDG uptake on PET/CT. Univariate analysis showed that the tumor size, the presence of extrathyroidal extension, BRAF mutation, and Hashimoto thyroiditis were associated with FDG avidity. However, except for pathological extrathyroidal extension, the other factors showed statistically significant correlations with FDG avidity (p < 0.001, p = 0.008, and p = 0.009, respectively). FDG uptake in lateral neck node metastasis showed high specificity and negative predictive value (NPV). In four cases of nonspecific findings on ultrasonography (USG)/CT, FDG avidity was helpful to diagnose the presence of lateral neck metastasis. The maximum standardized uptake value (SUVmax) of PET/CT was correlated with the maximum diameter of the involved lateral node. FDG avidity did not show any significance in the recurrence-free survival of both the thyroid tumor and lateral neck metastasis. The FDG avidity of PTC did not show prognostic predictive meaning. However, in the case of lateral neck metastasis, FDG avidity showed high sensitivity and NPV, and could provide better information in cases of nonspecific findings on USG and CT.

This paper reports turn-off fluorescence sensor for Fe(3+) ion in water using fluorescent N-doped carbon dots as a probe. A simple and efficient hydrothermal carbonization of Prunus avium fruit extract for the synthesis of fluorescent nitrogen-doped carbon dots (N-CDs) is described. This green approach proceeds quickly and provides good quality N-CDs. The mean size of synthesized N-CDs was approximately 7nm calculated from the high-resolution transmission electron microscopic images. X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy revealed the presence of -OH, -NH2, -COOH, and -CO functional groups over the surface of CDs. The N-CDs showed excellent fluorescent properties, and emitted blue fluorescence at 411nm upon excitation at 310nm. The calculated quantum yield of the synthesized N-CDs is 13% against quinine sulfate as a reference fluorophore. The synthesized N-CDs were used as a fluorescent probe towards the selective and sensitive detection of biologically important Fe(3+) ions in water by fluorescence spectroscopy and for bio-imaging of MDA-MB-231 cells. The limit of detection (LOD) and the Stern-Volmer quenching constant for the synthesized N-CDs were 0.96μM and 2.0958×10(3)M of Fe(3+) ions. The green synthesized N-CDs are efficiently used as a promising candidate for the detection of Fe(3+) ions and bio-imaging., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Retrosternal goiter is one of the common causes of anterior mediastinal masses. Scintigraphic diagnosis of retrosternal goiter plays an important role in avoiding invasive diagnostic procedures, and SPECT acquisition may enhance the diagnostic sensitivity of this technique as compared with planar scintigraphy. Here, I report a case of retrosternal goiter that was demonstrated on SPECT/CT obtained with Tc pertechnetate, but not on planar scintigraphy with the same tracer.