Value of [18F]AlF-NOTA-FAPI-04 PET/CT for differential diagnosis of malignant and various inflammatory lung lesions: comparison with [18F]FDG PET/CT.

OBJECTIVE: Uptake of the imaging tracers [18F]AlF-NOTA-FAPI-04 and [18F]FDG varies in some inflammatory lesions, which may result in false-positive findings for malignancy on PET/CT. Our aim was to compare the [18F]AlF-NOTA-FAPI-04 and [18F]FDG PET/CT imaging features of malignant and various inflammatory lung lesions and to analyze their value for differential diagnosis. METHODS: We retrospectively analyzed [18F]AlF-NOTA-FAPI-04 PET/CT scans from 67 cancer patients taken between December 2020 and January 2022, as well as the scans of 32 patients who also underwent [18F]FDG PET/CT imaging. The maximum and mean standardized uptake values (SUVmax and SUVmean, respectively) and lesion-to-background ratio (LBR) were calculated. The predictive capabilities of semiquantitative PET/CT parameters were analyzed by receiver operating characteristic curve analysis. RESULTS: A total of 70 inflammatory and 37 malignant lung lesions were evaluated by [18F]AlF­NOTA­FAPI­04 PET/CT, and 33 inflammatory and 26 malignant lung lesions also were evaluated by [18F]FDG PET/CT. Inflammatory lesions exhibited lower [18F]AlF-NOTA-FAPI-04 and [18F]FDG uptake compared to malignant lesions, with statistically significant differences in SUVmax, SUVmean, and LBR (all p < 0.001). [18F]AlF-NOTA-FAPI-04 uptake also varied among different types of inflammatory lesions (SUVmax, p = 0.005; SUVmean, p = 0.008; LBR, p < 0.001), with the highest uptake observed in bronchiectasis with infection, followed by postobstructive pneumonia, and the lowest in pneumonia. [18F]FDG uptake was higher in postobstructive pneumonia than in pneumonia (SUVmax, p = 0.009; SUVmean, p = 0.016; LBR, p = 0.004). CONCLUSION: [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT showed significantly lower uptake in inflammatory lesions than malignancies as well as variation in different types of inflammatory lesions, and thus, may be valuable for distinguishing malignant and various inflammatory findings. CLINICAL RELEVANCE STATEMENT: Our study confirmed that the uptake of [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT in inflammatory and malignant lung lesions is different, which is beneficial to distinguish inflammatory and malignant lung lesions in clinic. KEY POINTS: • Malignant and different inflammatory lung lesions showed varying degrees of uptake of [18F]AlF-NOTA-FAPI-04 and [18F]FDG. • Inflammatory lung lesions showed significantly less uptake than malignancies, and uptake varied among different types of inflammatory lesions. • Both types of PET/CT could differentiate malignant and various inflammatory lung findings.

Early detection of radiation-induced myocardial damage by [18F]AlF-NOTA-FAPI-04 PET/CT imaging.

PURPOSE: Retrospective analysis revealed increased [18F]AlF-NOTA-FAPI-04 uptake in the myocardium of patients with esophageal squamous cell cancer (ESCC) treated with concurrent chemoradiotherapy (CCRT). This study investigated and verified the feasibility of [18F]AlF-NOTA-FAPI-04 PET/CT for detecting radiation-induced myocardial damage (RIMD). METHODS: Myocardial FAPI uptake was analyzed before and during radiotherapy in thirteen ESCC patients treated with CCRT. In the animal study, a single dose of 50 Gy was delivered to the cardiac apex of Wistar rats (24 rats, including 16 RIMD model rats and 8 control model rats). RIMD model rats were scanned with [18F]AlF-NOTA-FAPI-04 PET/CT weekly for 12 weeks, and left ventricular ejection fraction (LVEF) was measured by magnetic resonance imaging. Dynamic, blocking, and [18F]FDG PET/CT studies (4 rats/group) were performed on RIMD rats at 5 weeks post-radiation, and histopathological analyses were conducted. RESULTS: Increased FAPI uptake in the myocardium was found after CCRT (1.53 ± 0.53 vs 1.88 ± 0.70, P = 0.015). In RIMD rats, significantly increased FAPI uptake in the damaged myocardium was observed from the 2nd week post-radiation exposure and peaked in the 5th week. Significantly more intense tracer accumulation was observed in the damaged myocardium than in the remote myocardium, as identified by decreased [18F]FDG uptake and confirmed by autoradiography, hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining. The LVEF remained unchanged at the 3rd week post-radiation exposure but was remarkably decreased compared with that in the control group at the 8th week. CONCLUSION: Through clinical phenomena and animal experimental studies, this study indicated that [18F]AlF-NOTA-FAPI-04 PET/CT imaging can detect RIMD noninvasively and before a decrease in LVEF, indicating the clinical potential of [18F]AlF-NOTA-FAPI-04 as a PET/CT tracer for early monitoring of RIMD.

Increased 18F-FAPI uptake in bones and joints of lung cancer patients: characteristics and distributions.

OBJECTIVE: This study investigated the distribution and characteristics of various bone and joint lesions on 18F-FAPI PET/CT in lung cancer patients. METHODS: Seventy-four lung cancer patients who underwent 18F-FAPI PET/CT were reviewed. Bone and joint lesions with elevated 18F-FAPI uptake were recorded and analyzed. The distribution and maximum uptake value (SUVmax) of different benign lesions or bone metastases were presented. In addition, the SUVmax of bone metastases on 18F-FDG and 18F-FAPI-04 PET/CT were also compared. RESULTS: In 53 patients, a total of 262 lesions presented 18F-FAPI accumulation. Bone metastases were mainly in vertebrae, pelvis, and ribs, while benign lesions were in vertebral margins, alveolar bone, and shoulder joints. The SUVmax of bone metastases was significantly higher than that of benign lesions ([Formula: see text] vs. [Formula: see text], [Formula: see text]), with NSCLC cases having higher SUVmax values than SCLC cases ([Formula: see text] vs. [Formula: see text], [Formula: see text]). Among benign lesions, arthritis and periodontitis demonstrated higher SUVmax than degenerative lesions (arthritis: [Formula: see text]; periodontitis: [Formula: see text]; degenerative diseases: [Formula: see text]; [Formula: see text] and [Formula: see text], respectively). The SUVmax of bone metastases was comparable between 18F-FDG and 18F-FAPI PET/CT. However, 18F-FAPI PET/CT was found to be superior in identifying cranial metastases compared to 18F-FDG PET/CT (TBRmet/brain: [Formula: see text] vs. [Formula: see text], [Formula: see text]). CONCLUSION: This study demonstrated that 18F-FAPI PET/CT is a valuable imaging modality for detecting bone and joint lesions in lung cancer patients. The SUVmax of malignant lesions was higher than that of benign lesions, but cannot accurately distinguish benign and malignant lesions. The uptake of FAPI differs among lesions with different pathological types.

Tumor angiogenesis at baseline identified by 18F-Alfatide II PET/CT may predict survival among patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

BACKGROUND: The study investigated the predictive value of tumor angiogenesis observed by 18F-ALF-NOTA-PRGD2 II (denoted as 18F-Alfatide II) positron emission tomography (PET)/computed tomography (CT) before concurrent chemoradiotherapy (CCRT) for treatment response and survival among patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Patients with unresectable stage IIIA or IIIB NSCLC (AJCC Cancer Staging 7th Edition) who received CCRT were included in this prospective study. All patients had undergone 18F-Alfatide PET/CT scanning before CCRT, and analyzed parameters included maximum uptake values (SUVmax) of primary tumor (SUVP) and metastatic lymph nodes (SUVLN) and mean uptake value of blood pool (SUVblood). Tumor-to-background ratios (TBRs) and changes in tumor diameter before and after CCRT (ΔD) were calculated. The ratios of SUVP to SUVblood, SUVLN to SUVblood, and SUVP to SUVLN were denoted as TBRP, TBRLN, and T/LN. Short-term treatment response, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: Of 38 enrolled patients, 28 completed CCRT. SUVP, SUVLN, TBRP, TBRLN and T/LN showed significant correlation with PFS (all P < 0.05). SUVP was negatively correlated with OS (P = 0.005). SUVP and TBRP were higher in non-responders than in responders (6.55 ± 2.74 vs. 4.61 ± 1.94, P = 0.039; 10.49 ± 7.58 vs. 7.73 ± 6.09, P = 0.023). ΔD was significantly greater in responders (2.78 ± 1.37) than in non-responders (-0.16 ± 1.33, P < 0.001). Exploratory receiver operating characteristic curve analysis identified TBRP (area under the curve [AUC] = 0.764, P = 0.018), with a cutoff value of 6.52, as the only parameter significantly predictive of the response to CCRT, with sensitivity, specificity, and accuracy values of 71.43%, 78.57%, and 75.00%, respectively. ROC curve analysis also identified SUVP (AUC = 0.942, P < 0.001, cutoff value 4.64) and TBRP (AUC = 0.895, P = 0.001, cutoff value 4.95) as predictive of OS with high sensitivity (84.21%, 93.75%), specificity (100.00%, 66.67%), and accuracy (89.29%, 82.14%). CONCLUSIONS: Evaluation of tumor angiogenesis by 18F-Alfatide II at baseline may be useful in predicting the short-term response to CCRT as well as PFS and OS in patients with LA-NSCLC.

The joint detection of CEA and ctDNA in cerebrospinal fluid: an auxiliary tool for the diagnosis of leptomeningeal metastases in cancer.

BACKGROUND: Leptomeningeal metastases (LMs) are highly invasive which leads to poor prognosis, but the accurate diagnosis of LM is challenging. It is necessary to investigate more advanced diagnostic methods to realize precision medicine. The main purpose of this study was to select a more effective method for the auxiliary diagnosis of LM by comparing various detection methods. The secondary purpose was to explore the value of cerebrospinal fluid (CSF) tumor markers (TMs) and circulating tumor DNA (ctDNA) testing in guiding clinical treatment. METHODS: TMs in serum and CSF of patients were detected by chemiluminescence. The ctDNA of CSF and plasma were detected by the next-generation sequencing (NGS) technology. RESULTS: In total, 54 tumor patients participated in this study, in which 39 with LM and 15 without LM (8 with parenchymal tumor and 7 without brain metastasis). The results showed that the sensitivity and accuracy of CSF cytology isolated during the first lumbar puncture were 0.31 (95% CI 0.17-0.48) and 0.50 (95% CI 0.36-0.64), respectively. The sensitivity and accuracy of CSF_CEA were 0.71 (95% CI 0.54-0.85) and 0.78 (95% CI 0.64-0.89), which were better than those of CSF_NSE and CSF_CFRA-211. The sensitivity and accuracy of CSF_ctDNA were 0.92 (95% CI 0.79-0.98) and 0.91 (95% CI 0.80-0.97), significantly higher than that of CSF cytology (P < 0.01). The sensitivity and accuracy of CSF_CEA combined with CSF_ctDNA were 0.97 (95% CI, 0.87-1.00) and 0.94 (95% CI 0.85-0.99), which were significantly higher than the traditional methods CSF cytology (P < 0.01). For LM patients with hydrocephalus, the sensitivity of CSF ctDNA even achieved 100% (14/14). CONCLUSION: CSF_CEA combined with CSF_ctDNA could be used to accurately distinguish patients with LM from those with no brain metastasis and from those with parenchymal tumors. CSF_ctDNA testing reveals a unique mutation profile for patients with LM. Dynamic detection of CSF TM and ctDNA can better predict the efficacy and reveal the cause of drug resistance to guide subsequent treatment. CLINICAL TRIAL REGISTRATION: Clinical trial registration number: NCT03029065.

The role of the chloroplast localised phosphate transporter GmPHT4;10 gene in plant growth, photosynthesis and drought resistance.

In view of the importance of inorganic phosphate to plant growth and development, the role of phosphate transporters responsible for absorption and transportation in crops has attracted increasing attention. In this study, bioinformatics analysis and subcellular localisation experiment showed that GmPHT4;10 is a member of PHT4 subfamily of phosphate transporters and located in chloroplasts. The gene was induced by phosphate deficiency and drought, and was the highest in leaves. After GmPHT4;10 gene was replenished to AtPHT4;5 gene deletion mutant lines (atpht4;5 ), the phenotype of the transgenic lines was basically recovered to the level of wild-type, but there were significant differences in phosphate content and photosynthetic indicators between wild-type and revertant lines. Meanwhile, the difference of proline content and catalase activity between the two lines also indicated that GmPHT4;10 gene and its orthologous gene AtPHT4;5 were different in drought resistance and drought resistance mechanism. After overexpression of GmPHT4;10 gene in Arabidopsis thaliana , more phosphate and proline were accumulated in chloroplasts and catalase activity was increased, thus improving photosynthesis and drought resistance of plants. The results further supplement the cognition of PHT4 subfamily function, and provides new ideas and ways to improve photosynthesis by revealing the function of chloroplast phosphate transporter.

Identification, characteristics and rice growth promotion of a highly efficient cellulolytic bacterial strain, Cellulomonas iranensis ZJW-6, isolated from paddy soil in central China.

The microbial degradation of lignocellulose is the best way to treat straw, which has a broad application prospect. It is consistent with the idea of agricultural sustainable development and has an important impact on the utilization of biomass resources. To explore and utilize the microbial resources of lignocellulose degradation, 27 lignocellulose degrading strains were screened from 13 regions in China. ZJW-6 was selected because of its 49.6% lignocellulose weight loss rate. According to the theoretical analysis of the experimental results, the following straw degradation conditions were obtained by ZJW-6: nitrogen source input of 8.45 g/L, a pH of 8.57, and a temperature of 31.63°C, the maximum weight loss rate of rice straw could reach 54.8%. It was concluded that ZJW-6 belonged to Cellulomonas iranensis according to 16S rRNA-encoding gene sequence comparison and identification. ZJW-6 is a Gram-positive bacterium that grows slowly and has a small yellowish green colony. To explain the degradation mechanism of lignocellulose, the experiment of enzymatic properties of the strain was prepared and carried out. It was discovered that ZJW-6 has an excellent ability to degrade cellulose, hemicellulose, and lignin, with cellulose and hemicellulose loss rates reaching almost 50% in 4 days and lignin loss rates reaching nearly 30%. Furthermore, ZJW-6 demonstrated lignocellulose degradation under aerobic and anaerobic conditions, indicating the strain's broad application potential. ZJW-6 was found to be more effective than ordinary humic acid in improving rice soil (available phosphorus, available nitrogen, organic matter) and promoting rice growth in a rice pot experiment (increasing root-shoot ratio, root activity, chlorophyll content and net photosynthetic rate). ZJW-6 plays an important role in promoting the development and utilization of straw resources. It has important significance for the advancement of green agriculture.

Diagnostic Value of 18F-NOTA-FAPI PET/CT in a Rat Model of Radiation-Induced Lung Damage.

In this study, we explore the diagnostic value of a novel PET/CT imaging tracer that specifically targets fibroblast activation protein (FAP), 18F-NOTA-FAPI, in a radiation induced lung damage (RILD) rat model. High focal radiation (40, 60, or 90 Gy) was administered to a 5-mm diameter area of the right lung in Wistar rats for evaluation of RILD induction. Lung tissues exposed to 90 Gy radiation were scanned with 18F-NOTA-FAPI PET/CT and with 18F-FDG. Dynamic 18F-NOTA-FAPI PET/CT scanning was performed on day 42 post-irradiation. After in vivo scanning, lung cryosections were prepared for autoradiography, hematoxylin and eosin (HE) and immunohistochemical (IHC) staining. An animal model of RILD was established and validated by histopathological analysis. On 18F-NOTA-FAPI PET/CT, RILD was first observed on days 42, 35 and 7 in the 40, 60 and 90 Gy groups, respectively. After treatment with 90 Gy, 18F-NOTA-FAPI uptake in an area of RILD emerged on day 7 (0.65 ± 0.05%ID/ml) and reappeared on day 28 (0.81 ± 0.09%ID/ml), remaining stable for 4-6 weeks. Autoradiography and HE staining IHC staining revealed that 18F-NOTA-FAPI accumulated mainly in the center of the irradiated area. IHC staining confirmed the presence of FAP+ macrophages in the RILD area, while FAP+ fibroblasts were observed in the peripheral area of irradiated lung tissue. 18F-NOTA-FAPI represents a promising radiotracer for in vivo imaging of RILD in a dose- and time-dependent manner. Noninvasive imaging of FAP may potentially aiding in the clinical management of radiotherapy patients.

Role and mechanism of the zinc finger protein ZNF580 in foam-cell formation.

Coronary atherosclerotic heart disease poses a significant threat to human health. The pathological basis is atherosclerosis and foam-cell formation is the key factor in the initiation of atherosclerosis. In the present study, foam cell models were established using 50 ng/ml oxidized low-density lipoprotein to stimulate in vitro cultures of THP-1 cells for 72 h. The expression of zinc finger protein 580 (ZNF580), a Cys2-His2 zinc finger protein containing 172 amino acids that was originally cloned by screening a human aortic cDNA library, was measured in foam cells and its interaction with various regulatory factors during foam-cell formation was investigated. Oil red O staining was used to observe cell morphology and intracellular lipid levels. Lentivirus transfection was employed to either overexpress or silence ZNF580 in THP-1 cells, and an inverted fluorescence microscope was used to observe the distribution of ZNF580 immunofluorescence to determine the transfection rate. RNA and total protein were extracted and the expression levels of ZNF580, CD36, peroxisome proliferator-activated receptor-γ (PPAR-γ), ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein E (ApoE) were measured by reverse transcription-quantitative PCR. The protein levels were examined by western blot analysis to evaluate the interaction between ZNF580 and associated regulatory factors. ZNF580 was able to significantly increase the expression levels of ApoE and ABCA1 and significantly decrease the expression levels of CD36 and PPAR-γ, suggesting that ZNF580-mediated inhibition of foam-cell formation is associated with the PPAR-γ-CD36 signalling pathway. Based on these findings, ZNF580 may be a potential therapeutic candidate for the treatment of coronary atherosclerotic heart disease.

Oxymatrine pretreatment protects H9c2 cardiomyocytes from hypoxia/reoxygenation injury by modulating the PI3K/Akt pathway.

Ischemia-reperfusion (I/R) plays an important role in myocardial damage, which has been widely recognized as a key procedure in the cardiovascular disease. A hypoxia/reoxygenation (H/R) model was established using H9c2 cardiomyocytes to investigate the possible positive effect of oxymatrine (OMT), an alkaloid originating from the traditional Chinese herb Sophora flavescens Aiton, on cardiomyocytes exposed to H/R injury and the underlying molecular mechanisms. Cell viability was measured using the MTT assay, lactate dehydrogenase release measurements and hematoxylin and eosin staining. Oxidative stress was detected by measuring cellular malondialdehyde (MDA) content, as well as superoxide dismutase (SOD) and catalase (CAT) activities. Apoptosis was detected using TUNEL staining and flow cytometric analysis, and the underlying mechanism was investigated using reverse transcription-quantitative PCR and western blot analyses. The results revealed that OMT increased the viability of H9c2 cardiomyocytes exposed to H/R. The OMT pretreatment decreased the production of MDA by reactive oxygen species and increased the activities of SOD and CAT. Furthermore, the OMT pretreatment reduced the expression of Bax and caspase-3, while inducing Bcl-2 expression. In addition, the protective effect of OMT was shown to be associated with the PI3K/Akt signaling pathway, and the PI3K inhibitor LY294002 attenuated the effects of OMT on the H9c2 cardiomyocytes exposed to H/R. These findings indicate that OMT could be a potential therapeutic candidate for the treatment of myocardial ischemia/reperfusion injury.

Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies in Regard to Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Evidence shows a positive association between the use of statins and new-onset diabetes. There is, however, contradictory evidence as to whether a similar association exists for the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. OBJECTIVE: The aim of this study was to investigate the safety of PCSK9 monoclonal antibodies (PCSK9-mAbs) in regard to incident diabetes. METHODS AND RESULTS: Randomized controlled trials that reported data on the incidence of new-onset diabetes mellitus or the worsening of pre-existing diabetes were searched, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the endpoints. Twenty-three studies including 65,957 participants were identified. Compared with controls, PCSK9-mAb treatment was not associated with the adverse event of diabetes (RR 0.97, 95% CI 0.91-1.02; p = 0.22). When we analysed the trials in terms of PCSK9-mAb type, alirocumab was associated with a significant reduction in the risk of diabetes (RR 0.91, 95% CI 0.85-0.98; p = 0.01), whereas no significant reduction was observed in participants receiving evolocumab or bococizumab. Interestingly, compared with ezetimibe, which was actively used as lipid-modifying therapy in the control group, PCSK9-mAbs seem to have a lower risk of incident diabetes (RR 0.60, 95% CI 0.37-0.99; p = 0.04). This meta-analysis also revealed a noticeable increase in the risk of incident diabetes in the evolocumab and alirocumab pool (RR 2.14, 95% CI 1.12-4.07; p = 0.02) when the use of statins was equivalent between the experimental and active comparator arms. CONCLUSION: Compared with placebo or any other comparator, PCSK9-mAb treatment was not associated with the adverse event of diabetes. However, evolocumab and alirocumab show high risk of incident diabetes when there is no interference from unbalanced use of statins. The imbalance in background lipid modifying therapy or different comparators used in the control arms of the studies might have masked the effect of PCSK9-mAb therapy on diabetes.