BACKGROUND:Dental mesenchymal stem cells are considered a promising source for bone tissue repair due to their high proliferation potential,osteogenic differentiation capacity,and immunomodulatory properties.However,some allogeneic applications of stem cells still have potential carcinogenic effects and immune rejection risks.Recently,studies have highlighted the paracrine effects mediated by secretions from dental mesenchymal stem cells in bone tissue repair.These secretions include the soluble factors and extracellular vesicles.OBJECTIVE:To review the research progress of dental mesenchymal stem cells in repairing bone defects through paracrine effects.METHODS:Using search terms"dental mesenchymal stem cell,paracrine,osteogenesis,conditioned medium,extracellular vesicle"in Chinese and English,relevant literature published between 2019 and 2024 was retrieved from databases including CNKI,PubMed,and Elsevier ScienceDirect.A total of 104 studies were ultimately selected for this review.RESULTS AND CONCLUSION:(1)Dental mesenchymal stem cells-conditioned medium contains multiple bioactive factors beneficial for bone repair.These factors directly promote bone formation through regulatory agents such as osteocalcin,osteopontin,bone morphogenetic protein,and dentin sialophosphoprotein.They also play an indirect promoting role in bone tissue repair through neurotrophic factors,vascular endothelial growth factor,and immunomodulatory and anti-inflammatory agents.(2)Dental derived mesenchymal stem cell-derived extracellular vesicles not only contain some cytokines from dental conditioned medium,but also various miRNAs,which promote bone repair by directly promoting osteogenesis,angiogenesis,regulating immune cells,and inflammation control.These extracellular vesicles can be engineered within different scaffold materials to achieve controlled or sustained release,enhancing therapeutic efficacy.

BACKGROUND:Dental mesenchymal stem cells are considered a promising source for bone tissue repair due to their high proliferation potential,osteogenic differentiation capacity,and immunomodulatory properties.However,some allogeneic applications of stem cells still have potential carcinogenic effects and immune rejection risks.Recently,studies have highlighted the paracrine effects mediated by secretions from dental mesenchymal stem cells in bone tissue repair.These secretions include the soluble factors and extracellular vesicles.OBJECTIVE:To review the research progress of dental mesenchymal stem cells in repairing bone defects through paracrine effects.METHODS:Using search terms"dental mesenchymal stem cell,paracrine,osteogenesis,conditioned medium,extracellular vesicle"in Chinese and English,relevant literature published between 2019 and 2024 was retrieved from databases including CNKI,PubMed,and Elsevier ScienceDirect.A total of 104 studies were ultimately selected for this review.RESULTS AND CONCLUSION:(1)Dental mesenchymal stem cells-conditioned medium contains multiple bioactive factors beneficial for bone repair.These factors directly promote bone formation through regulatory agents such as osteocalcin,osteopontin,bone morphogenetic protein,and dentin sialophosphoprotein.They also play an indirect promoting role in bone tissue repair through neurotrophic factors,vascular endothelial growth factor,and immunomodulatory and anti-inflammatory agents.(2)Dental derived mesenchymal stem cell-derived extracellular vesicles not only contain some cytokines from dental conditioned medium,but also various miRNAs,which promote bone repair by directly promoting osteogenesis,angiogenesis,regulating immune cells,and inflammation control.These extracellular vesicles can be engineered within different scaffold materials to achieve controlled or sustained release,enhancing therapeutic efficacy.

Objective To explore the predictive value of triglyceride-glucose index(TyG),C-reactive pro-tein to albumin ratio(CAR),and microRNA-21(miR-21)for the prognosis of ischemic heart failure(IHF)patients with type 2 diabetes(T2DM).Methods The medical records of totally 400 IHF patients with T2DM who were admitted to the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University from January 2022 to December 2023 were selected and divided into a favorable prognosis group(n=318)and a poor prog-nosis group(n=82)based on whether major adverse cardiovascular events(MACE)occurred within 6 months after diagnosis.General information,along with TyG,CAR,and miR-21 levels,was gathered for both groups.Univariate analysis and multivariate Logistic regression were applied to identify the factors influencing poor prognosis in IHF patients with T2DM.Receiver operating characteristic(ROC)curves were plotted to assess the predictive capacity of TyG,CAR,and miR-21 for poor prognosis in these patients.Results Univari-ate analysis showed that there were statistically significant differences in the history of hypertension,history of coronary heart disease,advanced age,TyG,CAR,and miR-21 between the two groups(P＜0.05).Multiva-riate Logistic regression indicated that advanced age,coronary artery disease,TyG,CAR,and miR-21 were in-dependent risk factors for poor prognosis in IHF patients with T2DM(P＜0.05).The area under the curve of the combined detection of TyG,CAR,and miR-21 for poor prognosis in IHF patients with T2DM was 0.841,with sensitivity of 0.814 and specificity of 0.707.Conclusion The levels of TyG,CAR and miR-21 in IHF pa-tients with T2DM and poor prognosis are increased,and the three are closely related to adverse cardiovascular events.Combined detection can be used as an auxiliary indicator for the prognosis of IHF patients with T2DM.

Objective:To explore whether multi-parametric MRI (mpMRI) combined with 68Ga-prostate specific membrane antigen (PSMA) PET/CT can improve the detection efficiency of clinically significant prostate cancer (csPCa). Methods:Clinical and imaging data of 152 patients (age (68.5±8.5) years) who underwent mpMRI and 68Ga-PSMA PET/CT examination for suspected prostate cancer in the First Affiliated Hospital of the Air Force Medical University from January 2021 to November 2022 were retrospectively analyzed, with the histopathological results from transrectal ultrasound guided biopsy as reference. Lesions with Gleason scores (GS) ≥3+ 4 from the biopsy were diagnosed with csPCa, and lesions with negative biopsy or GS 6 were diagnosed with non-csPCa. MpMRI was evaluated independently by two radiologists according to the Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. The radioactive uptake of 68Ga-PSMA PET/CT in prostate lesions was evaluated by SUV max. The independent-sample t test, Mann-Whitney U test and χ2 test were used to compare differences between the two groups, and then multivariate logistic regression analysis was performed. ROC curves analysis was used to analyze the diagnostic efficacies of individual and combined factors and Delong test was used. Results:There were 85 csPCa and 67 non-csPCa confirmed. Prostate specific antigen (PSA), PI-RADS score and SUV max were significantly different between the csPCa group and the non-csPCa group ( χ2=68.06, U values: -7.66, -8.98, all P<0.001). Multivariate logistic regression analysis indicated that PI-RADS score (odds ratio ( OR)=3.424, 95% CI: 1.651-7.100) and SUV max ( OR=1.931, 95% CI: 1.403-2.658) were independent predictors of csPCa (both P<0.001). ROC curves analysis revealed that the cut-off value for diagnosing csPCa was 4 for PI-RADS score and 5.6 for SUV max. The accuracy of mpMRI and PET/CT alone in csPCa diagnosis was 80%(122/152) (AUC of 0.789(95% CI: 0.711-0.866) with the sensitivity and specificity of 91%(77/85) and 67%(45/67)), and 87%(132/152) (AUC of 0.876(95% CI: 0.817-0.936) with the sensitivity and specificity of 81%(69/85) and 94%(63/67)), respectively. Several joint models incorporating 68Ga-PSMA PET/CT with mpMRI data were investigated, the model of PI-RADS 5 or PI-RADS 3-4 and SUV max>5.6 showed better performance than mpMRI and PET/CT alone and other joint models ( z values: 2.01-3.64, all P<0.05), with the accuracy of 91%(138/152) (AUC of 0.910(95% CI: 0.857-0.962) with the sensitivity and specificity of 89%(76/85) and 93%(62/67)). Conclusion:MpMRI combined with 68Ga-PSMA PET/CT can significantly improve the detection efficiency of csPCa, with the principal effect being improved in risk stratification of PI-RADS 3-4 lesions in mpMRI.

Objective:To explore the uptake characteristics and temporal changes of 68Ga-fibroblast activation protein inhibitors (FAPIs) and 18F-FDG in the anastomotic site of reconstructed digestive tracts after radical surgery for gastrointestinal adenocarcinoma. Methods:A cohort of 43 patients (28 males, 15 females; age range 28-79 years) who underwent radical surgery for gastrointestinal adenocarcinoma and underwent 18F-FDG PET/CT follow-up between November 2020 and June 2022 in the First Affiliated Hospital of the Air Force Medical University was prospectively included. One week after the 18F-FDG PET/CT examination, 68Ga-FAPI-04 PET/CT imaging was performed. ROIs were drawn on the PET images at the highest uptake level of anastomotic sites of reconstructed digestive tract and abdominal wall incisions, and SUV max and target-to-background ratio (TBR) were determined. χ2 test, one-way analysis of variance, Kruskal-Wallis rank sum test (Bonferroni correction) and Wilcoxon signed-rank test were supplied. Results:There were 86 surgical wounds (13 gastric-intestinal anastomotic sites, 14 esophagus-intestinal anastomotic sites, 16 intestinal-intestinal anastomotic sites, and 43 abdominal wall incisions) included. In 68Ga-FAPI-04 PET imaging, SUV max of gastric-intestinal anastomotic sites was higher than that of abdominal wall incisions, with a statistically significant difference (adjusted P=0.014). The TBR did not show statistically significant differences among different types of surgical wounds ( H=3.88, P=0.275). In 18F-FDG PET imaging, SUV max of gastric-intestinal, esophagus-intestinal, and intestinal-intestinal anastomotic sites were all higher than that of abdominal wall incisions, with statistically significant differences (adjusted all P<0.001). There were no statistically significant differences in TBR among different types of surgical wounds ( H=3.02, P=0.388). In 68Ga-FAPI-04 PET imaging, the TBR of all types of anastomotic sites exhibited a decreasing trend with increasing postoperative time. Except for intestinal-intestinal anastomotic sites, the differences in TBR between < 0.5-year and ≥ 1.5-year groups were statistically significant for other types of surgical wounds (adjusted P<0.05). In 18F-FDG PET imaging, the TBR of abdominal wall incisions showed a decreasing trend with increasing postoperative time. However, the TBR of other types of surgical wounds did not show a decreasing trend, and the differences in TBR among different time groups were not statistically significant ( H values: 0.53-2.75, P values: 0.252-0.768). In comparing the two PET imaging agents, for all surgical wounds within the <0.5-year and 0.5-1.5-year groups, the 68Ga-FAPI-04 TBR was consistently higher than the 18F-FDG TBR ( z values: -3.17 and -2.55, P values: 0.002 and 0.011). However, in the ≥1.5-year group, the TBR values tended to be consistent, and the differences were not statistically significant ( z=-0.70, P=0.485). Conclusions:The 18F-FDG uptake in the anastomotic sites of reconstructed digestive tracts reaches a low level under half a year after surgery and does not significantly change over time, while the 68Ga-FAPIs uptake remains relatively high within the first 1.5 years after surgery but decreases over time. These patterns suggest that clinical attention should be paid to the differential diagnosis of anastomotic inflammation or fibrosis, which resulting in agent uptake and local tumor recurrence.

【Objective】 To prepare positron emission computed tomography (PET) molecular probes targeting macrophages using Nb119 and BCⅡ10 labeled with ⁶⁸Ga nuclide. 【Methods】 To explore the labeling conditions of nanobodies with ⁶⁸Ga nuclides, first, the anti-Vsig4 nanobody Nb119 and isotype control antibody BCⅡ10 were incubated with NOTA and then purified to obtain the chelating agent-modified NOTA-Nb119 and NOTA-BCⅡ10. The NOTA-Nb119 and NOTA-BCⅡ10 were further incubated with ⁶⁸Ga. Finally, NOTA-Nb119 was identified by SDS-PAGE and MALDI-TOF methods, and the radiochemical purity was detected by radio-HPLC. 【Results】 The results of SDS-PAGE showed that the lanes of the successfully labeled NOTA-Nb119 had apparent hysteresis than the unlabeled nanobody band, which proved that the molecular weight of the labeled product was increased and NOTA successfully modified the nanobody. Subsequently, ⁶⁸Ga nuclides could successfully label Nb119 and BCⅡ10. According to radio-HPLC detection, the radiochemical purity of NOTA-Nb119 and NOTA-BCⅡ10 labeled with ⁶⁸Ga was greater than 90% and remained stable. 【Conclusion】 ⁶⁸Ga-labeled nanobodies have high radiochemical purity and high stability, indicating that this study can be applied to other nanobodies for modification and labeling and provides a practical and feasible method for the preparation of PET using nanobodies.

Objective:To exploring the uptake of fibroblast activation protein (FAP) inhibitor (FAPI) in pancreatic cancer through 68Ga-FAPI-04 PET/CT imaging, and provide a basis for the FAP-targeted imaging of pancreatic cancer. Methods:Pancreatic cancer-patient-derived tumor xenograft (PDX) mouse models ( n=8) were developed, then 68Ga-FAPI-04 and 18F-FDG microPET/CT imaging were performed (4 in each group). The differences of percentage activity of injection dose per gram of tissue (%ID/g) of 68Ga-FAPI-04 and 18F-FDG were analyzed by independent-sample t test. 68Ga-FAPI-04 and 18F-FDG PET/CT imaging were performed in 5 patients (4 males, 1 female, age: 46-74 (63.0±11.9) years) with pancreatic cancer, and the maximum standardized uptake value (SUV max) of 68Ga-FAPI-04 and 18F-FDG in primary pancreatic cancer and the SUV max ratio of liver metastases to liver tissue were compared by paired t test. Results:MicroPET/CT imaging showed that 68Ga-FAPI-04 was obviously uptaken at all time points in the tumor of PDX mice. The uptake of 68Ga-FAPI-04 in PDX mice 60 min after injection was significantly higher than that of 18F-FDG ((6.58±0.44) and (4.29±0.13) %ID/g; t=4.152, P=0.008 9). PET/CT showed that the SUV max of 68Ga-FAPI-04 in pancreatic cancer was significantly higher than that of 18F-FDG (16.82±3.08 and 5.14±2.20; t=6.893, P=0.000 1) and the SUV max ratio of liver metastases to liver tissue of 68Ga-FAPI-04 was also significantly higher than that of 18F-FDG (4.57±1.47 and 1.30±0.16; t=3.803, P=0.019 1). Conclusion:68Ga-FAPI-04 can be highly uptaken in pancreatic cancer, suggesting that FAP can be a potential target for PET/CT imaging of pancreatic cancer.

Objective:To explore the application value of radioisotope tracer technology in clinical research of biological drugs.Methods:The pharmacokinetic properties of mepuzumab in healthy volunteers were evaluated by measuring the radioactive concentrations of iodine in blood and urine samples of 3 healthy volunteers at different time points within 14 days after intravenous infusion of 131I-labeled international class I new drug mepuzumab (Trial 1). Positron emission computed tomography (PET/CT) was performed on 6 healthy volunteers after intravenous injection of 68Ga-labeled nucleic acid aptamer Sgc8, and the standard uptake values of 68Ga-Sgc8 in different organs were measured to evaluate its biodistribution in healthy humans (Trial 2). Nine patients with suspected neuroendocrine tumors underwent single photon emission and X-ray computed tomography (SPECT/CT) 4 hours after intravenous injection of 99mTc-labeled octreotide to determine the radioactive uptake level in the regions of interest; the affinity and targeting of 99mTc-labeled octreotide to somatostatin receptor subtype 2 (SSTR2) were evaluated in combination with the immunohistochemical staining results of SSTR2 in patients′ biopsy tissues (Trial 3). Results:The 3 healthy volunteers included in Trial 1 were male, aged 28, 45, and 25 years respectively; the injection doses of 131I-labeled mepuzumab were 21.0, 25.9, and 17.6 mg, and the injection doses of radioactivity were 364, 420, and 304 MBq, respectively. Among the 6 healthy volunteers included in Trial 2, 3 were male and 3 were female, with an age of (46±11) years, ranging from 35 to 63 years. The dose of radioactivity injected was (80±7) MBq, ranging from 69 to 87 MBq. Among the 9 patients included in Trial 3, 5 were male and 4 were female, with an age of (54±10) years, ranging from 39 to 69 years. The dose of radioactivity injected was (777±74) MBq, ranging from 740 to 925 MBq. After intravenous infusion of 131I-labeled mepuzumab, the blood radioactivity concentration reached the peak 1.5 hours later. 131I-labeled mepuzumab mainly bound to blood cells, and its whole-blood clearance half-life was 420 hours. The urine radioactivity concentration reached the peak 16-24 hours after administration and then gradually decreased after 24 hours of administration. After intravenous injection of 68Ga-labeled Sgc8, the organs with strong to weak radioactive signals were bladder, kidney, heart, uterus, liver, spleen, gallbladder, large intestine and lung. Within 3 hours after drug administration, the clearance rate was fastest in heart, followed by uterus, kidney, and liver; the clearance rate was slower in spleen and gallbladder and were slowest in large intestine and lung. All of the 9 patients had abnormal radioactivity accumulation 4 hours after intravenous injection of 99mTc-labeled octreotide and the immunohistochemical staining results of biopsy tissues showed strong positive expression of SSTR2, indicating that 99mTc-labeled octreotide had good affinity and targeting to SSTR2. The safety evaluation showed that in Trail 1, one subject developed iodine-related hyperthyroidism one month after intravenously infusion of 131I-labeled mepuzumab, which returned to normal after 8 months of continuous monitoring without intervention. No adverse reactions occurred in other subjects. Conclusions:Radioisotope tracer technology can noninvasively, dynamically, and visually evaluate the pharmacokinetics, biological distribution, and targeting of biological drugs in human body. It has good safety and great application value in the clinical evaluation of biological drugs.

Objective:To explore the application value of radioisotope tracer technology in clinical research of biological drugs.Methods:The pharmacokinetic properties of mepuzumab in healthy volunteers were evaluated by measuring the radioactive concentrations of iodine in blood and urine samples of 3 healthy volunteers at different time points within 14 days after intravenous infusion of 131I-labeled international class I new drug mepuzumab (Trial 1). Positron emission computed tomography (PET/CT) was performed on 6 healthy volunteers after intravenous injection of 68Ga-labeled nucleic acid aptamer Sgc8, and the standard uptake values of 68Ga-Sgc8 in different organs were measured to evaluate its biodistribution in healthy humans (Trial 2). Nine patients with suspected neuroendocrine tumors underwent single photon emission and X-ray computed tomography (SPECT/CT) 4 hours after intravenous injection of 99mTc-labeled octreotide to determine the radioactive uptake level in the regions of interest; the affinity and targeting of 99mTc-labeled octreotide to somatostatin receptor subtype 2 (SSTR2) were evaluated in combination with the immunohistochemical staining results of SSTR2 in patients′ biopsy tissues (Trial 3). Results:The 3 healthy volunteers included in Trial 1 were male, aged 28, 45, and 25 years respectively; the injection doses of 131I-labeled mepuzumab were 21.0, 25.9, and 17.6 mg, and the injection doses of radioactivity were 364, 420, and 304 MBq, respectively. Among the 6 healthy volunteers included in Trial 2, 3 were male and 3 were female, with an age of (46±11) years, ranging from 35 to 63 years. The dose of radioactivity injected was (80±7) MBq, ranging from 69 to 87 MBq. Among the 9 patients included in Trial 3, 5 were male and 4 were female, with an age of (54±10) years, ranging from 39 to 69 years. The dose of radioactivity injected was (777±74) MBq, ranging from 740 to 925 MBq. After intravenous infusion of 131I-labeled mepuzumab, the blood radioactivity concentration reached the peak 1.5 hours later. 131I-labeled mepuzumab mainly bound to blood cells, and its whole-blood clearance half-life was 420 hours. The urine radioactivity concentration reached the peak 16-24 hours after administration and then gradually decreased after 24 hours of administration. After intravenous injection of 68Ga-labeled Sgc8, the organs with strong to weak radioactive signals were bladder, kidney, heart, uterus, liver, spleen, gallbladder, large intestine and lung. Within 3 hours after drug administration, the clearance rate was fastest in heart, followed by uterus, kidney, and liver; the clearance rate was slower in spleen and gallbladder and were slowest in large intestine and lung. All of the 9 patients had abnormal radioactivity accumulation 4 hours after intravenous injection of 99mTc-labeled octreotide and the immunohistochemical staining results of biopsy tissues showed strong positive expression of SSTR2, indicating that 99mTc-labeled octreotide had good affinity and targeting to SSTR2. The safety evaluation showed that in Trail 1, one subject developed iodine-related hyperthyroidism one month after intravenously infusion of 131I-labeled mepuzumab, which returned to normal after 8 months of continuous monitoring without intervention. No adverse reactions occurred in other subjects. Conclusions:Radioisotope tracer technology can noninvasively, dynamically, and visually evaluate the pharmacokinetics, biological distribution, and targeting of biological drugs in human body. It has good safety and great application value in the clinical evaluation of biological drugs.