Synthesis and preliminary evaluation of novel 11C-labeled GluN2B-selective NMDA receptor negative allosteric modulators.

N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two 11C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [11C]31 and [11C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [11C]CH3I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [11C]CO2, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/µmol). In particular, PET ligand [11C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [11C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.

[18F]-Alfatide PET imaging of integrin αvß3 for the non-invasive quantification of liver fibrosis.

BACKGROUND & AIMS: The vitronectin receptor integrin αvß3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin αvß3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvß3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in the uptake of [18F]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis. METHODS: PET with [18F]-Alfatide, non-enhanced CT, histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin αvß3 levels and liver fibrosis progression in mouse models of fibrosis (carbon tetrachloride [CCl4] and bile duct ligation [BDL]). The liver AUC divided by the blood AUC over 30 min was used as an integrin αvß3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings. RESULTS: Fibrotic mouse livers showed enhanced [18F]-Alfatide uptake and retention compared to control livers. The radiotracer was demonstrated to bind specifically with integrin αvß3, which is mainly expressed on aHSCs. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA and protein level of integrin αvß3 and its signaling complex were higher in CCl4 and BDL models than controls. The results obtained from analyses on human fibrotic liver sections supported the animal findings. CONCLUSIONS: Imaging hepatic integrin αvß3 with PET and [18F]-Alfatide offers a potential non-invasive method for monitoring the progression of liver fibrosis. LAY SUMMARY: Integrin αvß3 expression on activated hepatic stellate cells (aHSCs) is associated with HSC proliferation during hepatic fibrogenesis. Herein, we show that a radioactive tracer, [18F]-Alfatide, binds to integrin αvß3 with high affinity and specificity. [18F]-Alfatide could thus be used as a non-invasive imaging biomarker to track hepatic fibrosis progression.

Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [11C]CO2 fixation method.

Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.98), is a monooxygenase and a member of the cytochrome P450 family. CYP46A1 is specifically expressed in the brain where it controls cholesterol elimination by producing 24S-hydroxylcholesterol (24-HC) as the major metabolite. Modulation of CYP46A1 activity may affect Aß deposition and p-tau accumulation by changing 24-HC formation, which thereafter serves as potential therapeutic pathway for Alzheimer's disease. In this work, we showcase the efficient synthesis and preliminary pharmacokinetic evaluation of a novel cholesterol 24-hydroxylase inhibitor 1 for use in positron emission tomography.

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[11C]methoxyphenethyl)pyridazin-3(2H)-one, a 11C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). 11C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [11C]8 failed to cross the blood-brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.

Radiosynthesis and preliminary evaluation of 11C-labeled 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e] [1,2,4] thiadiazine 1,1-dioxide for PET imaging AMPA receptors.

The α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) belong to the family of ionotropic transmembrane receptors for glutamate (iGluRs) that are implicated in the pathology of neurological disorders and neurodegenerative diseases. Inspired by a recently developed positive allosteric modulator of AMPARs, 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[ e ][1,2,4]thiadiazine 1,1-dioxide (16; EC50 = 2.0 nM), we designed a new synthetic route for N-protected phenolic precursor 13 and efficiently radiolabeled a PET ligand [11C]AMPA-1905 ([11C]16) using a modified one-pot two-step strategy in high radiochemical yield and high molar activity. Preliminary in vivo evaluation was carried out to investigate the suitability of [11C]16 as a potential PET probe for AMPAR imaging.

Chemistry for Positron Emission Tomography: Recent Advances in 11 C-, 18 F-, 13 N-, and 15 O-Labeling Reactions.

Positron emission tomography (PET) is a molecular imaging technology that provides quantitative information about function and metabolism in biological processes in vivo for disease diagnosis and therapy assessment. The broad application and rapid advances of PET has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron-emitting radionuclides. This Review provides an overview of commonly used labeling reactions through examples of clinically relevant PET tracers and highlights the most recent developments and breakthroughs over the past decade, with a focus on 11 C, 18 F, 13 N, and 15 O.

Construction and characterization of a recombinant reticuloendotheliosis virus expressing enhanced green fluorescent protein.

Reticuloendotheliosis virus (REV) causes an immunosuppressive and oncogenic disease in chickens and other birds. In this study, based on an infectious clone of REV, named HLJR0901, a recombinant virus containing the enhanced green fluorescence protein (EGFP) gene was constructed by inserting the EGFP expression cassette downstream of the 3' terminus of the viral env gene. An EGFP-tagged REV that stably expresses EGFP was rescued. This visible recombinant REV could contribute to the further understanding of the molecular mechanism involved in the replication and pathogenicity of REV.

First isolation of reticuloendotheliosis virus from mallards in China.

Reticuloendotheliosis virus (REV) causes an oncogenic, immunosuppressive and runting syndrome in many avian hosts worldwide. REV infection has never been reported in mallard ducks, however. To identify REV infection in mallards, we collected 40 mallard duck samples from Jilin Province of China. In this study, the REV strain, DBYR1102, was first isolated from a mallard in China and identified by PCR, indirect immunofluorescence assay and electron microscopy. The gp90 gene and complete LTR of DBYR1102 were amplified and sequenced. Phylogenetic analysis based on gp90 genes of REV indicated that the REV strain DBYR1102 is closely related to strain HLJR0901 from northeastern China, the prairie chicken isolate APC-566, and REV subtype III, represented by chick syncytial virus. This new strain is distantly related to two other subtypes of REV, 170A and SNV. Phylogenetic analysis based on the LTR yielded information similar to that obtained with the gp90 genes. The results of this study not only expand our epidemiological understanding of REV in the wild birds of China but also demonstrate the potential role of wild waterfowl in REV transmission.

Plk3 Enhances Cisplatin Sensitivity of Nonsmall-Cell Lung Cancer Cells through Inhibition of the PI3K/AKT Pathway via Stabilizing PTEN.

Polo-like kinase 3 (Plk3) is involved in tumor development with a tumor suppressive function. However, the effect of Plk3 on the chemoresistance remains unclear. It has been documented that activation of the PI3K/AKT signaling pathway by PTEN loss significantly enhances chemoresistance in nonsmall-cell lung cancer (NSCLC). This study aims to evaluate the PTEN regulation by Plk3 and identify targets and underlying mechanisms that could be used to relieve chemoresistance. Our results showed that silencing Plk3 reduced PTEN expression and activated PI3K/AKT signaling by dephosphorylating and destabilizing PTEN in NSCLC cells. Reducing Plk3 expression promoted drug resistance to cisplatin (DDP), while overexpressing Plk3 promoted DDP sensitivity. However, these effects were attenuated when MK2206, a PI3K/AKT inhibitor, was applied. In conclusion, upregulation of Plk3 sensitized NSCLC cells toward DDP, which provides a potential target to restore DDP chemoresponse. We provided novel evidence that the PTEN/PI3K/AKT signaling pathway could be regulated by Plk3 through phosphorylation of PTEN and highlighted the critical role of Plk3 in the DDP resistance of NSCLC.

Recent Advances of S-18F Radiochemistry for Positron Emission Tomography.

The click chemistry of sulfur(VI) fluoride exchange (SuFEx) has facilitated the widespread application of sulfur-fluoride compounds such as sulfonyl fluorides, fluorosulfates, and sulfamoyl fluorides in various fields, especially in the development of 18F ligands for PET (positron emission tomography) imaging. In recent years, the prominent progress of sulfur-[18F]fluoride compounds has been achieved through the combination of 18F and sulfur-fluoride chemistry. These compounds serve as potential 18F tracers, 18F synthons, and reagents for 18F-fluorination, thereby complementing the range of 18F ligands, typically C-18F structures, used in PET studies. This review aims to provide an overview of S-18F labeling reactions through examples of relevant 18F compounds and highlight the advancements and breakthroughs achieved in the past decade.

Radiosynthesis of 18F-Labeled Arenesulfonyl Fluorides through Two-Bond Construction with [18F]Fluoride.

A novel 18F labeling strategy was developed to directly construct aryl-SO2-18F from arenediazonium tosylates with a SO2 source and [18F]fluoride. This approach is compatible with a wide range of substrates and enabled the production of 18F-labeled drug-like derivatives through late-stage 18F fluorination, representing a significant advance in the radiosynthesis of 18F-labeled arenesulfonyl fluorides. A reactive 18F labeling synthon, bearing a maleimide-based prosthetic group, allowed for the generation of 18F-labeled temperature-sensitive biomolecules containing cysteine residues via maleimide-cysteine chemistry.

Silencing of crustacean hyperglycemic hormone gene expression reveals the characteristic energy and metabolic changes in the gills and epidermis of crayfish Procambarus clarkii.

The crustacean hyperglycemic hormone (CHH) is a multifaceted neuropeptide instrumental in regulating carbohydrate and lipid metabolism, reproduction, osmoregulation, molting, and metamorphosis. Despite its significance, there is a dearth of research on its metabolic impact on the gills and epidermis-key organs in osmoregulation and molting processes. This study employed CHH dsRNA injections to silence CHH gene expression in Procambarus clarkii, followed by a metabolomic analysis of the gills and epidermis using nuclear magnetic resonance spectroscopy. Metabolic profiling through principal component analysis revealed the most pronounced changes at 24 h post-injection (hpi) in the epidermis and at 48 hpi in the gills. At 24 hpi, the epidermis exhibited significant modulation in 25 enrichment sets and 20 KEGG pathways, while at 48 hpi, 5 metabolite sets and 6 KEGG pathways were prominently regulated. Notably, pathways associated with amino acid metabolism, carbohydrate metabolism, and cofactor and vitamin metabolism were affected. A marked decrease in glucose and other carbohydrates suggested a compromised carbohydrate supply, whereas increased levels of citrate cycle intermediates implied a potential boost in energy provision. The silencing of CHH gene expression hampered the carbohydrate supply, which was possibly the main energy derived substrates. Conversely, the gills displayed significant alterations in 15 metabolite sets and 16 KEGG pathways at 48 hpi, with no significant changes at 24 hpi. These changes encompassed amino acid, carbohydrate, and lipid metabolism pathways. The decline in TCA cycle intermediates pointed to a potential downregulation of the cycle, whereas a decrease in ketone bodies indicated a shift towards lipid metabolism for energy production. Additionally, increased levels of nicotinate, nicotinamide, and quinolinate were observed in both organs. Overall, CHH's impact on the epidermis was prominent at 24 hpi and diminished thereafter, whereas its influence on metabolism in gills was delayed but intensified at 48 hpi. This differential CHH effect between gills and epidermis in P. clarkii provides new insights into the organ-specific regulatory mechanisms of CHH on energy metabolism and osmoregulation, warranting further comparative studies to elucidate the distinct roles of CHH in these organs.

Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F]12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/µmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F]12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F]12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F]12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F]12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

[Cost-benefit study of different thrombolytic strategies in treating 156 patients with symptomatic pulmonary thromboembolism].

OBJECTIVE: To compare the costs and benefits of different thrombolytic strategies with urokinase (UK) and recombinant tissue plasminogen activator (rt-PA) in treating acute pulmonary thromboembolism (PTE), with aim of providing optimal thrombolytic medication. METHODS: Data from 156 patients with PTE from January 2006 to December 2011 in Tangshan Gongren Hospital was analyzed retrospectively. All patients were treated by thrombolysis, among them 104 patients were treated with 1×10(4) U/kg of UK and 52 patients were treated with 50 mg of rt-PA. The therapeutic effects of two methods were compared and the complication incidence rate and medical cost were also compared. RESULTS: There were no significant differences in the symptom remission rate, the recanalization rate, and the incidence of complications between UK group and rt-PA group (68.2% vs. 71.2%, 63.5% vs. 73.1%, 14.4% vs. 17.3%, all P > 0.05), but the treatment cost (yuan) of UK group was remarkably lower than that of rt-PA group (408 ± 120 vs. 6500 ± 634, P < 0.01). CONCLUSION: Different thrombolytic strategies with UK and rt-PA yield similar efficacy, however, the medical cost was significant decreased in UK group.

Synthesis and 18F Labeling of Alkenyl Sulfonyl Fluorides via an Unconventional Elimination Pathway.

A successful Cu-catalyzed addition of both Cl and SO2OCF2H groups into alkenes allows us to discover the unusual reactivity of the SO2OCF2H group. As opposed to common sulfonic esters (RSO2-O-R'), in which the R' group is highly electrophilic, the SO2 moiety demonstrates higher electrophilicity in RSO2-OCF2H. The unexpected reactivity is further developed not only as a synthetic tool for well-functionalized alkenyl sulfonyl fluorides but also for the first 18F labeling of alkenyl sulfonyl fluorides.

Influential factors for the emission inspection results of urban in-use vehicles: From an ensemble learning perspective.

Emission inspection of motor vehicles (emission inspection) is a crucial player in solving the problem of motor vehicle exhaust pollution, and research on the features affecting emission inspection results and their importance is a basis for optimizing the environmental management of motor vehicles. However, there is no study on the multi-feature impact analysis of the emission inspection results. This hinders the emission inspection from playing a better guiding role in the policy formulation of motor vehicle management. In this paper, the ensemble learning algorithm and interpretable machine learning theory are used. Nineteen feature indicators and over 400,000 vehicle mass analysis system (VMAS) detection data in Chengdu were selected from the emission inspection database to construct prediction models for emission inspection results. Moreover, the factors affecting emission inspection results and their ranks by importance were also obtained. The results revealed that the environment has a strong influence on the outcomes from emission inspections (accounting for about one-third of the total effect). Besides, the following eight feature indicators displayed great effects on emission inspection results in sequence: emission inspection agency (18.38%), world manufacturer code (15.01%), vehicle usage days (9.60%), transmission type (9.41%), accumulated mileage (9.21%), emission standard (5.82%), temperature (5.54%), and driving mode (5.50%). In this study, prediction models for emission inspection results are established, and the results are interpreted based on the interpretable machine learning theory. It is considered that more attention should be paid to the effect of inspection differences among emission inspection agencies on fairness, as well as the effects of differences in world manufacturer and transmission type on vehicle deterioration in future research. The supervision of emission inspection agencies, training of inspectors, elimination of obsolete vehicles, and government-guided purchase should be strengthened. This study provides empirical support for optimizing the formulation of motor vehicle environmental management policies.Implications: Emission inspection of motor vehicles (emission inspection) is a crucial player in solving the problem of motor vehicle exhaust pollution. In this work, prediction models for emission of motor vehicles inspection results are established. The results revealed that following eight feature indicators displayed great effects on emission inspection results in sequence: emission inspection agency (18.38%), world manufacturer code (15.01%), vehicle usage days (9.60%), transmission type (9.41%), accumulated mileage (9.21%), emission standard (5.82%), temperature (5.54%), and driving mode (5.50%). It is considered that more attention should be paid to the effect of inspection differences among emission inspection agencies on fairness, as well as the effects of differences in world manufacturer and transmission type on vehicle deterioration in future research. The supervision of emission inspection agencies, training of inspectors, elimination of obsolete vehicles, and government-guided purchase should be strengthened. This study provides empirical support for optimizing the formulation of motor vehicle environmental management policies.

Serum Markers CA125, CA153, and CEA along with Inflammatory Cytokines in the Early Detection of Lung Cancer in High-Risk Populations.

Lung cancer mortality and morbidity rates are the first among malignant tumors. It is extremely crucial to pay more attention to the early diagnosis and treatment of lung cancer and to grasp and judge the progress of the patient's condition promptly. In this study, lung cancer patients' early diagnosis with tumor markers and inflammatory variables is examined. The general surgery department of our hospital treated 98 patients with lung cancer and 100 patients with benign pulmonary hyperplasia from January 2017 to February 2018. Additionally, 100 healthy subjects who completed physical examinations during this time period were included. Based on the findings of the pathological examination, 100 patients with benign pulmonary hyperplasia were chosen as the benign group, 100 patients with lung cancer were chosen as the malignant group, and 100 healthy individuals were chosen as the healthy group. The tumor markers carbohydrate antigen 125 (CA125), CA153, and carcinoembryonic antigen (CEA), as well as inflammatory factors such as tumor necrosis factor- (TNF-) and high-sensitivity C-reactive protein, were measured in the venous blood of three groups of patients (hs-CRP). There was no discernible difference in tumor marker levels between the benign and healthy groups (P > 0.05). In comparison to the benign and healthy groups, the malignant group had higher serum levels of CA153, CA125, and CEA (P 0.05). Between the benign and healthy groups, there was no discernible difference in the levels of inflammatory factors (P > 0.05). TNF- and hs-CRP serum levels were observed to be higher in the malignant group compared to the benign and healthy groups (P 0.05). The combined detection of CA153 + CA125 + CEA + TNF - +hs - CRP showed the highest sensitivity and specificity, which were, respectively, 62.22 percent and 92.00 percent, when compared to single or mixed detection of tumor markers or inflammatory factors solely. Serum levels of inflammatory agents TNF- and hs-CRP may be related to the pathophysiology and other functions of patients with lung cancer, as well as to the development and metastasis of the disease. These markers include CA153, CA125, and CEA. For the early detection of lung cancer and the evaluation of the disease's severity, the detection of tumor markers in combination with inflammatory variables has a significant reference value.

PET imaging of an optimized anti-PD-L1 probe 68Ga-NODAGA-BMS986192 in immunocompetent mice and non-human primates.

BACKGROUND: Adnectin is a protein family derived from the 10th type III domain of human fibronectin (10Fn3) with high-affinity targeting capabilities. Positron emission tomography (PET) probes derived from anti-programmed death ligand-1 (PD-L1) Adnectins, including 18F- and 68Ga-labeled BMS-986192, are recently developed for the prediction of patient response to immune checkpoint blockade. The 68Ga-labeled BMS-986192, in particular, is an attractive probe for under-developed regions due to the broader availability of 68Ga. However, the pharmacokinetics and biocompatibility of 68Ga-labeled BMS-986192 are still unknown, especially in non-human primates, impeding its further clinical translation. METHODS: We developed a variant of 68Ga-labeled BMS-986192 using 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) as the radionuclide-chelator. The resultant probe, 68Ga-NODAGA-BMS986192, was evaluated in terms of targeting specificity using a bilateral mouse tumor model inoculated with wild-type B16F10 and B16F10 transduced with human PD-L1 (hPD-L1-B16F10). The dynamic biodistribution and radiation dosimetry of this probe were also investigated in non-human primate cynomolgus. RESULTS: 68Ga-NODAGA-BMS986192 was prepared with a radiochemical purity above 99%. PET imaging with 68Ga-NODAGA-BMS986192 efficiently delineated the hPD-L1-B16F10 tumor at 1 h post-injection. The PD-L1-targeting capability of this probe was further confirmed using in vivo blocking assay and ex vivo biodistribution studies. PET dynamic imaging in both mouse and cynomolgus models revealed a rapid clearance of the probe via the renal route, which corresponded to the low background signals of the PET images. The probe also exhibited a favorable radiation dosimetry profile with a total-body effective dose of 6.34E-03 mSv/MBq in male cynomolgus. CONCLUSIONS: 68Ga-NODAGA-BMS986192 was a feasible and safe tool for the visualization of human PD-L1. Our study also provided valuable information on the potential of targeted PET imaging using Adnectin-based probes.

[18F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models.

Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an 18F-labeled MAGL inhibitor ([18F]MAGL-4-11) for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver cirrhosis; we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models; [18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosis severity, while its levels in normal liver tissue are high; in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that [18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.

Ultrasound-Guided Percutaneous Core Needle Biopsy of Peripheral Pulmonary Nodules ≤ 2 cm: Diagnostic Performance, Safety and Influence Factors.

PURPOSE: To evaluate diagnostic performance and safety of ultrasound-guided needle biopsy in the diagnosis of peripheral pulmonary nodules (PPLs) ≤ 2 cm, and the influence factors of sample adequacy and safety. MATERIALS AND METHODS: 194 patients (99 men, 95 women; mean age, 56.2 ± 13.7 years) who received biopsy for PPLs ≤ 2 cm between January 2014 to January 2019 were included. Variables including patient demographics, lesion location, lesion size, presence of lesion necrosis, presence of emphysema on CT, patient position, biopsy needle size and number of needle passes were recorded. Univariate analysis and multivariate logistic regression analysis were performed to explore the influence factor of sample adequacy and safety. RESULTS: Biopsy specimens were adequate for diagnosis in 161/194 (83%) cases; the diagnostic accuracy was 81.4% (158/194). The overall complication rate was 8.8% (17/194), including pneumothorax, hemoptysis and pleural effusion, which occurred in 2.1% (4/194), 5.2% (10/194), and 1.5% (3/194) of patients, respectively. The incidence of pneumothorax in the 16-gauge-needle group were significantly higher than that of the 18-gauge-needle group (5.6% vs 0%, P=0.018). Adequate sampling of 16-gauge and 18-gauge needles were achieved in 90.3%(65/72) and 78.7%(96/122) cases, respectively. Multivariate logistic regression analysis revealed needle size (16-gauge vs 18-gauge) was an independent influence factors of sample adequacy (P=0.015, odds ratio=3.419). A receiver operating characteristic curve was plotted and the area under the curve was 0.774. CONCLUSION: US-guided percutaneous needle biopsy is a feasible and safe technique for small PPLs ≤ 2 cm. Needle size is an independent influence factor of sample adequacy and post-procedure pneumothorax. Sixteen-gauge needle has the advantage of achieving adequate sample for pathological analysis, though the risk of pneumothorax should be alerted.