High intakes of iodine among women during pregnancy and the postpartum period has no adverse effect on thyroid function.

PURPOSE: Given the high consumption of seaweed soup by pregnant and lactating Korean women, concerns have been raised about excessive iodine intake. We evaluated the effects of maternal iodine intake on maternal thyroid function and birth outcomes. We also evaluated iodine intake via seaweed soup during late pregnancy and the early postpartum period. METHODS: A total of 349 pregnant women of the Ideal Breast Milk cohort were recruited in late pregnancy, of whom 302 revisited after delivery. Three-day dietary records were assessed at each visit. Blood was collected for thyroid function test. Obstetrical and birth outcomes were obtained. RESULTS: The median dietary iodine intake was 459 µg/day (interquartile range [IQR] 326.5-647.4 µg/day) during pregnancy. Dietary iodine intake by quartile was not significantly associated with maternal thyroid status, or obstetrical or neonatal outcomes. However, the dietary iodine intake in the early postpartum period was 1759 µg/day (IQR 1026.7-2491.1 µg/day) because of a marked increase in seaweed soup consumption. Of all women, 25.8% consumed seaweed soup more than once over the 3 days of dietary records when pregnant, but the figure rose to 93.4% postpartum. Of postpartum women who consumed seaweed soup daily, the median dietary iodine intakes were 1355, 2394, and 3063 µg/day (soup at one, two, and three-or-four meals). CONCLUSIONS: In these iodine-replete pregnant women, dietary iodine intake during pregnancy showed no effect on maternal thyroid function or birth outcomes. However, iodine intake in the early postpartum period was markedly increased by the frequency of seaweed soup consumption.

Overexpression of Both Human Sodium Iodide Symporter (NIS) and BRG1-Bromodomain Synergistically Enhances Radioiodine Sensitivity by Stabilizing p53 through NPM1 Expression.

Improved therapeutic strategies are required to minimize side effects associated with radioiodine gene therapy to avoid unnecessary damage to normal cells and radiation-induced secondary malignancies. We previously reported that codon-optimized sodium iodide symporter (oNIS) enhances absorption of I-131 and that the brahma-associated gene 1 bromodomain (BRG1-BRD) causes inefficient DNA damage repair after high-energy X-ray therapy. To increase the therapeutic effect without applying excessive radiation, we considered the combination of oNIS and BRG1-BRD as gene therapy for the most effective radioiodine treatment. The antitumor effect of I-131 with oNIS or oNIS+BRD expression was examined by tumor xenograft models along with functional assays at the cellular level. The synergistic effect of both BRG1-BRD and oNIS gene overexpression resulted in more DNA double-strand breaks and led to reduced cell proliferation/survival rates after I-131 treatment, which was mediated by the p53/p21 pathway. We found increased p53, p21, and nucleophosmin 1 (NPM1) in oNIS- and BRD-expressing cells following I-131 treatment, even though the remaining levels of citrulline and protein arginine deiminase 4 (PAD4) were unchanged at the protein level.

Pattern of F-18 FDG Uptake in Colon Cancer after Bacterial Cancer Therapy Using Engineered Salmonella Typhimurium: A Preliminary In Vivo Study.

Purpose: Bacterial cancer therapy (BCT) research using engineered Salmonella typhimurium has increased in recent years. 2-Deoxy-2[18F] fluoro-D-glucose positron emission tomography (FDG PET) is widely used in cancer patients to detect cancer, monitor treatment responses, and predict prognoses. The aim of this pilot study was to investigate FDG uptake patterns in a mouse tumor model after BCT. Procedures. BCT was performed via the intravenous injection of attenuated S. typhimurium (SLΔppGpp/lux) into female mice bearing a tumor (derived from CT26 murine colon cancer cells) in the right thigh. 18F-FDG PET images acquired before BCT and at different time points after BCT. In vivo bioluminescence imaging confirmed bacterial presence in the tumor. The tumor volume, standardized uptake value (SUV) of FDG (SUVmax and SUVmean), early SUV reduction%, and normalized tumor volume change were analyzed. Results: Early after BCT (1 or 2 days post-injection (dpi)), FDG tumor uptake decreased in 10 out of 11 mice and then increased at later stages. FDG uptake before BCT was correlated with normalized tumor volume change after BCT. Early FDG reduction% after BCT was correlated with normalized volume change after BCT. Conclusions: Early after BCT, FDG tumor uptake decreased and then increased at later stages. The higher the FDG tumor uptake before BCT, the better the BCT response. FDG uptake patterns were related to tumor volume change after BCT. Therefore, FDG uptake was a good candidate for evaluating BCT.

Glucose-Thymidine Ratio as a Metabolism Index Using 18F-FDG and 18F-FLT PET Uptake as a Potential Imaging Biomarker for Evaluating Immune Checkpoint Inhibitor Therapy.

Immune checkpoint inhibitors (ICIs) are widely used in cancer immunotherapy, requiring effective methods for response monitoring. This study evaluated changes in 18F-2-fluoro-2-deoxy-D-glucose (FDG) and 18F-fluorothymidine (FLT) uptake by tumors following ICI treatment as potential imaging biomarkers in mice. Tumor uptakes of 18F-FDG and 18F-FLT were measured and compared between the ICI treatment and control groups. A combined imaging index of glucose-thymidine uptake ratio (GTR) was defined and compared between groups. In the ICI treatment group, tumor growth was effectively inhibited, and higher proportions of immune cells were observed. In the early phase, 18F-FDG uptake was higher in the treatment group, whereas 18F-FLT uptake was not different. There was no difference in 18F-FDG uptake between the two groups in the late phase. However, 18F-FLT uptake of the control group was markedly increased compared with the ICI treatment group. GTR was consistently higher in the ICI treatment group in the early and late phases. After ICI treatment, changes in tumor cell proliferation were observed with 18F-FLT, whereas 18F-FDG showed altered metabolism in both tumor and immune cells. A combination of 18F-FLT and 18F-FDG PET, such as GTR, is expected to serve as a potentially effective imaging biomarker for monitoring ICI treatment.

Therapeutic efficacy of modified anti-miR21 in metastatic prostate cancer.

Despite improved therapeutic efficacy of the locked nucleic acid (LNA)- and peptide nucleic acid (PNA)-modified antisense microRNAs (anti-miRs), their wider application in clinical practice is still not thoroughly investigated. This study aimed to investigate the stability and therapeutic efficacy of the modified LNA- and PNA-type anti-miRs in a murine prostate cancer model under various treatment conditions. After verifying the anti-cancer potential of anti-miR21 by targeting tumor suppressor PTEN, the potential of the modified LNA- and PNA-type anti-miR21s was compared in vitro and in vivo. We found that PNA-type anti-miR21 showed better stability and therapeutic efficacy in the xenografted mouse tumor model than the LNA-type anti-miR21. Furthermore, PNA-type anti-miR21 treatment showed reduced tumor metastasis. This study may serve as a ground for exploring diverse choices in therapeutic oligonucleotide modification techniques to improve cancer treatment.

Identification of Lymphatic and Hematogenous Routes of Rapidly Labeled Radioactive and Fluorescent Exosomes through Highly Sensitive Multimodal Imaging.

There has been considerable interest in the clinical use of exosomes as delivery vehicles for treatments as well as for promising diagnostic biomarkers, but the physiological distribution of exosomes must be further elucidated to validate their efficacy and safety. Here, we aimed to develop novel methods to monitor exosome biodistribution in vivo using positron emission tomography (PET) and optical imaging. Exosomes were isolated from cultured mouse breast cancer cells and labeled for PET and optical imaging. In mice, radiolabeled and fluorescently labeled exosomes were injected both via lymphatic and hematogenous metastatic routes. PET and fluorescence images were obtained and quantified. Radioactivity and fluorescence intensity of ex vivo organs were measured. PET signals from exosomes in the lymphatic metastatic route were observed in the draining sentinel lymph nodes. Immunohistochemistry revealed greater exosome uptake in brachial and axillary versus inguinal lymph nodes. Following administration through the hematogenous metastasis pathway, accumulation of exosomes was clearly observed in the lungs, liver, and spleen. Exosomes from tumor cells were successfully labeled with 64Cu (or 68Ga) and fluorescence and were visualized via PET and optical imaging, suggesting that this simultaneous and rapid labeling method could provide valuable information for further exosome translational research and clinical applications.

Efficacy and Safety of Human Serum Albumin-Cisplatin Complex in U87MG Xenograft Mouse Models.

Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is a chemotherapeutic drug widely used against many solid tumors. A pharmacokinetics study found that CDDP can bind to human serum albumin (HSA), which is the most abundant plasma protein in serum. HSA has the advantage of being a nanocarrier and can accumulate in tumors by passive targeting and active targeting mediated by the secreted protein acidic and rich in cysteine (SPARC). In this study, we investigated the possibility of using a CDDP-HSA complex (HSA-CDDP) as a SPARC-mediated therapeutic agent. To investigate the HSA-dependent therapeutic effect of HSA-CDDP, we used two types of U87MG glioma cells that express SPARC differently. HSA-CDDP was highly taken up in SPARC expressing cells and this uptake was enhanced with exogenous SPARC treatment in cells with low expression of SPARC. The cytotoxicity of HSA-CDDP was also higher in SPARC-expressing cells. In the tumor model, HSA-CDDP showed a similar tumor growth and survival rate to CDDP only in SPARC-expressing tumor models. The biosafety test indicated that HSA-CDDP was less nephrotoxic than CDDP, based on blood markers and histopathology examination. Our findings show that HSA-CDDP has the potential to be a novel therapeutic agent for SPARC-expressing tumors, enhancing the tumor targeting effect by HSA and reducing the nephrotoxicity of CDDP.

Prognostic value of metabolic tumour volume on baseline 18F-FDG PET/CT in addition to NCCN-IPI in patients with diffuse large B-cell lymphoma: further stratification of the group with a high-risk NCCN-IPI.

PURPOSE: The purpose of this study was to determine the prognostic value of metabolic volumetric parameters as a quantitative index on pre-treatment 18F-FDG PET/CT in addition to the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 103 consecutive patients with DLBCL and baseline FDG PET/CT were retrospectively evaluated. Quantitative metabolic parameters, including total metabolic tumour volume (TMTV) using a standardized uptake value (SUV) of ≥2.5 as the threshold, were estimated. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values for the metabolic parameters. The relationships between study variables and patient survival were tested using Cox regression analysis. Patient survival rates were derived from Kaplan-Meier curves and compared using the log-rank test. RESULTS: Median follow-up was 34 months. In patients with a low TMTV (<249 cm3), the 3-year progression free survival (PFS) rate was 83% and the overall survival (OS) rate was 92%, in contrast to 41% and 57%, respectively, in those with a high TMTV (≥249 cm3). In univariate analysis, a high TMTV and NCCN-IPI ≥4 were associated with inferior PFS and OS (P < 0.0001 for all), as was a high total lesion glycolysis (P = 0.004 and P = 0.005, respectively). In multivariate analysis, TMTV and NCCN-IPI were independent predictors of PFS (hazard ratio, HR, 3.11, 95% confidence interval, CI, 1.37-7.07, P = 0.007, and HR 3.42, 95% CI 1.36-8.59, P = 0.009, respectively) and OS (HR 3.41, 95% CI 1.24-9.38, P = 0.017, and HR 5.06, 95% CI 1.46-17.60, P = 0.014, respectively). TMTV was able to separate patients with a high-risk NCCN-IPI of ≥4 (n = 62) into two groups with significantly different outcomes; patients with low TMTV (n = 16) had a 3-year PFS rate of 75% and an OS rate of 88%, while those with a high TMTV had a 3-year PFS rate of 32% and an OS rate of 47% (χ2 = 7.92, P = 0.005, and χ2 = 8.26, P = 0.004, respectively). However, regardless of TMTV, patients with a low-risk NCCN-IPI of <4 (n = 41) had excellent outcomes (3-year PFS and OS rates of 85% and 95%, respectively). CONCLUSION: Pretreatment TMTV was an independent predictor of survival in patients with DLBCL. Importantly, TMTV had an additive prognostic value in patients with a high-risk NCCN-IPI. Thus, the combination of baseline TMTV with NCCN-IPI may improve the prognostication and may be helpful guide the decision for intensive therapy and clinical trials, especially in DLBCL patients with a high-risk NCCN-IPI.

Comprehensive gene expression analysis for exploring the association between glucose metabolism and differentiation of thyroid cancer.

BACKGROUND: The principle of loss of iodine uptake and increased glucose metabolism according to dedifferentiation of thyroid cancer is clinically assessed by imaging. Though these biological properties are widely applied to appropriate iodine therapy, the understanding of the genomic background of this principle is still lacking. We investigated the association between glucose metabolism and differentiation in advanced thyroid cancer as well as papillary thyroid cancer (PTC). METHODS: We used RNA sequencing of 505 patients with PTC obtained from the Cancer Genome Archives and microarray data of poorly-differentiated and anaplastic thyroid cancer (PDTC/ATC). The signatures of GLUT and glycolysis were estimated to assess glucose metabolic profiles. The glucose metabolic profiles were associated with tumor differentiation score (TDS) and BRAFV600E mutation status. In addition, survival analysis of glucose metabolic profiles was performed for predicting recurrence-free survival. RESULTS: In PTC, the glycolysis signature was positively correlated with TDS, while the GLUT signature was inversely correlated with TDS. These correlations were significantly stronger in the BRAFV600E negative group than the positive group. Meanwhile, both GLUT and glycolysis signatures were negatively correlated with TDS in advanced thyroid cancer. The high glycolysis signature was significantly associated with poor prognosis in PTC in spite of high TDS. The glucose metabolic profiles are intricately associated with tumor differentiation in PTC and PDTC/ATC. CONCLUSIONS: As glycolysis was an independent prognostic marker, we suggest that the glucose metabolism features of thyroid cancer could be another biological progression marker different from differentiation and provide clinical implications for risk stratification. TRIAL REGISTRATION: Not applicable.

Protective efficacy of a plasmid DNA vaccine against transgene-specific tumors by Th1 cellular immune responses after intradermal injection.

With DNA vaccines, it is important to monitor the movement of transfectants and to overcome immune deviations. We used a pCMV-LacZ plasmid (expressing ß-galactosidase) and a pcDNA-hNIS plasmid (expressing the human sodium/iodide symporter [hNIS] gene) as non-secreted visual-imaging markers. Transfectants carrying the hNIS or LacZ gene migrated to peripheral lymphoid tissues. hNIS-expressing cells were observed specifically in the LNs and spleen. Anti-ß-galactosidase was detected in LacZ DNA immunized mice after boosting twice, suggestive of Th2 humoral immune responses. Antibody isotyping defined the humoral immune response. A dominant IgG2a type occurred in hNIS-immunized mice in ELISAs. IgG2a/IgG1 ratios increased after hNIS DNA vaccination. High levels of INF-γ-secreting cells were identified in ELISpot and increased IFN-γ levels were found in cytokine ELISAs. Tumor growth decreased in hNIS DNA-immunized mice. In conclusion, humoral immune responses switched to the Th1 cellular immune response, even though we administered plasmid DNA by intra dermal injection.

Dual-time point 18F-FDG PET/CT for the staging of oesophageal cancer: the best diagnostic performance by retention index for N-staging in non-calcified lymph nodes.

PURPOSE: The purpose of this study is to investigate the role of dual time point (DTP) 18F-FDG PET/CT in the staging of oesophageal cancer, especially in lymph node metastasis. METHODS: A total of 35 patients with oesophageal squamous cell carcinoma who underwent surgical treatment without neoadjuvant chemotherapy were enrolled as a test set and another 19 patients were enrolled as a validation set. The DTP PET/CT scans were obtained in dual time points at 60 and 120 min each, following the administration of 18F-FDG. Visual analysis was performed and semiquantitative analysis was performed using several PET parameters such as maximal standardized uptake values (SUVmax), peak SUV (SUVpeak) and retention indexes using SUVmax (RImax) and SUVpeak (RIpeak). RESULTS: Primary oesophageal lesions exhibited a significant difference for SUVmax at each time point scan (ANOVA, p < 0.001). For nodal staging, a total of 276 non-calcified nodal stations of the test set were evaluated. Sensitivity, specificity and accuracy of visual analysis were 32.0% (8 of 25), 96.8% (243 of 251) and 90.9% (251 of 276) in the test set. Using ROC analysis, RImax had the largest area under the curve (AUC) to detect metastatic lymphadenopathy at the optimal cut-off value of 6% (AUC 0.853, P < 0.001) in the test set (sensitivity, specificity and accuracy; 80.0% (20 of 25), 94.8% (238 of 251) and 93.5% (258 of 276)). In the validation set (179 non-calcified nodal stations), sensitivity, specificity and accuracy of RImax at the optimal cut-off of 6% were 71.4% (5 of 7), 99.4% (171 of 172) and 98.4% (176 of 179), whereas those of visual analysis were 14.3% (1 of 7), 98.8% (170 of 172) and 95.5% (171 of 179). CONCLUSIONS: The best diagnostic performance of nodal staging in patients with oesophageal cancer was achieved by application of RImax with a cut-off of more than 6% on DTP 18F-FDG PET/CT with the exclusion of calcified lymph nodes. Optimal clinical management in surgically-candidate oesophageal cancer patients could be achieved using the diagnostic flow on DTP 18F-FDG PET/CT.

Relation of EGFR Mutation Status to Metabolic Activity in Localized Lung Adenocarcinoma and Its Influence on the Use of FDG PET/CT Parameters in Prognosis.

OBJECTIVE: The purposes of this study were to assess the relation between epidermal growth factor receptor (EGFR) mutation status and FDG PET/CT findings and to evaluate the influence of this relation on the use of FDG PET/CT parameters to establish a prognosis in cases of localized lung adenocarcinoma. MATERIALS AND METHODS: Patients with stage I and II lung adenocarcinomas were retrospectively enrolled. At the initial FDG PET/CT examination, maximum and peak standardized uptake, tumor-to-background ratio, and volumetric parameters of metabolic tumor volume and total lesion glycolysis were measured. RESULTS: The values of all the metabolic and volumetric FDG PET/CT parameters were significantly lower in EGFR mutant than in EGFR wild-type lung adenocarcinomas. All parameters were statistically significant for predicting recurrence-free survival. In multivariate analyses, peak standardized uptake and total lesion glycolysis were more significant prognostic factors than was TNM stage (p < 0.001). Optimal cutoff values of parameters for predicting recurrence-free survival were slightly different between the two groups. CONCLUSION: EGFR mutation is related to low metabolic activity of localized lung adenocarcinoma at FDG PET/CT. Because of differences in the metabolic activity of EGFR mutant and wild-type tumors, EGFR mutation status must be considered when FDG PET/CT parameters are used for prognosis.

Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting.

Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent. We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling with 68Ga. NOTA-GUL and DOTA-GUL were synthesized and labeled with 68Ga using generator-eluted 68GaCl3 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5. The stabilities of 68Ga-labeled compounds in human serum were tested at 37.5 °C. A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [125I]MIP-1072 (PSMA-specific binding agent) as a tracer. Biodistribution and micro-PET studies were performed using 22Rv1-xenograft BALB/c nude mice. The radiolabeling efficiency of NOTA-GUL (>99%) was higher than that of DOTA-GUL (92%). The IC50 of Ga-NOTA-GUL was 18.3 nM. In the biodistribution study, tumor uptake of 68Ga-NOTA-GUL (5.40% ID/g) was higher than that of 68Ga-DOTA-GUL (4.66% ID/g) at 1 h. Tumor/muscle and tumor/blood uptake ratios of 68Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68Ga-DOTA-GUL (16.1 and 31.1, respectively). The tumor/kidney uptake ratio of 68Ga-NOTA-GUL was 3.4-fold higher than that of 68Ga-DOTA-GUL. 68Ga-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand. In conclusion, we successfully synthesized 68Ga-NOTA-GUL and 68Ga-DOTA-GUL for prostate cancer imaging. 68Ga-NOTA-GUL showed better radiochemical and biodistribution results. 68Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical.

Prediction of breast cancer recurrence using lymph node metabolic and volumetric parameters from 18F-FDG PET/CT in operable triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer has a poor prognosis. We evaluated several metabolic and volumetric parameters from preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the prognosis of triple-negative breast cancer and compared them with current clinicopathologic parameters. METHODS: A total of 228 patients with triple-negative breast cancer (mean age 47.0 ± 10.8 years, all women) who had undergone preoperative PET/CT were included. The PET/CT metabolic parameters evaluated included maximum, peak, and mean standardized uptake values (SUVmax, SUVpeak, and SUVmean, respectively). The volumetric parameters evaluated included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Metabolic and volumetric parameters were evaluated separately for tumor (T) and lymph nodes (N). The prognostic value of these parameters was compared with that of clinicopathologic parameters. RESULTS: All lymph node metabolic and volumetric parameters showed significant differences between patients with and without recurrence. However, tumor metabolic and volumetric parameters showed no significant differences. In a univariate survival analysis, all lymph node metabolic and volumetric parameters (SUVmax-N, SUVpeak-N, SUVmean-N, MTV-N, and TLG-N; all P < 0.001), T stage (P = 0.010), N stage (P < 0.001), and TNM stage (P < 0.001) were significant parameters. In a multivariate survival analysis, SUVmax-N (P = 0.005), MTV (P = 0.008), and TLG (P = 0.006) with TNM stage (all P < 0.001) were significant parameters. CONCLUSIONS: Lymph node metabolic and volumetric parameters were significant predictors of recurrence in patients with triple-negative breast cancer after surgery. Lymph node metabolic and volumetric parameters were useful parameters for evaluating prognosis in patients with triple-negative breast cancer by 18F-FDG PET/CT, rather than tumor parameters.

Heterogeneity index evaluated by slope of linear regression on 18F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma.

PURPOSE: 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of 18F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and 18F-FDG PET/CT parameters. METHODS: A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative 18F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each 18F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and 18F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. RESULTS: Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the 18F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0.001, respectively) demonstrated significant results. CONCLUSIONS: The heterogeneity index obtained using the linear regression slope, could be an effective predictor of pancreatic cancer recurrence after pancreatic cancer surgery, in addition to 18F-FDG PET/CT volumetric parameters and clinicopathologic parameters.

Neural correlates of the popular music phenomenon: evidence from functional MRI and PET imaging.

PURPOSE: Music can induce different emotions. However, its neural mechanism remains unknown. The aim of this study was to use functional magnetic resonance imaging (fMRI) and position emission tomography (PET) imaging for mapping of neural changes under the most popular music in healthy volunteers. METHODS: Blood-oxygen-level-dependent (BOLD) fMRI and monoamine receptor PET imaging with 11C-N-methylspiperone (11C-NMSP) were conducted under the popular music Gangnam Style and light music A Comme Amour in healthy subjects. PET and fMRI images were analyzed by using the Statistical Parametric Mapping software (SPM). RESULTS: Significantly increased fMRI BOLD signals were found in the bilateral superior temporal cortices, left cerebellum, left putamen and right thalamus cortex. Monoamine receptor availability was increased significantly in the left superior temporal gyrus and left putamen, but decreased in the bilateral superior occipital cortices under the Gangnam Style compared with the light music condition. Significant positive correlation was found between 11C-NMSP binding and fMRI BOLD signals in the left temporal cortex. Furthermore, increased 11C-NMSP binding in the left putamen was positively correlated with the mood arousal level score under the Gangnam Style condition. CONCLUSION: Popular music Gangnam Style can arouse pleasure experience and strong emotional response. The left putamen is positively correlated with the mood arousal level score under the Gangnam Style condition. Our results revealed characteristic patterns of brain activity associated with Gangnam Style, and may also provide more general insights into the music-induced emotional processing.

Gray matter correlates of dopaminergic degeneration in Parkinson's disease: A hybrid PET/MR study using (18) F-FP-CIT.

Dopaminergic degeneration is a hallmark of Parkinson's disease (PD), which causes various symptoms affected by corticostriatal circuits. So far, the relationship between cortical changes and dopamine loss in the striatum is unclear. Here, we evaluate the gray matter (GM) changes in accordance with striatal dopaminergic degeneration in PD using hybrid PET/MR. Sixteen patients with idiopathic PD underwent (18) F-FP-CIT PET/MR. To measure dopaminergic degeneration in PD, binding ratio (BR) of dopamine transporter in striatum was evaluated by (18) F-FP-CIT. Voxel-based morphometry (VBM) was used to evaluate GM density. We obtained voxelwise correlation maps of GM density according to the striatal BR. Voxel-by-voxel correlation between BR maps and GM density maps was done to evaluate region-specific correlation of striatal dopaminergic degeneration. There was a trend of positive correlation between striatal BR and GM density in the cerebellum, parahippocampal gyri, and frontal cortex. A trend of negative correlation between striatal BR and GM density in the medial occipital cortex was found. Voxel-by-voxel correlation revealed that the positive correlation was mainly dependent on anterior striatal BR, while posterior striatal BR mostly showed negative correlation with GM density in occipital and temporal cortices. Decreased GM density related to anterior striatal dopaminergic degeneration might demonstrate degeneration of dopaminergic nonmotor circuits. Furthermore, the negative correlation could be related to the motor circuits of posterior striatum. Our integrated PET/MR study suggests that the widespread structural progressive changes in PD could denote the cortical functional correlates of the degeneration of striatal dopaminergic circuits. Hum Brain Mapp 37:1710-1721, 2016. © 2016 Wiley Periodicals, Inc.

A new fluorescence/PET probe for targeting intracellular human telomerase reverse transcriptase (hTERT) using Tat peptide-conjugated IgM.

Despite an increasing need for methods to visualize intracellular proteins in vivo, the majority of antibody-based imaging methods available can only detect membrane proteins. The human telomerase reverse transcriptase (hTERT) is an intracellular target of great interest because of its high expression in several types of cancer. In this study, we developed a new probe for hTERT using the Tat peptide. An hTERT antibody (IgG or IgM) was conjugated with the Tat peptide, a fluorescence dye and (64)Cu. HT29 (hTERT+) and U2OS (hTERT-) were used to visualize the intracellular hTERT. The hTERT was detected by RT-PCR and western blot. Fluorescence signals for hTERT were obtained by confocal microscopy, live cell imaging, and analyzed by Tissue-FAXS. In nude mice, tumors were visualized using the fluorescence imaging devices Maestro™ and PETBOX. In RT-PCR and western blot, the expression of hTERT was detected in HT29 cells, but not in U2OS cells. Fluorescence signals were clearly observed in HT29 cells and in U2OS cells after 1 h of treatment, but signals were only detected in HT29 cells after 24 h. Confocal microscopy showed that 9.65% of U2OS and 78.54% of HT29 cells had positive hTERT signals. 3D animation images showed that the probe could target intranuclear hTERT in the nucleus. In mice models, fluorescence and PET imaging showed that hTERT in HT29 tumors could be efficiently visualized. In summary, we developed a new method to visualize intracellular and intranuclear proteins both in vitro and in vivo.

Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells.

UNLABELLED: Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Epithelial-mesenchymal transition (EMT) is related to self-renewal capacity and circulating tumor cell (CTC) characteristics for tumor metastasis. Although tumor metastasis is a life-threatening, complicated process that occurs through circulation of tumor cells, mechanistic aspects of self-renewal and circulating capacities have been largely unknown. Hepatic transmembrane 4 L six family member 5 (TM4SF5) promotes EMT for malignant growth and migration, so it was rationalized that TM4SF5, as a hepatocellular carcinoma (HCC) biomarker, might be important for metastatic potential. Here, self-renewal capacity by TM4SF5 was mechanistically explored using hepatocarcinoma cells with or without TM4SF5 expression, and we explored whether they became CTCs using mouse liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24(-) , aldehyde dehydrogenase (ALDH) activity, as well as a physical association between CD44 and TM4SF5. Interaction between TM4SF5 and CD44 was through their extracellular domains with N-glycosylation modifications. TM4SF5/CD44 interaction activated proto-oncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3)/Twist-related protein 1 (Twist1)/B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling for spheroid formation, whereas disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts using 200∼5,000 cells per injection, TM4SF5-positive tumors exhibited subpopulations with locally increased CD44 expressions, supporting for tumor cell differentiation. TM4SF5-positive, but not TM4SF5- or CD44-knocked-down, cells were identified circulating in blood 4-6 weeks after orthotopic liver injection using in vivo laser scanning endomicroscopy. Anti-TM4SF5 reagent blocked their metastasis to distal intestinal organs. CONCLUSION: TM4SF5 promotes self-renewal and CTC properties supported by TM4SF5(+) /CD44(+(TM4SF5-bound)) /ALDH(+) /CD24(-) markers during HCC metastasis.

Development of a complementary PET/MR dual-modal imaging probe for targeting prostate-specific membrane antigen (PSMA).

We tried to develop a dual-modal PET/MR imaging probe using a straightforward one-pot method by encapsulation with specific amphiphiles. In this study, iron oxide (IO) nanoparticles were encapsulated with three amphiphiles containing PEG, DOTA and the prostate-specific membrane antigen (PSMA)-targeting ligand in aqueous medium. The diameter of the prepared nanoparticle DOTA-IO-GUL was 11.01±1.54nm. DOTA-IO-GUL was labeled with (68)Ga in high efficiency. The DOTA-IO-GUL showed a dose-dependent binding to LNCaP (PSMA positive) cells via a competitive binding study against (125)I-labeled MIP-1072 (PSMA-targeting agent). Additionally, PET and MR imaging results showed PSMA selective uptake by only 22Rv1 (PSMA positive) but not PC-3 (PSMA negative) in dual-tumor xenograft mouse model study. MR imaging showed high resolution, and PET imaging enabled quantification and confirmation of the specificity. In conclusion, we have successfully developed the specific PSMA-targeting IO nanoparticle, DOTA-IO-GUL, as a dual-modality probe for complementary PET/MR imaging. FROM THE CLINICAL EDITOR: The combination of using Positron Emission Tomography (PET) and computed tomography (CT) in clinical practice is now the norm. With advances in technology, the next step would be to develop combined PET and Magnetic Resonance (MR) dual-imaging. In this article, the authors described their positive study on the development of a dual-modal PET/MR imaging probe using a prostate cancer model.