Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase.

Background: Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4'-amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods: An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution (V t), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results: At the end of synthesis, the yield of [18F]FBAT was 2.2-3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125-137 GBq/µmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18, 1.53 ± 0.25, 1.41 ± 0.21, and 1.90 ± 0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution (V t, mL/cm3), and K i (influx rate) of [18F]FBAT were 1.9 ± 0.21- and 1.4 ± 0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain K i of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and V t values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion: An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.

Development of Radiofluorinated Nicotinamide/Picolinamide Derivatives as Diagnostic Probes for the Detection of Melanoma.

Regarding the increased incidence and high mortality rate of malignant melanoma, practical early-detection methods are essential to improve patients' clinical outcomes. In this study, we successfully prepared novel picolinamide-benzamide (18F-FPABZA) and nicotinamide-benzamide (18F-FNABZA) conjugates and determined their biological characteristics. The radiochemical yields of 18F-FPABZA and 18F-FNABZA were 26 ± 5% and 1 ± 0.5%, respectively. 18F-FPABZA was more lipophilic (log P = 1.48) than 18F-FNABZA (log P = 0.68). The cellular uptake of 18F-FPABZA in melanotic B16F10 cells was relatively higher than that of 18F-FNABZA at 15 min post-incubation. However, both radiotracers did not retain in amelanotic A375 cells. The tumor-to-muscle ratios of 18F-FPABZA-injected B16F10 tumor-bearing mice increased from 7.6 ± 0.4 at 15 min post-injection (p.i.) to 27.5 ± 16.6 at 3 h p.i., while those administered with 18F-FNABZA did not show a similarly dramatic increase throughout the experimental period. The results obtained from biodistribution studies were consistent with those derived from microPET imaging. This study demonstrated that 18F-FPABZA is a promising melanin-targeting positron emission tomography (PET) probe for melanotic melanoma.

Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer's Disease.

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.

Effect of Cerenkov Radiation-Induced Photodynamic Therapy with 18F-FDG in an Intraperitoneal Xenograft Mouse Model of Ovarian Cancer.

Ovarian cancer (OC) metastases frequently occur through peritoneal dissemination, and they contribute to difficulties in treatment. While photodynamic therapy (PDT) has the potential to treat OC, its use is often limited by tissue penetration depth and tumor selectivity. Herein, we combined Cerenkov radiation (CR) emitted by 18F-FDG accumulated in tumors as an internal light source and several photosensitizer (PS) candidates with matched absorption bands, including Verteporfin (VP), Chlorin e6 (Ce6) and 5'-Aminolevulinic acid (5'-ALA), to evaluate the anti-tumor efficacy. The in vitro effect of CR-induced PDT (CR-PDT) was evaluated using a cell viability assay, and the efficiency of PS was assessed by measuring the singlet oxygen production. An intraperitoneal ES2 OC mouse model was used for in vivo evaluation of CR-PDT. Positron emission tomography (PET) imaging and bioluminescence-based imaging were performed to monitor the biologic uptake of 18F-FDG and the therapeutic effect. The in vitro studies demonstrated Ce6 and VP to be more effective PSs for CR-PDT. Moreover, VP was more efficient in the generation of singlet oxygen and continued for a long time when exposed to fluoro-18 (18F). Combining CR emitted by 18F-FDG and VP treatment not only significantly suppressed tumor growth, but also prolonged median survival times compared to either monotherapy.

Simplified quantification of 13N-ammonia PET myocardial blood flow: A comparative study with the standard compartment model to facilitate clinical use.

BACKGROUND: Short imaging protocol to quantify myocardial blood flow (MBF) and myocardial flow reserve (MFR) may enhance the clinical application of 13N-ammonia cardiac PET. We assessed the flow quantitation of 13N-ammonia PET implementing simple retention model and two-compartment model. METHODS: Fourteen healthy volunteers (HVT) and twenty-three clinical patients received 13N-ammonia PET/CT. The simple retention model used the first 7-minute image to quantify MBF. Global and regional MBF and MFR of the two models were compared. RESULTS: Global and regional MBF and MFR of these two models were highly correlated with mildly inferior correlation in RCA territory (global R2: rest MBF = 0.79, stress MBF = 0.65, MFR = 0.77; regional R2: rest MBF ≥ 0.72, stress MBF ≥ 0.52, MFR ≥ 0.68). There were significant differences for MFR (4.04 ± 0.72, 3.66 ± 0.48, p = .02) and rest MBF (0.69 ± 0.12, 0.78 ± 0.12, p = .02) between the two models in the HVT group. CONCLUSIONS: 13N-ammonia global and regional MBF and MFR from the simple retention model demonstrate strong correlations with that from the two-compartment model. Significant differences of MFR and rest MBF are noted in the HVT group, with a proposed normal reference value for the 13N-ammonia short simple retention protocol.

Effects of the Acute and Chronic Ethanol Intoxication on Acetate Metabolism and Kinetics in the Rat Brain.

BACKGROUND: Ethanol (EtOH) intoxication inhibits glucose transport and decreases overall brain glucose metabolism; however, humans with long-term EtOH consumption were found to have a significant increase in [1-11 C]-acetate uptake in the brain. The relationship between the cause and effect of [1-11 C]-acetate kinetics and acute/chronic EtOH intoxication, however, is still unclear. METHODS: [1-11 C]-acetate positron emission tomography (PET) with dynamic measurement of K1 and k2 rate constants was used to investigate the changes in acetate metabolism in different brain regions of rats with acute or chronic EtOH intoxication. RESULTS: PET imaging demonstrated decreased [1-11 C]-acetate uptake in rat brain with acute EtOH intoxication, but this increased with chronic EtOH intoxication. Tracer uptake rate constant K1 and clearance rate constant k2 were decreased in acutely intoxicated rats. No significant change was noted in K1 and k2 in chronic EtOH intoxication, although 6 of 7 brain regions showed slightly higher k2 than baseline. These results indicate that acute EtOH intoxication accelerated acetate transport and metabolism in the rat brain, whereas chronic EtOH intoxication status showed no significant effect. CONCLUSIONS: In vivo PET study confirmed the modulatory role of EtOH, administered acutely or chronically, in [1-11 C]-acetate kinetics and metabolism in the rat brain. Acute EtOH intoxication may inhibit the transport and metabolism of acetate in the brain, whereas chronic EtOH exposure may lead to the adaptation of the rat brain to EtOH in acetate utilization. [1-11 C]-acetate PET imaging is a feasible approach to study the effect of EtOH on acetate metabolism in rat brain.

HIF-1α triggers long-lasting glutamate excitotoxicity via system xc- in cerebral ischaemia-reperfusion.

Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-d-aspartate receptor (NMDAR) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF-1α mainly regulates the cystine-glutamate transporter (system xc- ) subunit xCT by directly binding to its promoter; xCT and its function are up-regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR) or CIR-mediated glutamate excitotoxicity in vitro and in vivo. Pharmaceutical inhibition of system xc- by a clinically approved anti-cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF-1α plays a role in CIR-induced glutamate excitotoxicity via the long-lasting activation of system xc- -dependent glutamate outflow and suggest that system xc- is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Protective Effect of Low-Intensity Pulsed Ultrasound on Memory Impairment and Brain Damage in a Rat Model of Vascular Dementia.

Purpose To investigate the neuroprotective effects of low-intensity pulsed (LIP) ultrasound on memory impairment and central nervous system injury in a rat model of vascular dementia. Materials and Methods All animal experiments were approved by the animal care and use committee and adhered to experimental animal care guidelines. A 1.0-MHz focused ultrasound transducer was used to stimulate the brain noninvasively with 50-msec bursts at a 5% duty cycle, repetition frequency of 1 Hz, and spatial peak temporal average intensity of 528 mW/cm2. LIP ultrasound treatment was performed daily with triple sonications in each hemisphere. The duration of each sonicaton was 5 minutes, with a 5-minute interval between each sonication. Permanent bilateral common carotid artery occlusion (BCCAO) was used as a model of vascular dementia. After 2 weeks of LIP ultrasound, neuroprotective effects of LIP ultrasound were evaluated with behavioral analysis, including the passive avoidance task and elevated plus maze. Myelin content was detected with carbon 11 (11C) Pittsburgh compound B (PIB). Brain sections were stained with hematoxylin-eosin and Luxol fast blue. Two-way analysis of variance and Student t test were used for statistical analyses, with a significance level of .05. Results Protein expressions of brain-derived neurotrophic factor (BDNF) in the BCCAO rats treated with LIP ultrasound were significantly higher than those in BCCAO rats (1.1 ± 0.0 vs 0.8 ± 0.1, P < .05). BCCAO rats exhibited neuronal damage and demyelination. Compared with the BCCAO group, 11C PIB accumulation in the BCCAO rats treated with LIP ultrasound was significantly (P < .05) increased by 67.4% and 203.0% in the hippocampus and corpus callosum, respectively. Hematoxylin-eosin staining showed that neuronal injury in the hippocampal cornu ammonis 1 region was alleviated with LIP ultrasound. Luxol fast blue staining of the corpus callosum was significantly greater in the BCCAO rats treated with LIP ultrasound than in the untreated BCCAO rats (mean, 94.5% ± 2.3 [standard error] vs 86.6% ± 1.0; P < .05). Moreover, LIP ultrasound stimulation significantly improved learning and memory abilities and morphology in rats with vascular dementia compared with rats with untreated vascular dementia (P < .05). Conclusion These results suggest LIP ultrasound stimulation protects against brain injury in the hippocampus and corpus callosum in rats with vascular dementia. The beneficial effect of LIP ultrasound may be partly induced by upregulation of protein expression of BDNF. © RSNA, 2016.

Long-term outcomes of pediatric sinus bradycardia.

OBJECTIVES: To delineate the long-term outcomes and mechanisms of pediatric sinus bradycardia. STUDY DESIGN: Participants with sinus bradycardia who were identified from a survey of 432,166 elementary and high school students, were enrolled 10 years after the survey. The clinical course, heart rate variability, and hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene were assessed. RESULTS: A total of 104 (male:female was 60:44; prevalence, 0.025%) participants were observed to have sinus bradycardia at age 15.5 ± 0.2 years with a mean heart rate of 48.4 ± 0.4 beats per minute; 86 study participants (83%) responded to clinical assessment and 37 (36%) underwent laboratory assessment. Athletes composed 37.8% of the study participants. During the extended 10-year follow-up, 15 (17%) of the participants had self-limited syncopal episodes, but none had experienced life-threatening events. According to Holter recordings, none of the participants had heart rate <30 beats per minute or a pause longer than 3 seconds. Compared with 67 age- and sex-matched controls, the variables of heart rate based on the spectral and time domain analysis of the participants with sinus bradycardia were all significantly higher, indicating higher parasympathetic activity. The results of mutation analysis were negative in the HCN4 gene in all of our participants. CONCLUSIONS: The long-term outcomes of the children and adolescents with sinus bradycardia identified using school electrocardiographic survey are favorable. Parasympathetic hyperactivity, instead of HCN4 gene mutation, is responsible for the occurrence of sinus bradycardia.

Radiofrequency Catheter Ablation of Atrial Tachyarrhythmias in Adults with Repaired Congenital Heart Disease: Constraints from Multiple and New Arrhythmic Foci.

BACKGROUND: Radiofrequency catheter ablation (RFCA) for atrial tachyarrhythmias in postoperative congenital heart disease (CHD) patients has a low success rate and a high recurrence rate. This study explores the reasons for these constraints. METHODS: A total of 49 consecutive postoperative CHD patients who received RFCA for atrial tachyarrhythmias between 1993 and 2010 were enrolled. RESULTS: Overall, there were 86 RFCA procedures performed, 32 with the conventional method and 54 using CARTO-guided mapping. The interval between the operation and the first ablation was 13 years. Isthmus-dependent atrial flutter (AFL) was the most common type of tachycardia (37, 76%), followed by intra-atrial re-entry tachycardia (IART; 37%), and ectopic atrial tachycardia (EAT; 31%). By applying CARTO-guided mapping, the success rate was elevated compared to that of conventional ablation (84% vs. 56%, p = 0.006), but there was no improvement in the recurrence rate (22% vs. 28%, p = 0.75). Multiple atrial tachyarrhythmias occurred in 26 (53%) patients, and 17 presented during the initial electrophysiological study. The presence of multiple arrhythmias during the initial study predicted ablation failure or multiple ablations (11/17 vs. 3/32, p < 0.001). Among the 15 patients with new tachyarrhythmias, EAT and IART predominated. However, applying antiarrhythmia agents immediately following ablation may decrease arrhythmia recurrence (1/10 vs. 14/25, p = 0.02). CONCLUSIONS: Although electroanatomical mapping improves the results of RFCA in atrial tachyarrhythmias, the recurrence rate remains high because of multiple and new atrial tachyarrhythmias. Therefore, short-term pharmacological treatment following RFCA for positive remodeling should be considered. KEY WORDS: Ablation; Antiarrhythmia agents; Atrial tachyarrhythmia; Congenital heart disease; Multiple arrhythmias.

Comparison of the Detection Performance Between FAP and FDG PET/CT in Various Cancers: A Systemic Review and Meta-analysis.

PURPOSE: 18F-FDG is the dominant radiotracer in oncology; however, it has limitations. Novel labeled fibroblast activation protein (FAP) radiotracers have been developed and published in several studies. Thus, this meta-analysis aimed to compare the detection rates (DRs) of FDG and FAP, based on previous studies from a systematic review. METHODS: PubMed/MEDLINE and Cochrane library databases were used to perform a comprehensive and systematic search and are updated to April 30, 2022. The DR, relative risk, and the SUVmax were calculated between the FAP and FDG tracers. Finally, the sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve of FAP and FDG were analyzed using gold and reference standards. RESULTS: Thirty studies (1170 patients) were included in the meta-analysis. The relative risks of FAP DR for the primary tumor, recurrent tumor, lymph node metastasis, and distant metastasis were FDG 1.06- to 3.00-fold per patient and per lesion. For the primary tumor, FAP uptake was most intense in pancreatic cancer, followed by head and neck, cervical, colorectal, lung, gastric, and hepatocellular carcinoma, and was higher than FDG except for urological system cancer. The sensitivity (0.84-0.98), diagnostic odds ratio (19.36-358.47), and summary receiver operating characteristic curve (0.94-0.99) of FAP based on patient and lesion were better for primary tumors, LN metastasis, and distant metastasis than FDG. CONCLUSIONS: Fibroblast activation protein is an extremely potential radiotracer to replace most of the use of FDG in oncology. It is noteworthy that the FAP tracers for primary tumors had low specificity despite excellent sensitivity and had lower uptake than FDG in urological system cancer. In addition, the difference in detection between FAP and FDG for LN metastasis could not be certain in sarcoma.

Comparison of the synthesis and biological properties of no-carrier-added and carrier-added 4-borono-2-[18F]fluorophenylalanine ([18F]FBPA).

PURPOSE: Boron neutron capture therapy (BNCT), an attractive strategy for cancer treatment, can kill tumor cells and avoid injury to surrounding healthy cells. 4-Borono-2-[18F]fluorophenylalanine ([18F]FBPA) positron emission tomography (PET) is a reliable tool for patient screening. Due to the relatively low radiochemical yield when employing the electrophilic route, this study was able to develop a new method to produce no-carrier-added (NCA) [18F]FBPA and compare the biological characteristics with carrier-added (CA) characteristics. PROCEDURES: By starting from 4-bromo-2-nitrobenzaldehyde, NCA [18F]FBPA was prepared using radiofluorination, alkylation, borylation, and hydrolysis. Cellular uptake analyses, microPET imaging, and biodistribution analyses were conducted to characterize the biological properties of NCA and CA [18F]FBPA. RESULTS: The radiochemical yield of NCA [18F]FBPA was 20 % ± 6 % (decay corrected) with a radiochemical purity of >98 % and molar activity of 56 ± 15 GBq/µmol in a 100-min synthesis. The in vitro accumulation was significantly higher for NCA [18F]FBPA than for CA [18F]FBPA in both SAS and CT-26 cells. However, no apparent differences in tumor uptake were observed between NCA and CA [18F]FBPA-injected tumor-bearing mice. CONCLUSIONS: We successfully prepared NCA [18F]FBPA through nucleophilic substitution and achieved improved radiochemical yield and purity. We also demonstrated the effects of the amount of nonradioactive FBPA on in vitro cellular uptake and in vivo imaging studies.

Comparing the Detection Performance Between Multiparametric Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen PET/CT in Patients With Localized Prostate Cancer: A Systematic Review and Meta-analysis.

PURPOSE: Multiparametric MRI (mpMRI) has been promoted as an auxiliary diagnostic tool for prostate biopsy. However, prostate-specific membrane antigen (PSMA) including 68 Ga-PSMA-11, 18 F-DCFPyL, and 18 F-PSMA-1007 applied PET/CT imaging was an emerging diagnostic tool in prostate cancer patients for staging or posttreatment follow-up, even early detecting. Many studies have used PSMA PET for comparison with mpMRI to test the diagnostic ability for early prostate cancer. Unfortunately, these studies have shown conflicting results. This meta-analysis aimed to compare the differences in diagnostic performance between PSMA PET and mpMRI for detecting and T staging localized prostatic tumors. METHODS: This meta-analysis involved a systematic literature search of PubMed/MEDLINE and Cochrane Library databases. The pooling sensitivity and specificity of PSMA and mpMRI verified by pathological analysis were calculated and used to compare the differences between the 2 imaging tools. RESULTS: Overall, 39 studies were included (3630 patients in total) from 2016 to 2022 in the current meta-analysis and found that the pooling sensitivity values for localized prostatic tumors and T staging T3a and T3b of PSMA PET were 0.84 (95% confidence interval [CI], 0.83-0.86), 0.61 (95% CI, 0.39-0.79), and 0.62 (95% CI, 0.46-0.76), respectively, whereas those of mpMRI were found to be 0.84 (95% 0.78-0.89), 0.67 (95% CI, 0.52-0.80), and 0.60 (95% CI, 0.45-0.73), respectively, without significant differences ( P > 0.05). However, in a subgroup analysis of radiotracer, the pooling sensitivity of 18 F-DCFPyL PET was higher than mpMRI (relative risk, 1.10; 95% CI, 1.03-1.17; P < 0.01). CONCLUSIONS: This meta-analysis found that whereas 18 F-DCFPyL PET was superior to mpMRI at detecting localized prostatic tumors, the detection performance of PSMA PET for localized prostatic tumors and T staging was comparable to that of mpMRI.

Dual-tracer positron emission tomography/computed tomography as an imaging probe of de novo lipogenesis in preclinical models of hepatocellular carcinoma.

Background: De novo lipogenesis is upregulated in many cancers, and targeting it represents a metabolic approach to cancer treatment. However, the treatment response is unpredictable because lipogenic activity varies greatly among individual tumors, thereby necessitating the assessment of lipogenic activity before treatment. Here, we proposed an imaging probe, positron emission tomography/computed tomography (PET/CT) with dual tracers combining 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG), to assess the lipogenic activity of hepatocellular carcinoma (HCC) and predict the response to lipogenesis-targeted therapy. Methods: We investigated the association between 11C-acetate/18F-FDG uptake and de novo lipogenesis in three HCC cell lines (from well-differentiated to poorly differentiated: HepG2, Hep3B, and SkHep1) by examining the expression of lipogenic enzymes: acetyl-CoA synthetase 2 (ACSS2), fatty acid synthase (FASN), and ATP citrate lyase (ACLY). The glycolysis level was determined through glycolytic enzymes: pyruvate dehydrogenase expression (PDH). On the basis of the findings of dual-tracer PET/CT, we evaluated the treatment response to a lipase inhibitor (orlistat) in cell culture experiments and xenograft mice. Results: Dual-tracer PET/CT revealed the lipogenic activity of various HCC cells, which was positively associated with 11C-acetate uptake and negatively associated with 18F-FDG uptake. This finding represents the negative association between 11C-acetate and 18F-FDG uptake. Because these two tracers revealed the lipogenic and glycolytic activity, respectively, which implies an antagonism between lipogenic metabolism and glucose metabolism in HCC. In addition, dual-tracer PET/CT not only revealed the lipogenic activity but also predicted the treatment response to lipogenesis-targeted therapy. For example, HepG2 xenografts with high 11C-acetate but low 18F-FDG uptake exhibited high lipogenic activity and responded well to orlistat treatment, whereas SkHep1 xenografts with low 11C-acetate but high 18F-FDG uptake exhibited lower lipogenic activity and poor response to orlistat. Conclusion: The proposed non-invasive dual-tracer PET/CT imaging can reveal the lipogenesis and glycolysis status of HCC, thus providing an ideal imaging probe for predicting the therapeutic response of HCC to lipogenesis-targeted therapy.

The role of mechanical-electrical interaction in ventricular arrhythmia: evidence from a novel animal model for repaired tetralogy of Fallot.

Pulmonary regurgitation and prolonged QRS duration of right bundle branch (RBB) block are common in repaired tetralogy of Fallot (TOF) and increase the risk of sudden death. We sought to establish an animal model to reflect both abnormalities. Twenty-one canines: group I (n = 7) received a surgical right ventricular outflow tract (RVOT) transannular patch plus pulmonary valve destruction; group II (n = 5) received RBB ablation and sham operation; and group III (n = 9) received combined interventions. Serial electrophysiological data were obtained up to 1 y. Procedure mortality was 27.6%. At 1 y, although severe pulmonary regurgitation was documented in most dogs in groups I (71%) and III (100%), progressive RVOT dilatation was noted in group III. RBB block was present in all dogs in groups II and III. However, the increments of QRS duration, QTc, JTc, and QT dispersion progression between 1 mo and 1 y were all greatest in group III. Ventricular arrhythmia events were frequent in group III (median 3.3/mo) but uncommon in groups I and II (median 1/mo). We have created a novel animal model that adequately reflects both the hemodynamic and electrophysiological characteristics of repaired TOF patients and can be applied to examine the risk of ventricular arrhythmias.

iWRAP: A Theranostic Wearable Device With Real-Time Vital Monitoring and Auto-Adjustable Compression Level for Venous Thromboembolism.

OBJECTIVE: Venous Thromboembolism (VTE) is a commonly underdiagnosed disease with severe consequences and an exceedingly high mortality rate. Conventional compression wraps are devised for therapeutic purpose but lack diagnostic capacity. Recent advances in flexible electronics and wearable technologies offer many possibilities for chronic disease management. In particular, vital signs have been studied to show a strong correlation with the risk of VTE patients. In this study, we aim to develop an intelligent theranostic compression device, referred to as iWRAP, with the built-in capacity of real-time vital sign monitoring together with auto-adjustable compression level. METHODS: An instantaneous pneumatic feedback control with a high-resolution pressure sensor is integrated to provide a highly stabilized compression level at the prescribed interface pressure for an improved therapeutic outcome. Meanwhile, arterial pulse waveforms extracted from the pressure readings from the smart compression device can be utilized to derive the body vital signs, including heart rate (HR), respiratory rate (RR) and blood pressure (BP). RESULTS: A reliable delivery of the targeted compression level within ±5% accuracy in the range of 20-60 mmHg has been achieved through the feedback of the interface pressure. Both HR and RR have been measured within clinical-grade accuracies. Moreover, BP estimated using an ALA model has been achieved at low compression levels, which is also within a clinical-acceptable accuracy. The acquired vital information has been instantaneously fit into the clinically acceptable criteria for life-threatening PE risk with timely assessments. CONCLUSION: The iWRAP has shown the potential to become the first theranostic wearable device with both continuous delivery of accurate and effective compression therapy and real-time monitoring of life-threatening conditions for VTE patients.

Blink-sensing glasses: A flexible iontronic sensing wearable for continuous blink monitoring.

Blink reflex has long been considered closely related to physiological states, from which abundant information on ocular health and activities can be revealed. In this study, a smart glasses wearable has been developed, incorporating a flexible and sensitive pressure sensor, to monitor blink patterns by continuously detecting ocular muscular movements, referred to as blink-sensing glasses. By applying the emerging flexible iontronic sensing (FITS) sensor with the sensitivity of 340 pF/mmHg, the skin pressure variations induced by movements of the orbicularis oculi muscles can be monitored in real time. The blink-sensing glasses can successfully capture blink patterns with a high accuracy of 96.3% and have been used to differentiate the blink features from both dry-eye subjects and healthy controls. This device can be potentially used as a new clinical and research monitoring tool for continuous eye blink analysis, while providing patients with high comfortableness in long-term ambulatory and home settings.

Mesenchymal Stem Cell-Derived Exosomes Ameliorate Alzheimer's Disease Pathology and Improve Cognitive Deficits.

The accumulation of extracellular ß-amyloid (Aß) plaques within the brain is unique to Alzheimer's disease (AD) and thought to induce synaptic deficits and neuronal loss. Optimal therapies should tackle the core AD pathophysiology and prevent the decline in memory and cognitive functions. This study aimed to evaluate the therapeutic performance of mesenchymal stem cell-derived exosomes (MSC-exosomes), which are secreted membranous elements encapsulating a variety of MSC factors, on AD. A human neural cell culture model with familial AD (FAD) mutations was established and co-cultured with purified MSC-exosomes. 2-[18F]Fluoro-2-deoxy-d-glucose ([18F]FDG) and novel object recognition (NOR) testing were performed before/after treatment to evaluate the therapeutic effect in vivo. The AD-related pathology and the expression of neuronal memory/synaptic plasticity-related genes were also evaluated. The results showed that MSC-exosomes reduced Aß expression and restored the expression of neuronal memory/synaptic plasticity-related genes in the cell model. [18F]FDG-PET imaging and cognitive assessment revealed a significant improvement in brain glucose metabolism and cognitive function in AD transgenic mice. The phase of neurons and astrocytes in the brain of AD mice were also found to be regulated after treatment with MSC-exosomes. Our study demonstrates the therapeutic mechanism of MSC-exosomes and provides an alternative therapeutic strategy based on cell-free MSC-exosomes for the treatment of AD.

Multiplexed Molecular Imaging Strategy Integrated with RNA Sequencing in the Assessment of the Therapeutic Effect of Wharton's Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles for Osteoporosis.

INTRODUCTION: Osteoporosis is a result of an imbalance in bone remodeling. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been considered as a potentially promising treatment for osteoporosis. However, the therapeutic effect, genetic alterations, and in vivo behavior of exogenous EVs for osteoporosis in mice models remain poorly understood. METHODS: A multiplexed molecular imaging strategy was constructed by micro-positron emission tomography (µPET)/computed tomography (CT), µCT, and optical imaging modality which reflected the osteoblastic activity, microstructure, and in vivo behavior of EVs, respectively. RNA sequencing was used to analyze the cargo of EVs, and the bone tissues of ovariectomized (OVX) mice post EV treatment. RESULTS: The result of [18F]NaF µPET showed an increase in osteoblastic activity in the distal femur of EV-treated mice, and the bone structural parameters derived from µCT were also improved. In terms of in vivo behavior of exogenous EVs, fluorescent dye-labeled EVs could target the distal femur of mice, whereas the uptakes of bone tissues were not significantly different between OVX mice and healthy mice. RNA sequencing demonstrated upregulation of ECM-related genes, which might associate with the PI3K/AKT signaling pathway, in line with the results of microRNA analysis showing that mir-21, mir-29, mir-221, and let-7a were enriched in Wharton's jelly-MSC-EVs and correlated to the BMP and PI3K/AKT signaling pathways. CONCLUSION: The therapeutic effect of exogenous WJ-MSC-EVs in the treatment of osteoporosis was successfully assessed by a multiplexed molecular imaging strategy. The RNA sequencing demonstrated the possible molecular targets in the regulation of bone remodeling. The results highlight the novelty of diagnostic and therapeutic strategies of EV-based treatment for osteoporosis.

GMP-compliant fully automated radiosynthesis of [18F]FEPPA for PET/MRI imaging of regional brain TSPO expression.

BACKGROUND: Expression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. The second-generation PET ligand [18F]FEPPA specifically binds TSPO to enable in vivo visualization and quantification of neuroinflammation. We optimized a fully automated radiosynthesis method and evaluated the utility of [18F]FEPPA, the second-generation PET ligand specifically binds TSPO, in a mouse model of systemic LPS challenge to detect TSPO-associated signals of central and peripheral inflammation. In vivo dynamic PET/MR imaging was performed in LPS-induced and control mice after [18F]FEPPA administration. The relationship between the [18F]FEPPA signal and the dose of LPS was assessed. The cytokine levels (i.e., TNF-α, Il-1ß, Il-6) in LPS-induced mice were measured by RT-PCR. Standard uptake value (SUV), total volume of distribution (VT) and area under the curve (AUC) were determined based on the metabolite-uncorrected plasma input function. Western blotting and immunostaining were used to measure TSPO expression in the brain. RESULTS: The fully automated [18F]FEPPA radiosynthesis produced an uncorrected radiochemical yield of 30 ± 2% within 80 min, with a radiochemical purity greater than 99% and specific activity of 148.9‒216.8 GBq/µmol. Significant differences were observed in the brain after [18F]FEPPA administration: SUV, VT and AUC were 1.61 ± 0.1, 1.25 ± 0.12 and 1.58 ± 0.09-fold higher in LPS-injected mice than controls. TNF-α, Il-1ß and Il-6 mRNA levels were also elevated in the brains of LPS-injected mice. Western blotting revealed TSPO (p < 0.05) and Iba-1 (p < 0.01) were upregulated in the brain after LPS administration. In LPS-injected mice, TSPO immunoactivity colocalized with Iba-1 in the cerebrum and TSPO was significantly overexpressed in the hippocampus and cerebellum. The peripheral organs (heart, lung) of LPS-injected mice had higher [18F]FEPPA signal-to-noise ratios than control mice. CONCLUSIONS: Based on the current data on ligand specificity and selectivity in central tissues using 7 T PET/MR imaging, we demonstrate that [18F]FEPPA accumulations significant increased in the specific brain regions of systemic LPS-induced neuroinflammation (5 mg/kg). Future investigations are needed to determine the sensitivity of [18F]FEPPA as a biomarker of neuroinflammation as well as the correlation between the PET signal intensity and the expression levels of TSPO.