An overview of recent advances and future prospects of three-dimensional biofilm electrode reactors (3D-BERs).

Three-dimensional biofilm electrode reactors (3D-BERs) have attracted extensive attention in recent years due to their wide application range, high efficiency and energy saving. On the basis of traditional bio-electrochemical reactor, 3D-BERs are filled with particle electrodes, also known as the third electrodes, which can not only be used as a carrier for microbial growth, but also improve the electron transfer rate of the whole system. This paper reviews the constitution, advantages and basic principles of 3D-BERs as well as current research status and progress of 3D-BERs in recent years. The selection of electrode materials, including cathode, anode and particle electrode are listed and analyzed. Different constructions of reactors, like 3D-unipolar extended reactor and coupled 3D-BERs are introduced and discussed. Various contaminants degraded by 3D-BERs including nitrogen, azo dyes, antibiotics and the others are calculated and the corresponding degradation effects are described. The influencing factors and mechanisms are also introduced. At the same time, according to the research advances of 3D-BERs, the shortcomings and weakness of this technology in the current research process are analyzed, and the future research direction of this technology is prospected. This review aims to summarize recent studies of 3D-BERs in bio-electrochemical reaction and open a bright window to this booming research theme.

Mesoporous Polydopamine Loaded Pirfenidone Target to Fibroblast Activation Protein for Pulmonary Fibrosis Therapy.

Recently, fibroblast activation protein (FAP), an overexpressed transmembrane protein of activated fibroblast in pulmonary fibrosis, has been considered as the new target for diagnosing and treating pulmonary fibrosis. In this work, mesoporous polydopamine (MPDA), which is facile prepared and easily modified, is developed as a carrier to load antifibrosis drug pirfenidone (PFD) and linking FAP inhibitor (FAPI) to realize lesion-targeted drug delivery for pulmonary fibrosis therapy. We have found that PFD@MPDA-FAPI is well biocompatible and with good properties of antifibrosis, when ICG labels MPDA-FAPI, the accumulation of the nanodrug at the fibrosis lung in vivo can be observed by NIR imaging, and the antifibrosis properties of PFD@MPDA-FAPI in vivo were also better than those of pure PFD and PFD@MPDA; therefore, the easily produced and biocompatible nanodrug PFD@MPDA-FAPI developed in this study is promising for further clinical translations in pulmonary fibrosis antifibrosis therapy.

Clinical Utility of F-18 Labeled Fibroblast Activation Protein Inhibitor (FAPI) for Primary Staging in Lung Adenocarcinoma: a Prospective Study.

PURPOSE: The purpose of this study was to compare the primary staging of F-18 labeled fibroblast activation protein inhibitor ([18F]F-FAPI) with that of F-18 labeled fluordesoxyglucose positron emission tomography/computed tomography ([18F]F-FDG PET/CT) in patients with lung adenocarcinoma (LAD). PROCEDURES: We prospectively analyzed the images of LAD patients who underwent [18F]F-FAPI and [18F]F-FDG PET/CT between May 2020 and August 2021. [18F]F-FAPI and [18F]F-FDG uptakes were compared using the paired samples t test, and lesion numbers were compared using the Wilcoxon signed-rank test. RESULTS: Thirty-four LAD patients were evaluated. Patients showed high [18F]F-FAPI uptake in primary lesions (SUVmax 12.54 ± 3.77). Both [18F]F-FAPI and [18F]F-FDG had 100% detection rates for primary tumors. However, [18F]F-FAPI showed higher SUVmax than [18F]F-FDG in lesions of the lymph nodes, pleura, bones, and other tissues (all P ≤ 0.05). Although the absolute uptake values of [18F]F-FAPI in brain lesions were lower than those of [18F]F-FDG (1.56 ± 2.19 vs.7.34 ± 3.54, P < 0.0001), the tumor-to-background (T/B) ratios were significantly higher than those of [18F]F-FDG (9.53 ± 12.07 vs.1.01 ± 0.49, P < 0.0001). Generally, [18F]F-FAPI PET/CT could visualize more total lesions than [18F]F-FDG (554 vs.464, P = 0.003), especially in lymph nodes (258 vs.229, P = 0.039), the brain (34 vs.9, P = 0.002), and pleura (56 vs.30, P = 0.041). However, contrast-enhanced brain magnetic-resonance imaging (MRI) showed more brain lesions than [18F]F-FAPI PET/CT (56 vs.34, P = 0.002). Compared with the [18F]F-FDG-based TNM stage, the [18F]F-FAPI-based TNM stage was upgraded in six patients (17.6%). CONCLUSIONS: [18F]F-FAPI PET/CT showed a very high detection rate for primary LAD. In addition, 18F-FAPI PET/CT demonstrated clearer tumor delineation and more lesions than [18F]F-FDG PET/CT, especially in lymph nodes, the brain, and pleura. Therefore, [18F]F-FAPI had an advantage over [18F]F-FDG for primary staging of LAD. However, brain MRI could identify more and smaller lesions than [18F]F-FAPI PET/CT.

Noninvasively visualize the expression of LAPTM4B protein using a novel 18F-labeled peptide PET probe in hepatocellular carcinoma.

OBJECTIVE: Lysosomal protein transmembrane 4 beta (LAPTM4B) is selectively expressed in hepatocellular carcinoma (HCC) cells and thus a potential biomarker for diagnosing HCC. In this study, we designed a novel 18F-labeled PET probe to non-invasively visualize LAPTM4B expression in mouse model of HCC tumor. METHODS: A PET targeting tracer named [18F]FP-LAP2H was radio-synthesized using a LAPTM4B targeting peptide, LAP2H, coupled with 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP). Radio-stability, cell uptake, micro PET/CT imaging and ex vivo biodistribution were performed for determining its stability, cell binding specificity, and tumor targeting in vivo. RESULTS: [18F]FP-LAP2H was successfully synthesized with radiochemical yields of 6-14% (decay-corrected yield) and molar activity of 10-44 GBq/µmol. The tracer showed stable (~90%) in phosphate-buffered saline, pH 7.4, and in human serum (~80%) for 2 h. In vitro cell uptake studies indicated the radioactivity accumulation in HCC cells was LAPTM4B protein-specific. Micro PET/CT demonstrated that implanted LAPTM4B positive HepG2 and BEL7402 tumors could be clearly visualized. The ex vivo biodistribution studies demonstrated that the tumor/liver ratio were 1.80 ± 0.65 and 2.09 ± 0.68 in implanted HepG2 and BEL7402 tumors respectively. Negative control and blocking experiments revealed that the radioactivity uptake in the HCC tumor was LAPTM4B protein-specific. CONCLUSIONS: [18F]FP-LAP2H appears to be a potential PET tracer for imaging LAPTM4B-positive HCC tumor. Further endeavors need to do to improve tumor/liver ratio.

Radiomics analysis of [18F]FDG PET/CT for microvascular invasion and prognosis prediction in very-early- and early-stage hepatocellular carcinoma.

As a reliable preoperative predictor for microvascular invasion (MVI) and disease-free survival (DFS) is lacking, we developed a radiomics nomogram of [18F]FDG PET/CT to predict MVI status and DFS in patients with very-early- and early-stage (BCLC 0, BCLC A) hepatocellular carcinoma (HCC). METHODS: Patients (N = 80) with BCLC0-A HCC who underwent [18F]FDG PET/CT before surgery were enrolled in this retrospective study and were randomized to a training cohort and a validation cohort. Texture features from patients obtained using Lifex software in the training cohort were subjected to LASSO regression to select the most useful predictive features of MVI and DFS. Then, the radiomics nomogram was constructed using the radiomics signature and clinical features and further validated. RESULTS: To predict MVI, the [18F]FDG PET/CT radiomics signature consisted of five texture features from the PET and six texture features from CT. The signature was significantly associated with MVI status in the training cohort (P = 0.001). None of the clinical features was independent predictors for MVI status (P > 0.05). The area under the curve value of the M-PET/CT model was 0.891 (95% CI: 0.799-0.984) in the training cohort and showed good discrimination and calibration. To predict DFS, the [18F]FDG PET/CT radiomics nomogram (D-PET/CT model) and a clinicopathologic nomogram were built in the training cohort. The D-PET/CT model, which integrated the D-PET/CT radiomics signature with INR and TB, provided better predictive performance (C-index: 0.831, 95% CI: 0.761-0.900) and larger net benefits than the simple clinical model, as determined by decision curve analyses. CONCLUSION: The newly developed [18F]FDG PET/CT radiomics signature was an independent biomarker for the estimation of MVI and DFS in patients with very-early- and early-stage HCC. Moreover, PET/CT nomogram, which incorporated the radiomics signature of [18F]FDG PET/CT and clinical risk factors in patients with very-early- and early-stage HCC, performed better for individualized DFS estimation, which might enable a step forward in precise medicine.

Imaging algorithm and multimodality evaluation of spinal osteoblastoma.

BACKGROUND: To analyze the features of CT, MRI and PET/CT and their diagnostic value for spinal osteoblastomas (OBs). METHODS: The radiological and clinical data of 21 patients with histopathologically-confirmed spinal OBs were analyzed retrospectively. RESULTS: Sixteen of the 21 cases were benign and 5 were aggressive OBs. Tumors were located in the lumbar (n = 11), cervical (n = 4), thoracic (n = 5), and sacral (n = 1) spinal regions. Nineteen cases were centered in the posterior elements of the spine, 13 of which extended into the vertebral body. Punctate or nodular calcifications were found in all cases on CT with a complete sclerotic rim (n = 12) or incomplete sclerotic rim (n = 8). The flare phenomenon (indicative of surrounding tissue inflammation) was found in 17/21 cases on CT, thin in 11 cases and thick in 6 cases, and in 19/19 cases on MRI, thin in 1 case and thick in 18 cases. On 18F-FDG PET/CT, all cases (8/8) were metabolically active with the SUVmax of 12.3-16.0; the flare sign was observed in 8 cases, including 7 cases of hypometabolism and 1 case of coexistence of hypermetabolism and hypometabolism. Based on CT, 3, 12, and 6 cases were classified as Enneking stage 1, 2 and 3, respectively. Of 19 cases with MRI, 1 and 18 cases were classified as Enneking stage 2 and 3, respectively. CONCLUSIONS: Spinal OB has multiple unique characteristic radiological features. Although a larger sample size is needed, combining CT, MRI and PET may be beneficial to optimize preoperative diagnosis and care of patients with OBs.

Radiofluorinated GPC3-Binding Peptides for PET Imaging of Hepatocellular Carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) remains one of the most challenging diseases worldwide. Glypican-3 (GPC-3) is a cell surface proteoglycan that is overexpressed on the membrane of HCC cells. The purpose of this study was to develop a target-specific radiofluorinated peptide for positron emission tomography (PET) imaging of GPC3 expression in hepatocellular carcinoma. PROCEDURES: New GPC3-binding peptides (GP2076 and GP2633) were radiolabeled with F-18 using Al[18F]F labeling approach, and the resulting PET probes were subsequently subject to biological evaluations. A highly hydrophilic linker was incorporated into GP2633 with an aim of reducing the probe uptake in liver and increasing tumor-to-liver (T/L) contrast. Both GP2076 and GP2633 were radiolabeled using Al[18F]F chelation approach. The binding affinity, octanol/water partition coefficient, cellular uptake and efflux, and stability of both F-18 labeled peptides were tested. Tumor targeting efficacy and biodistribution of Al[18F]F-GP2076 and Al[18F]F-GP2633 were determined by PET imaging in HCC-bearing mice. Immunohistochemistry analyses were performed to compare the findings from PET scans. RESULTS: Al[18F]F-GP2076 and Al[18F]F-GP2633 were rapidly radiosynthesized within 20 min in excellent radiochemical purity (> 97 %). Al[18F]F-GP2633 was determined to be more hydrophilic than Al[18F]F-GP2076 in terms of octanol/water partition coefficient. Both Al[18F]F-GP2076 and Al[18F]F-GP2633 demonstrated good in vitro and in vivo stability and binding specificity to GPC3-positive HepG2 cells. For PET imaging, Al[18F]F-GP2633 exhibited enhanced uptake in HepG2 tumor (%ID/g 3.37 ± 0.35 vs. 2.13 ± 0.55, P = 0.031) and reduced accumulation in liver (%ID/g 1.70 ± 0.26 vs. 3.70 ± 0.98, P = 0.027) at 60 min post-injection (pi) as compared to Al[18F]F-GP2076, resulting in significantly improved tumor-to-liver (T/L) contrast (ratio 2.00 ± 0.18 vs. 0.59 ± 0.14, P = 0.0004). Higher uptake of Al[18F]F-GP2633 in GPC3-positive HepG2 tumor was observed as compared to GPC3-negative McA-RH7777 tumor (%ID/g 3.37 ± 0.35 vs. 1.64 ± 0.03, P = 0.001) at 60 min pi, confirming GPC3-specific accumulation of Al[18F]F-GP2633 in HepG2 tumor. CONCLUSION: The results demonstrated that Al[18F]F-GP2633 is a promising probe for PET imaging of GPC3 expression in HCC. Convenient preparation, excellent GPC3 specificity in HCC, and favorable excretion profile of Al[18F]F-GP2633 warrant further investigation for clinical translation. PET imaging with a GPC3-specific probe would provide clinicians with vital diagnostic information that could have a significant impact on the management of HCC patients.

Synthesis and Preclinical Evaluation of the Fibrin-Binding Cyclic Peptide 18F-iCREKA: Comparison with Its Contrasted Linear Peptide.

Purpose: Cys-Arg-Glu-Lys-Ala (CREKA) is a pentapeptide which can target fibrin-fibronectin complexes. Our previous study has built a probe called iCREKA which was based on CREKA and has proved the feasibility and specificity of iCREKA by the fluorescence experiment. The purpose of this study is to achieve the 18F-labeled iCREKA and make preclinical evaluation of the 18F-iCREKA with comparison of its contrasted linear peptide (LP). Methods: CREKA, LP, and iCREKA were labeled by the Al18F labeling method, respectively. These 18F-labeled peptides were evaluated by the radiochemistry, binding affinity, in vitro stability, in vivo stability, micro-PET imaging, and biodistribution tests. Results: 18F-NOTA-iCREKA was stable both in vitro and in vivo. However, 18F-NOTA-CREKA and 18F-NOTA-LP were both unstable. The FITC or 18F-labeled iCREKA could be abundantly discovered only in matrix metalloproteinases- (MMPs-) 2/9 highly expressed U87MG cells, while the FITC or 18F-labeled LP could also be abundantly discovered in MMP-2/9 lowly expressed Caov3 cells. Biodistribution and micropositron emission tomography (PET) imaging revealed that the U87MG xenografts showed a higher uptake of 18F-NOTA-iCREKA than 18F-NOTA-LP while the Caov3 xenografts showed very low uptake of both 18F-NOTA-iCREKA and 18F-NOTA-LP. The tumor-to-muscle (T/M) ratio of 18F-NOTA-iCREKA (9.93 ± 0.42) was obviously higher than 18F-NOTA-LP (2.69 ± 0.35) in U87MG xenografts. Conclusions: The novel CREKA-based probe 18F-NOTA-iCREKA could get a high uptake in U87MG cells and high T/M ratio in U87MG mice. It was more stable and specific than the 18F-NOTA-LP.

Synthesis and Evaluation of 18F-Labeled Peptide for Gonadotropin-Releasing Hormone Receptor Imaging.

The gonadotropin-releasing hormone (GnRH) receptor is overexpressed in the majority of tumors of the human reproductive system. The purpose of this study was to develop an 18F-labeled peptide for tumor GnRH receptor imaging. In this study, the GnRH (pGlu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Gly10-NH2) peptide analogues FP-d-Lys6-GnRH (FP = 2-fluoropropanoyl) and NOTA-P-d-Lys6-GnRH (P = ethylene glycol) were designed and synthesized. The IC50 values of FP-d-Lys6-GnRH and NOTA-P-d-Lys6-GnRH were 2.0 nM and 56.2 nM, respectively. 4-Nitrophenyl-2-[18F]fluoropropionate was conjugated to the ε-amino group of the d-lysine side chain of d-Lys6-GnRH to yield the new tracer [18F]FP-d-Lys6-GnRH with a decay-corrected yield of 8 ± 3% and a specific activity of 20-100 GBq/µmol (n=6). Cell uptake studies of [18F]FP-d-Lys6-GnRH in GnRH receptor-positive PC-3 cells and GnRH receptor-negative CHO-K1 cells indicated receptor-specific accumulation. Biodistribution and PET studies in nude mice bearing PC-3 xenografted tumors showed that [18F]FP-d-Lys6-GnRH was localized in tumors with a higher uptake than in surrounding muscle and heart tissues. Furthermore, the metabolic stability of [18F]FP-d-Lys6-GnRH was determined in mouse blood and PC-3 tumor homogenates at 1 h after tracer injection. The presented results indicated a potential of the novel tracer [18F]FP-d-Lys6-GnRH for tumor GnRH receptor imaging.

Low glucose metabolism in hepatocellular carcinoma with GPC3 expression.

AIM: To investigate the relationship between glucose metabolism and glypican-3 (GPC3) expression in hepatocellular carcinoma (HCC). METHODS: Immunohistochemical staining of pathological samples for GPC3 and glucose transporter 1 (GLUT1), and whole-body 18F-FDG PET/CT for measuring tumour glucose uptake were performed in 55 newly diagnosed HCC patients. The maximum standard uptake value (SUVmax) and tumour-to-non-tumourous liver uptake (T/NT) ratio were used to quantify 18F-FDG uptake. In vitro18F-FDG uptake assay of GPC3-expressing HepG2 and non-GPC3-expressing RH7777 cells was used to examine the effect of GPC3 in cellular glucose metabolism. The relationships between GPC3 expression and 18F-FDG uptake, GLUT1 expression, tumour differentiation, and other clinical indicators were analysed using Spearman rank correlation, univariate and multiple logistic regression analyses. RESULTS: Positive GPC3 expression was observed in 67.3% of HCC patients, including 75.0% of those with well or moderately differentiated HCC and 36.4% of those with poorly differentiated HCC. There was an inverse relationship between GPC3 expression and SUVmax (Spearman correlation coefficient = -0.281, P = 0.038) and a positive relationship between GLUT1 expression and SUVmax (Spearman correlation coefficient = 0.681, P < 0.001) in patients with HCC. Univariate analysis showed that two glucose metabolic parameters (SUVmax and T/NT ratio), tumour differentiation, lymph node metastasis, and TNM stage were all significantly associated with GPC3 expression (P < 0.05), whereas GLUT1 expression, sex, age, tumour size, intrahepatic lesion number, and distant metastasis showed no statistical association (P > 0.05). Further multivariate analysis revealed that only the T/N ratio was significantly correlated with GPC3 expression in patients with HCC (P < 0.05). In vitro assay revealed that the uptake of 18F-FDG in GPC3-expressing HepG2 cells was significantly lower than that of non-GPC3-expressing RH7777 cells (t = -20.352, P < 0.001). CONCLUSION: The present study demonstrated that GPC3 expression is inversely associated with glucose metabolism, suggesting that GPC3 may play a role in regulating glucose metabolism in HCC.

[Combined use of thin-section CT and 18F-FDG PET/CT for characterization of solitary pulmonary nodules].

OBJECTIVE: To investigate whether fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) combined with thin-section CT improves the diagnostic performance for solitary pulmonary nodules (SPNs). METHODS: A total of 267 patients underwent examinations with 18F-FDG PET/CT and thin-section CT for evaluating the SPNs with undetermined nature, which was further confirmed by pathological examination or clinical follow-up. The performance of two diagnostic criteria based on findings in PET/CT alone (Criterion 1) and in PET/CT combined with thin-section CT (Criterion 2) were compared. RESULTS: Thin-section CT provided greater diagnostic information for SPNs in 84.2% of the patients. Compared with Criterion 1, the diagnosis based on Criterion 2 significantly increased the diagnostic sensitivity (80.4% vs 91%, P<0.01) and accuracy (76.4% vs 87.2%, P<0.01) for lung cancer. The lesion size and the CT features including lobulation, air bronchogram, and feeding vessel, but not SUVmax, were all helpful for characterizing non-solid SPNs. Thin-section CT rectified diagnostic errors in 50% (20/40) of the cancerous lesions, which had been diagnosed as benign by PET due to their low metabolism. For non-solid SPNs, Criterion 2 showed a significantly higher diagnostic sensitivity than Criterion 1 (90.0% vs 40.0%, P=0.000) but their diagnostic specificity were comparable (75.2% vs 58.3%, P=0.667). For solid nodules, the use of thin-section CT resulted in no significant improvement in the diagnostic performance (P<0.05). CONCLUSION: The combination of PET/CT and thin-section CT creates a synergistic effect for the characterization of SPNs, especially non-solid nodules.

Whole-body 18F-FDG PET/CT for M staging in the patient with newly diagnosed nasopharyngeal carcinoma: Who needs?

OBJECTIVE: Although whole-body fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) (18F-FDG PET/CT) is commonly used for M staging of newly diagnosed nasopharyngeal carcinoma (NPC), some patients may not benefit from this procedure. The present study investigated which patients require this modality for M staging. METHODS: Whole-body 18F FDG PET/CT results and clinical data were collected for 264 patients with newly diagnosed NPC. The relationships between distant metastasis and age, gender, pathological type, lesion size, SUVmax-T, T staging, N staging, SUVmax-N and Epstein-Barr virus (EBV) quantity were retrospectively analysed to identify factors associated with increased risk. RESULTS: Of the 264 patients, only 37 (14.0%) were diagnosed with distant metastasis. Using multiple logistic regression analysis, EBV-positivity (OR=13.1; 95% CI:1.61,106.80), N staging (OR=3.05; 95% CI:1.41,6.63) and T staging (OR=2.16; 95% CI:1.10, 4.24) were significantly related to distant metastasis (all P<0.05). EBV DNA levels≥9000copies/ml, N3 stage and T4 stage were identified as high risk factors. A low risk of distant metastasis was found in patients with 0-1 risk factors and in those with 2 specific risk factors, T3/T4 and N2/N3 staging. Patients with EBV DNA levels ≥9000copies/ml and N3 or T4 staging and those with 3 risk factors had a medium or high risk, with a much higher incidence of distant metastasis (χ2=29.896, P=0.000), and needed a whole-body 18F FDG PET/CT for M staging. CONCLUSIONS: Due to the low incidence of distant metastasis, only patients with medium or high risk need to undergo a whole-body scan.