Transarterial Chemoembolization Followed by Hepatic Arterial Infusion Chemotherapy Combined a Tyrosine Kinase Inhibitor for Treatment of Large Hepatocellular Carcinoma.

OBJECTIVE: Evaluate the efficacy and safety of transarterial chemoembolization (TACE) sequential with hepatic arterial infusion chemotherapy (HAIC) and a tyrosine kinase inhibitor (TKI) for unresectable large hepatocellular carcinoma (HCC). METHODS: Patients with HCC size > 70 mm were included. They received 1-3 cycles of TACE and sequential HAIC every 3-6 weeks for 2-6 cycles, with each cycle given over a period of 48 hours (oxaliplatin plus fluorouracil/leucovorin). Patients also received sorafenib or lenvatinib beginning at the first TACE cycle and continuing until disease progression. Objective response rate (ORR) at 3 months was the primary endpoint. Progression-free survival (PFS) and safety were the secondary endpoints. RESULTS: From January 2020 to December 2020, 41 patients were included, who were divided into the drug-eluting bead TACE (DEB-TACE) group (n=13) and conventional TACE (cTACE) group (n=28). The overall ORR was 56.1% (23/41) using mRECIST criteria and 34.1% (14/41) using RECIST1.1 criteria. The median PFS of the cohort was 8 months. The ORR of the DEB-TACE group was 76.9% (10/13) vs. 46.4% (13/28) for the cTACE group (p = 0.06). The median PFS of the DEBTACE group was 12 months, and 6 months in the cTACE group (p = 0.09). Conversion hepatectomy was performed in 2 patients in the DEB-TACE group (15.4%), and in 3 patients in the cTACE group (10.7%). ALT/AST elevated, hypertension, nausea, and vomiting were the common treatment related adverse events. There was no treatment related death. CONCLUSION: TACE sequential with HAIC combined a TKI is a well-tolerated and promising tripletherapy for large, unresectable HCC.

Impact of Digital Transformation on Enterprise Carbon Intensity: The Moderating Role of Digital Information Resources.

In the context of China's "digital power" strategy, the realization of a green and low-carbon shift in manufacturing has become a necessary condition to promote the economy, and the digital factor has increasingly become a new driving force. The text mining and IPCC methods were used to measure manufacturing enterprise digitalization and the level of enterprise carbon emission intensity from 2011 to 2021, respectively. This study then explored the impact of digitalization on manufacturing enterprise carbon emission intensity based on the least squares method model and instrumental variable method model. This research comes to three conclusions. (1) Digitalization can significantly reduce the enterprise carbon emission intensity of China's manufacturing industry, and the influence shows a "marginal increase." (2) Notably, a mechanism analysis indicates the intermediary effect sizes of four crucial intermediaries: green technology innovation > financing constraint > information asymmetry > energy use efficiency. Interestingly, digital information resources positively moderate the positive effect of digitalization on carbon emission intensity through three paths: financing constraints, green technology innovation, and information asymmetry. (3) The influence shows evident signs of heterogeneity-as environmental regulation, financial development, executive education, and R&D quality advance, the inhibiting effect of digitalization on enterprise carbon emission intensity becomes more pronounced. Finally, corresponding policy suggestions are proposed.

Towards high-quality development: how does digital economy impact low-carbon inclusive development?: mechanism and path.

High-quality development is the primary task of building a modern socialist country in an all-around way. Innovation, coordination, green development, openness, and sharing are the main connotations of high-quality development. Based on panel data from 286 cities in China, this paper empirically analyzes the impact of the digital economy on low-carbon inclusive development (hereinafter referred to as LIG). The results show that the digital economy has a salient promoting effect on LIG, and with the increase of quantile level, the promoting effect shows a marginal decreasing trend. Heterogeneity analysis found that the cities with low resource dependence and marketization of the digital economy and high environmental concern and competition have more salient promoting effects on LIG. The dimensionality reduction analysis shows that the impact of digital economy on economic growth, social inclusion, and low-carbon ecology gradually increases in turn. The mechanism test shows that R&D investment, green innovation, and market integration play a partial mediating role, while entrepreneurial activity, industrial upgrading, and development imbalance play a fully mediating role. Digital economy promotes urban economic growth and low-carbon ecological development through R&D investment and market integration and mainly promotes low-carbon ecological development through green innovation. The digital economy will promote low-carbon and inclusive urban development by stimulating entrepreneurship, promoting industrial upgrading, and alleviating development imbalances.

XperCT facilitates sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients.

OBJECTIVE: Our objective was to evaluate the feasibility of XperCT combined fluoroscopy to guide sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients. METHODS: The records of hemodialysis patients with chronic thoracic venous occlusive disease who received endovascular sharp recanalization after conventional techniques failed were retrospectively reviewed. The sharp devices used for recanalization included the stiff end of a guidewire, Chiba biopsy needle, RUPS-100 set, and transseptal needle. The needle was advanced toward a target placed at the opposite end of the occlusion and was guided by fluoroscopy and/or XperCT. While the guidewire crossed the occlusion, endovascular procedures such as percutaneous angioplasty were performed for the treatment of the occlusion. RESULTS: The analysis included 32 sharp thoracic vein recanalization procedures in 29 patients. Two attempts in one patient failed, and in one patient the first attempt failed but the second attempt was successful. In one patient, two separate successful procedures were performed, and the other 26 procedures in 26 patients were successful. The overall technical success rate of sharp recanalization was 90%. The mean number of puncture attempts in the combined group was less than that of the fluoroscopy-guided alone group (2 vs 5, p < 0.05). The success rate of sharp recanalization in the combined group was higher (100% vs 86%), and the recanalization time (28.5 min vs 36 min, p > 0.05) was no different. There was no statistical difference in procedure-related complications between the groups. CONCLUSION: XperCT can facilitate sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients.

Silencing of peroxiredoxin 2 suppresses proliferation and Wnt/ß-catenin pathway, and induces senescence in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a common malignancy worldwide, still lacks effective clinical treatment. The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms. In our study, we initially confirmed a higher level of PRDX2 in the bile of HCC patients compared to those with choledocholithiasis by 2-DE, LC-MS, and ELISA. Subsequently, we demonstrated the high expression of peroxiredoxin 2 (PRDX2) in HCC based on the TCGA database and clinical sample analysis. Furthermore, PRDX2 overexpression enhanced the viability of HCC cells. And PRDX2 silencing induced senescence of HCC cells. In vivo, knockdown of PRDX2 significantly reduced the weight of xenograft tumors. PRDX2 also was found to activate the Wnt/ß-catenin pathway by inducing ß-catenin nuclear translocation. Consequently, we proved that silencing PRDX2 could inhibit proliferation and Wnt/ß-catenin pathway while promoting senescence in HCC cells.

Clinical Implications of Phenotypes of Hemodialysis Patients With Central Venous Occlusion or Central Venous Stenosis Defined by Cluster Analysis.

Objective: This study aims to investigate the association between clinical factors of patients with central (superior vena cava, brachiocephalic, or subclavian) venous occlusion or central venous stenosis (CVO/CVS) and the difficulty of interventional recanalization as well as the duration of postoperative patency. Methods: A total of 103 hemodialysis patients with CVO/CVS treated with endovascular treatment were enrolled. The two-step cluster analysis was selected to differentiate the cases into distinct phenotypes automatically. Differences in characteristics, the difficulty of interventional recanalization, and the duration of postoperative primary patency time between the two clusters were statistically compared. Results: The 103 cases were divided into distinct two clusters by the two-step cluster analysis with 48 (46.6%) in cluster 1 and 55 (53.4%) in cluster 2. Compared to cluster 2, patients in cluster 1 have a higher proportion of blunt stump, side branches, occlusion lesions >2 cm, calcification, or organization. Moreover, the above four factors were, in turn, the most critical four predictors distinguishing 103 patients into two clusters. The remaining six factors were, in turn, occlusion located in the superior vena cava (SVC), duration of central venous catheterization (CVC), lesion location, vessel diameter, number of CVC, and previously failed lesion. Of the four most important factors, with the exception of occlusion lesions exceeding 2 cm, there were significant differences in the length of procedure time between the groups grouped by the remaining three factors. And there was a significant difference in the primary patency rate between the group with blunt stump and the group without blunt stump and also between the group with occlusion lesions ≥ 2 cm and the group with occlusion lesions <2 cm. The operation time of cluster 1 was longer than that of cluster 2. In terms of postoperative patency time, the primary patency time was significantly longer in the patients of cluster 2 compared with cluster 1 (P = 0.025). Conclusion: Patients were divided into distinct two clusters. CVO/CVS of patients in cluster 1 was more challenging to be recanalized than that in cluster 2, and the primary patency time was significantly longer in the patients of cluster 2 compared with cluster 1. Blunt stump, side branches, occlusion lesions exceeding 2 cm, and calcification or organization are the four most critical predictors distinguishing 103 patients into two clusters.

Mediastinal Hepatoid Adenocarcinoma Treated With Arterial Interventional Therapy: A Case Report and Review of Literature.

Hepatoid adenocarcinoma (HAC) is an extremely rare extrahepatic carcinoma, which is pathologically featured by hepatocellular carcinoma (HCC) and marked by producing alpha-fetoprotein (AFP). HAC of mediastinum is extremely rare. For inoperable patients, the curative treatment options have not been established, and the outcome of HAC is usually poor. Here, we present a case of mediastinal HAC with normal serum AFP level who achieved well-controlled and good response after local-regional interventional approach combined with systemic PD-1 inhibitor. A 53-year-old male who complained of chest pain was admitted to our hospital in February 2021. A chest CT scan revealed several tumors in his mediastinum. The laboratory data showed normal serum AFP level. HAC was diagnosed through pathological assessment of biopsy. Surgery was not available due to the infiltration of sternum. Local regional FOLFOX chemotherapy was given by transarterial infusion, followed by transcatheter arterial chemoembolization, and thereafter combined with systemic anti-PD-1 treatment. The patient achieved favorable disease control and apparent symptom relief. So transarterial interventional therapy combined immunotherapy may be a possible and promising treatment for mediastinal HAC.

Computational fluid dynamics simulation of hemodynamic changes in a hemodialysis patient with central venous stenosis treated with stent.

BACKGROUND: It has not been demonstrated that computational fluid dynamics (CFD) can be used to model central venous stenosis (CVS), nor that hemodynamic changes in CVS treated with stent placement can be anticipated. The purpose of this study was to demonstrate the hemodynamic performance of CVS patients treated with stent placement. METHODS: Patient-specific geometric models were constructed using computed tomography images of veins from hemodialysis patients treated with stent placement. CFD simulation based on geometry was performed using ANSYS-15 to compare pressure quantitatively, wall shear stress (WSS), and flow velocity in the brachial vein before and after stent placement. RESULTS: Following a covered stent placement, the swelling of the left upper extremity was relieved. Prior to stent implantation, the maximum and mean brachial vein wall pressures were 465.2 Pa and 224.609 Pa, respectively. It was determined that the maximum WSS value was 8.449 Pa and that the mean WSS value was 0.743 Pa. The maximum and mean flow velocities were 1.16 and 0.173 m/s, respectively. After stent placement, the maximum wall pressure, maximum WSS, and maximum flow velocity dropped by 59.4%, 71.2%, and 57.8%, respectively. The mean wall pressure, mean WSS, and mean flow rate decreased by 43.5%, 52.7%, and 17.6%, respectively. CONCLUSION: Hemodynamics of CVS in hemodialysis patients exhibited turbulent, imbalances and disorders, which can be improved by stent placement.

Quantitative synthetic MRI reveals grey matter abnormalities in children with drug-naïve attention-deficit/hyperactivity disorder.

To investigate the quantitative profiles of brain grey matter (GM) in pediatric drug-naïve ADHD patients using synthetic magnetic resonance imaging (SyMRI). A total of 37 drug-naïve pediatric ADHD and 27 age- and gender-matched healthy controls (HC) were enrolled in this study. Each subject underwent both SyMRI and conventional 3D T1-FSPGR scans. Quantitative parameters, T1 and T2 maps, were extracted from the SyMRI data. Between-group quantitative maps were compared using a general linear model analysis. Pearson correlation analysis was conducted to assess the association between significantly altered MR indices and clinical measurements in ADHD. Compared with the HC group, altered T1 and T2 relaxometry times in the ADHD group were mainly distributed in GM regions of the cerebellum, attention and execution control network, default mode network, and limbic areas. Moreover, the T1 value of the right cerebellum 8 was negatively correlated with the attention concentration level in ADHD (R = 0.140, P = 0.0225). With regards to T2 map, the associations were observed between the attention level of ADHD patients and left fusiform gyrus (R = 0.251, P = 0.0016), and right cerebellum crus2 (R = 0.142, P = 0.0214). Altered T1, T2 values found in specific regions of GM, including cerebellum, attention and execution control network, default mode network, and limbic areas, may reveal widespread micromorphology changes, i.e., brain iron deficiency, low myelin content, and enlarged vascular interstitial space in ADHD patients. Thus, T1, T2 values might be promising imaging markers for future ADHD studies.

Prognostic value of splenic volume in hepatocellular carcinoma patients receiving transarterial chemoembolization.

BACKGROUND: Liver function is a key determinant for the survival of hepatocellular carcinoma (HCC) patients receiving transarterial chemoembolization (TACE). However, establishing robust prognostic indicators for liver insufficiencies and patient survival remains an unmet demand. This retrospective study evaluated the prognostic value of splenic volume (SV) in HCC patients undergoing TACE. METHODS: A total of 67 HCC patients who underwent at least two consecutive TACE procedures were retrospectively included in this study. Comprehensive clinical information and follow-up data were collected, and the SV was measured based on dynamic contrast enhanced images. Risk factors of SV enlargement were assessed. The prognostic value of SV on survival was analyzed and compared with Child-Pugh (CP) classification and albumin-bilirubin (ALBI) grade. RESULTS: The baseline SV was 299.74±143.63 cm3, and showed a moderate and statistically significant correlation with CP classification (R=0.31, P<0.05). The SV increased remarkably after the first and second TACE procedures (330.16±155.38 cm3, P<0.01, and 355.63±164.26 cm3, P<0.01, respectively). In survival analysis, the optimal cut-off value of SV was determined as 373 cm3 using X-tile software, and the patients were divided into the small SV group and the large SV groups accordingly. Based on the pre-TACE SV, the median overall survival (mOS) for patients in the small SV group and the large SV group was 458 days and 249 days, respectively (P<0.05). After the first and second TACE, the mOS in the small SV group and the large SV group were 454 vs. 266 days (P<0.05) and 526 vs. 266 days (P<0.05), respectively. No prognostic value of CP classification and ALBI grade was identified for these patients. Furthermore, there were no significant differences between the small and large SV groups in age, tumor stage, and ALBI grade, except for CP classification (P<0.05). CONCLUSIONS: SV was correlated with CP classification and was a robust predictor for HCC patients undergoing TACE treatment.

Cell death PET/CT imaging of rat hepatic fibrosis with 18F-labeled small molecule tracer.

PURPOSE: To evaluate the potential feasibility of Al[18F]F-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA)-tripolyethylene glycol (PEG3)-Duramycin (Al[18F]F-NOTA-PEG3-Duramycin) positron emission tomography (PET) for imaging of rat hepatic fibrosis. PROCEDURES: Hepatic fibrosis rat models were injected with thioacetamide (TAA), control rats received saline (n = 12 per group). Rats in the two groups underwent PET imaging using Al[18F]F-NOTA-PEG3-Duramycin and [18F]FDG at multiple time points (2, 4, 6, and 8 weeks after TAA or saline treatment). Between-group differences in the apoptosis rate, fibrotic activity, and liver uptake of Al[18F]F-NOTA-PEG3-Duramycin or [18F]FDG were assessed using Student's t-test. Imaging results were cross-validated using histopathology detection and Pearson's correlation test was used to assess the association relationships between radioactive uptake value and quantified histopathological data. RESULTS: Compared with control group at multiple time points, each TAA group showed a higher radioactive liver uptake of Al[18F]F-NOTA-PEG3-Duramycin (each P < 0.05). Furthermore, the increase in the liver uptake of Al[18F]F-NOTA-PEG3-Duramycin was proportional to the progression of fibrosis (R2 = 0.8846, P < 0.001) and apoptosis rate (R2 = 0.9208, P < 0.001) in the TAA group. Meanwhile, there were also between-group differences in [18F]FDG uptake in each phase (P < 0.05), however, no relationship between [18F]FDG uptake and the fibrotic activity was observed. CONCLUSIONS: Al[18F]F-NOTA-PEG3-Duramycin PET/CT could be applied to monitor the progression of liver fibrosis, whereas [18F]FDG PET/CT could not. Implications of this work for noninvasive diagnosis of liver fibrosis, assessment of fibrotic activity, and evaluation of antifibrotic therapy are expected.

Biological Evaluation of [18F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma.

Purpose: N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) for hepatocellular carcinoma (HCC) imaging has been performed in our previous studies, but its radiosynthesis method and stability in vivo need to be improved. Hence, we evaluated the synthesis and biological properties of a simple [18F]-labeled glutamate analog, [18F]AlF-1,4,7-triazacyclononane-1,4,7-triacetic-acid-2-S-(4-isothiocyanatobenzyl)-l-glutamate ([18F]AlF-NOTA-NSC-GLU), for HCC imaging. Procedures: [18F]AlF-NOTA-NSC-GLU was synthesized via a one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [18F]AlF-NOTA-NSC-GLU in HCC, we conducted positron emission tomography/computed tomography (PET/CT) imaging and competitive binding of [18F]AlF-NOTA-NSC-GLU in human Hep3B tumor-bearing mice. The transport mechanism of [18F]AlF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments in vitro. Results: [18F]AlF-NOTA-NSC-GLU was prepared with an overall radiochemical yield of 29.3 ± 5.6% (n = 10) without decay correction within 20 min. In vitro competitive inhibition experiments demonstrated that the Na+-dependent systems X AG - , B0+, ASC, and minor X C - were involved in the uptake of [18F]AlF-NOTA-NSC-GLU, with the Na+-dependent system X AG - possibly playing a more dominant role. Protein incorporation studies of the Hep3B human hepatoma cell line showed almost no protein incorporation. Micro-PET/CT imaging with [18F]AlF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B human hepatoma-bearing mouse models. After [18F]AlF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [18F]AlF-NOTA-NSC-GLU was 2.06 ± 0.17 at 30 min post-injection. In vivo competitive binding experiments showed that the tumor-to-liver uptake ratio decreased with the addition of inhibitors to block the XAG system. Conclusions: We have successfully synthesized [18F]AlF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our findings indicate that [18F]AlF-NOTA-NSC-GLU may be a potential candidate for HCC imaging. Also, a further biological evaluation is underway.

Propionic Acid-Based PET Imaging of Prostate Cancer.

PURPOSE: This study aimed to evaluate the potential value of 2-[18F]fluoropropionic acid ([18F]FPA) for PET imaging of prostate cancer (PCa) and to explore the relationship between [18F]FPA accumulation and fatty acid synthase (FASN) levels in PCa models. The results of the first [18F]FPA PET study of a PCa patient are reported. PROCEDURES: The LNCaP, PC-3 cell lines with high FASN expression, and DU145 cell lines with low FASN expression were selected for cell culture. A PET imaging comparison of [18F]FDG and [18F]FPA was performed in LNCaP, PC-3, and DU145 tumors. Additionally, in vivo inhibition experiments in those models were conducted with orlistat. In a human PET study, a patient with PCa before surgery was examined with [18F]FPA PET and [18F]FDG PET. RESULTS: The uptake of [18F]FPA in the LNCaP and PC-3 tumors was higher than that of [18F]FDG (P<0.05 and P<0.05), but was lower in DU145 tumors (P<0.05). The accumulation (% ID/g) of [18F]FPA in the LNCaP, PC-3, and DU145 tumors decreased by 27.6, 40.5, and 11.7 %, respectively, after treatment with orlistat. The [18F]FPA showed higher radioactive uptake than [18F]FDG in the first PCa patient. CONCLUSIONS: The [18F]FPA uptake in PCa models may be varies with fatty acid synthase activity and could be reduced after administration of a single FASN inhibitor, albeit the activity that is not measured directly. The [18F]FPA seems to be a potential broad-spectrum PET imaging agent and may serve as a valuable tool in the diagnosis of PCa in humans.

A prognostic score model for predicting the survival benefits of patients undergoing sorafenib plus transarterial chemoembolization for hepatocellular carcinoma with portal vein invasion.

PURPOSE: The survival benefits and which patients with advanced hepatocellular carcinoma (HCC) would benefit from sorafenib plus transarterial chemoembolization (TACE) therapy remain controversial. We aimed to develop a prognostic score model for predicting different prognoses of patients with HCC and portal vein invasion who received sorafenib plus TACE. METHODS: This observational study included 167 patients with HCC and portal vein invasion undergoing sorafenib combined with TACE from January 2013 to June 2018 at two hospitals. Multivariate Cox regression analysis was performed using a training cohort (n = 83) to identify critical factors associated with survival. Then, a prognostic score model was established to classify different outcomes and confirmed using a validation cohort (n = 84). RESULTS: Three factors were determined to critically impact survival in the training cohort: portal vein invasion extent, sorafenib-related dermatologic response, and initial radiological response. Using the ß-coefficients of these factors, a prognostic score was calculated, and the survival time decreased as the score increased. Based on the prognostic score model, three different prognoses of patients with 0 points, 2-3 points, and > 3 points were stratified with a median survival of 38.0 months, 20.0 months, and 7.0 months, respectively (P < 0.001). Time to progression was also significantly different using the same prognostic index. The prognostic score model was confirmed by the validation cohort. CONCLUSION: Sorafenib plus TACE is a potential therapy for selected HCC patients with portal vein invasion. This prognostic score model can predict the survival benefits for these patients.

Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice.

α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration.

Targeting Phosphatidylethanolamine with Fluorine-18 Labeled Small Molecule Probe for Apoptosis Imaging.

PURPOSE: Externalization of phosphatidylethanolamine (PE) in dying cells makes the phospholipid an attractive target for apoptosis imaging. However, no ideal PE-targeted positron emission tomography (PET) radiotracer was developed. The goal of the study was to develop a novel PE-targeted radiopharmaceutical to imaging apoptosis. PROCEDURE: In this study, we have radiolabeled PE-binding polypeptide duramycin with fluorine-18 for PET imaging of apoptosis. Al[18F]F-NOTA-PEG3-duramycin was synthesized via chelation reaction of NOTA-PEG3-duramycin with Al[18F]F. PE-binding capacity of Al[18F]F-NOTA-PEG3-duramycin was determined in a competitive radiometric PE-binding assay. The pharmacokinetic profile was evaluated in Kunming mice. The apoptosis imaging capacity of Al[18F]F-NOTA-PEG3-duramycin was evaluated using in vitro cell uptake assay with camptothecin-treated Jurkat cells, along with in vivo PET imaging using erlotinib-treated nude mice. RESULTS: The total synthesis procedure lasted for 30 min, with a decay-uncorrected radiochemical yield of 21.3 ± 2.6 % (n = 10). Compared with the control cells, the binding of Al[18F]F-NOTA-PEG3-duramycin with camptothecin-induced apoptotic cells resulted in a tripling increase. A competitive radiometric PE-binding assay strongly confirmed the binding of Al[18F]F-NOTA-PEG3-duramycin to PE. The biodistribution study showed rapid blood clearance, prominent kidney retention, and low liver uptake. In the in vivo PET/CT imaging, Al[18F]F-NOTA-PEG3-duramycin demonstrated 2-fold increase in erlotinib-treated HCC827 tumors in nude mice. CONCLUSION: Considering the facile preparation and improved biological properties, Al[18F]F-NOTA-PEG3-duramycin seems to be a promising PET tracer candidate for imaging apoptosis in the monitoring of cancer treatment.

Preclinical In Vitro and In Vivo Characterization of Synaptic Vesicle 2A-Targeting Compounds Amenable to F-18 Labeling as Potential PET Radioligands for Imaging of Synapse Integrity.

PURPOSE: Current synaptic vesicle 2A (SV2A) positron emission tomography (PET) imaging agents include the nanomolar affinity probes [11C]UCB-J and [18F]UCB-H derived from the anti-epileptic drug levitaracetam (Keppra®). An industry-utilized "de-risking" approach was used to carry out initial pharmacological characterization and to assess potential next-generation candidates amenable to F-18 radiolabeling for preliminary evaluation. PROCEDURES: Radioligand binding methods were employed in mammalian brain homogenates to determine the SV2A affinity (Kd) and maximal binding capacity (Bmax) of [3H]UCB-J. Novel leads were then screened to identify compounds minimally with comparable binding affinities with UCB-J in order to select a F-18-labeled candidate for subsequent in vivo assessment in rat. In parallel, mammalian brain tissue section autoradiography was performed to assess specific SV2A distribution. RESULTS: [3H]UCB-J bound with high affinity to a single population of sites in the rat brain (Kd = 2.6 ± 0.25 nM; Bmax = 810 ± 25 fmol/mg protein) and control human cortex (Kd = 2.9 ± 0.54 nM; Bmax = 10,000 ± 640 fmol/mg protein). Distribution of specific SV2A binding was shown to be homogeneous throughout the rodent brain and primarily in gray matter regions of rodent and human brain sections. Analog screening identified MNI-1038, MNI-1126/SDM-8, and SDM-2 as having comparable binding affinities with the currently available PET ligands. Subsequent [18F]MNI-1126/[18F]SDM-8 dynamic micro-PET imaging in rats revealed in vivo uptake and accumulation in the brain with favorable kinetics. Chase studies using 30 mg/kg levetiracetam confirmed that in vivo brain uptake of [18F]MNI-1126/[18F]SDM-8 was reversible. CONCLUSIONS: Taken together, these data suggest [18F]MNI-1126/[18F]SDM-8 (since renamed as [18F]SynVesT-1) characterized via an in vitro screening cascade provided a measurable in vivo SV2A specific signal in the rodent brain. This tracer as well as the close analog [18F]SDM-2 (since renamed as [18F]SynVesT-2) is currently undergoing further evaluation in preclinical and clinical studies.

Validation of R-2-[18F]Fluoropropionic Acid as a Potential Tracer for PET Imaging of Liver Cancer.

PURPOSE: 2-[18F]Fluoropropionic acid (RS-[18F]FPA) has shown potential value as a short-chain fatty acid positron emission tomography (PET) tracer for the detection of liver cancer. However, RS-[18F]FPA is a mixture of 2-R-[18F]fluoropropionic acid (R-[18F]FPA) and 2-S-[18F]fluoropropionic acid (S-[18F]FPA). The aim of this study is to validate the feasibility of R-[18F]FPA in preclinical PET imaging of liver cancer and to compare the use of R-[18F]FPA with that of RS-[18F]FPA and S-[18F]FPA. PROCEDURES: A comparative study of R-[18F]FPA, RS-[18F]FPA, S-[18F]FPA, and [18F]FDG micro-PET imaging was performed in HepG2 and SK-Hep-1 tumor-bearing mice. A comparison of R-[18F]FPA uptake with that of S-[18F]FPA by HepG2 and SK-Hep-1 cells was made at different time points. Additionally, in vivo blocking experiments in HepG2 and SK-Hep-1 tumor models were conducted with orlistat and 3-nitropropionic acid (3-NP). In vitro blocking experiments with orlistat or 3-NP were performed with HepG2 and SK-Hep-1 cells. RESULTS: The radioactivity uptake values of R-[18F]FPA were comparable to those of RS-[18F]FPA but were higher than those of S-[18F]FPA and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in HepG2 tumors. The radioactivity uptake values of R-[18F]FPA in large HepG2 tumors were lower than those of [18F]FDG (P < 0.05), while R-[18F]FPA PET was significantly superior to [18F]FDG PET in detecting small tumors (both SK-Hep-1 and HepG2 tumors). The in vivo PET imaging experiments showed that R-[18F]FPA uptake in HepG2 tumor-bearing mice was blocked by 19.3 % and 31.8 % after treatment with orlistat and 3-NP, respectively. The radioactivity uptake values of R-[18F]FPA in SK-Hep-1 tumor-bearing mice was blocked by 39.5 % with orlistat. CONCLUSION: R-[18F]FPA seems to be more potential than S-[18F]FPA as an optically pure PET probe, with effective compensation for the deficiencies of [18F]FDG, particularly in PET imaging of small liver cancer. The uptake mechanism of [18F]FPA in liver cancer may be related to fatty acid synthesis and the tricarboxylic acid cycle. However, compared with the racemic RS-[18F]FPA, the possible advantages of R-enantiomer R-[18F]FPA still needs further research.

Inactivation of antibiotic resistance genes in antibiotic fermentation residues by ionizing radiation: Exploring the development of recycling economy in antibiotic pharmaceutical factory.

Antibiotic fermentation residues are a kind of hazardous waste due to the existence of the residual antibiotics and the potential risk to generate antibiotics resistance genes (ARGs). The appropriate treatment and disposal of antibiotic fermentation residues is imperative. In this study ionizing radiation was applied to treat the antibiotic fermentation residues and the removal efficiencies of antibiotic (erythromycin), ARGs (ermB and ermF) and antibiotic resistant bacteria were investigated. The experimental results showed that erythromycin A content in antibiotic fermentation residues decreased by 86% when the dose was 10 kGy. Moreover, the abundance of ermB and ermF reduced by 89% and 98% at 10 kGy irradiation. Over 99% of total bacteria was removed and antibiotic resistant bacteria (ARB) were less than detection limit after 10 kGy irradiation. Ionizing radiation process is a promising technology for simultaneously removing antibiotic and inactivating ARGs and ARB in antibiotic fermentation residues. Moreover, the irradiation at 10 kGy had no significant influence on the macromolecules organic matters (protein, polysaccharides) of the antibiotic fermentation residues, suggesting that the treated fermentative residues can be used as fertilizer, which could provide the technical support for the development of recycling economy in antibiotic pharmaceutical factory.

Three-dimensional nanostructured substrates enable dynamic detection of ALK-rearrangement in circulating tumor cells from treatment-naive patients with stage III/IV lung adenocarcinoma.

BACKGROUND: Circulating tumor cells (CTC) shows great prospect to realize precision medicine in cancer patients. METHODS: We developed the NanoVelcro Chip integrating three functional mechanisms. NanoVelcro CTC capture efficiency was tested in stage III or IV lung adenocarcinoma. Further, ALK-rearrangement status was examined through fluorescent in situ hybridization in CTCs enriched by NanoVelcro. RESULTS: NanoVelcro system showed higher CTC-capture efficiency than CellSearch in stage III or IV lung adenocarcinoma. CTC counts obtained by both methods were positively correlated (r = 0.45, p < 0.05). Further, Correlation between CTC counts and pTNM stage determined by NanoVelcro was more significant than that determined by CellSearch (p < 0.001 VS p = 0.029). All ALK-positive patients had 3 or more ALK-rearranged CTC per ml of blood. Less than 3 ALK-rearranged CTC was detected in ALK-negative patients. NanoVelcro can detect the ALK-rearranged status with consistent sensitivity and specificity compared to biopsy test. Furthermore, the ALK-rearranged CTC ratio correlated to the pTNM stage in ALK-positive patients. Following up showed that CTCs counting by NanoVelcro was more stable and reliable in evaluating the efficacy of Clozotinib both in the short and long run compared with CellSearch. Changing of NanoVlecro CTC counts could accurately reflect disease progression. CONCLUSION: NanoVelcro provides a sensitive method for CTC counts and characterization in advanced NSCLC. ALK-rearrangement can be detected in CTCs collected from advanced NSCLC patients by NanoVelcro, facilitating diagnostic test and prognosis analysis, most importantly offering one noninvasive method for real-time monitoring of treatment reaction.