The role of [99mTc]Tc-HFAPi SPECT/CT in patients with malignancies of digestive system: first clinical experience.

BACKGROUND: Recently, PET/CT imaging with radiolabelled FAP inhibitors (FAPIs) has been widely evaluated in diverse diseases. However, rare report has been published using SPECT/CT, a more available imaging method, with [99mTc]Tc-labelled FAPI. In this study, we evaluated the potential effect of [99mTc]Tc-HFAPi in clinical analysis for digestive system tumours. METHODS: This is a single-centre prospective diagnostic efficiency study (Ethic approved No.: XJTU1AF2021LSK-021 of the First Affiliated Hospital of Xi'an Jiaotong University and ChiCTR2100048093 of the Chinese Clinical Trial Register). Forty patients with suspected or confirmed digestive system tumours underwent [99mTc]Tc-HFAPi SPECT/CT between January and June 2021. For dynamic biodistribution and dosimetry estimation, whole-body planar scintigraphy was performed at 10, 30, 90, 150, and 240 min post-injection in four representative patients. Optimal acquisition time was considered in all the patients at 60-90 min post-injection, then quantified or semi-quantified using SUVmax and T/B ratio was done. The diagnostic performance of [99mTc]Tc-HFAPi was calculated and compared with those of contrast-enhanced CT (ceCT) using McNemar test, and the changes of tumour stage and oncologic management were recorded. RESULTS: Physiological distribution of [99mTc]Tc-HFAPi was observed in the liver, pancreas, gallbladder, and to a lesser extent in the kidneys, spleen and thyroid. Totally, 40 patients with 115 lesions were analysed. The diagnostic sensitivity of [99mTc]Tc-HFAPi for non-operative primary lesions was similar to that of ceCT (94.29% [33/35] vs 100% [35/35], respectively; P = 0.5); in local relapse detection, [99mTc]Tc-HFAPi was successfully detected in 100% (n = 3) of patients. In the diagnosis of suspected metastatic lesions, [99mTc]Tc-HFAPi exhibited higher sensitivity (89.66% [26/29] vs 68.97% [20/29], respectively, P = 0.03) and specificity (97.9% [47/48] vs 85.4% [41/48], respectively, P = 0.03) than ceCT, especially with 100% (24/24) specificity in the diagnosis of liver metastases, resulting in 20.0% (8/40) changes in TNM stage and 15.0% (6/40) changes in oncologic management. CONCLUSION: [99mTc]Tc-HFAPi demonstrates a greater diagnostic efficiency than ceCT in the detection of distant metastasis, especially in identifying liver metastases.

SOX18 exerts tumor-suppressive functions in papillary thyroid carcinoma through inhibition of Wnt/ß-catenin signaling.

Sex-determining region on the Y chromosome-related high mobility group box 18 (SOX18) has emerged as a key tumor-related protein in a wide range of human tumors. Yet, the involvement of SOX18 in papillary thyroid carcinoma has not been determined. This study aimed to explore the expression and biological function of SOX18 in papillary thyroid carcinoma. There was a significant decrease in SOX18 expression in papillary thyroid carcinoma tissues compared with that in normal tissues. Low expression of SOX18 was also detected in papillary thyroid carcinoma cell lines and upregulation of SOX18 effectively repressed the proliferative, colony-forming and invasive abilities of papillary thyroid carcinoma cells in vitro. In contrast, knockdown of SOX18 in papillary thyroid carcinoma cells was associated with a significant increase in cell proliferation and invasion. Further studies revealed that SOX18 upregulation was associated with the reduced nuclear accumulation of ß-catenin and the downregulation of Wnt/ß-catenin signaling in thyroid carcinoma cells. Moreover, inhibition of Wnt/ß-catenin signaling markedly attenuated SOX18 knockdown-evoked oncogenic effects in papillary thyroid carcinoma cells. In addition, SOX18 overexpression remarkably retarded the tumor growth of papillary thyroid carcinoma cell-derived xenograft tumors in nude mice. Taken together, these results demonstrate that SOX18 suppresses the proliferation and invasion of papillary thyroid carcinoma by inhibiting Wnt/ß-catenin signaling. Our study reveals a tumor-suppressive role of SOX18 in papillary thyroid carcinoma and suggests that SOX18 is an attractive candidate target for treatment of papillary thyroid carcinoma.

A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway.

In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O2-), hydroxyl radical (·OH) and peroxynitrite anion (ONOO-) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury.

miR-539 enhances chemosensitivity to cisplatin in non-small cell lung cancer by targeting DCLK1.

microRNAs (miRNAs) have been implicated to play critical roles in non-small celllung cancer (NSCLC) progression and participate in the regulation of drug resistance during cancer chemotherapy. However, the underlying molecular mechanism of how miR-539 modulates the chemosensitivity to cisplatin (DDP) in NSCLC cells remains largely unknown. In this study, we found that miR-539 was significantly downregulated in DDP-resistant cell lines (A549/DDP and H1299/DDP). Overexpression of miR-539 enhanced the sensitivity of DDP-resistant NSCLC cells to DDP by suppressing cell proliferation, causing cell cycle arrest, inducing apoptosis, repressing invasion and migration. Whereas, downregulation of miR-539 inhibited the sensitivity of parental NSCLC cells to DDP by promoting cell proliferation and decreasing DDP-induced apoptosis. Furthermore, the luciferase report assay identified doublecortin-like kinase 1 (DCLK1) was a direct target of miR-539. Knockdown of DCLK1 mimicked the function of miR-539-mediated cell chemosensitivity in DDP-resistant NSCLC cells, while restoration of DCLK1 reversed the effect of miR-539 overexpression. We also found that P13 K/AKT/mTOR signaling pathway was also involved in miR-539/DCLK1 axis -mediated chemosensitivity in DDP-resistant NSCLC cells. Additionally, the downregulation of miR-539 was closely correlated with severe clinicopathological parameters including the upregulation of DCLK1, chemosensitivity to DDP, and tumor aggressiveness in NSCLC patients. In conclusion, miR-539 increased the chemosensitivity to DDP in NSCLC cells by directly targeting DCLK1, which might provide potential biomarkers for DDP-resistant NSCLC therapy.

A novel Danshensu/tetramethylpyrazine derivative induces vasorelaxation on rat aorta and exerts cardioprotection in dogs.

ADTM, a previously reported novel Danshensu (DSS)/tetramethylpyrazine (TMP) derivative with cardioprotective and antiplatelet aggregative effects, is a promising therapeutic candidate for ischemic heart diseases. In the present study, ADTM increased coronary blood flow and protected myocardium against ischemic injury in dogs. In addition, the relaxing effect of ADTM on rat thoracic aorta and its underlying mechanisms were examined. ADTM relaxed KCl- and phenylephrine-precontracted arotic rings in a concentration-dependent manner. The relaxation by ADTM was greater than that by DSS, TMP and the mixture of DSS and TMP. ADTM induced endothelium-independent relaxation, which couldn't be abolished by removal of endothelium and the preincubation with inhibitors of nitric oxide synthase (L-NAME) and guanylate cyclase (ODQ). Potassium channel blockers including tetraethylammonium, BaCl2 and glibenclamide failed to inhibit the relaxation by ADTM. In addition, cyclooxygenase (COX), muscarine receptor and ß-adrenoceptor were not involved in ADTM-induced vasorelaxation. ADTM inhibited contraction induced by CaCl2 and phenylephrine in Ca2+-free buffer, suggesting that ADTM inhibited both extracellular Ca2+ influx and intracellular Ca2+ release. Taken together, the vasorelaxation of ADTM may be possibly involved in its cardioprotection. ADTM may serve as a promising candidate for the treatment of ischemic heart diseases.

A Novel Danshensu-Tetramethylpyrazine Conjugate DT-018 Provides Cardioprotection by Preserving Mitochondrial Function Through the MEF2D/PGC-1α Pathway.

In this work, we explored the protective effect of DT-018, a danshensu and tetramethylpyrazine conjugate, on mitochondrial injury induced by tert-butylhydroperoxide (t-BHP) and its possible mechanisms of action. DT-018 effectively quenched intracellular and mitochondrial reactive oxygen species (ROS), preserved the mitochondrial function, restored the intracellular level of ATP and augmented mitochondrial membrane potential (Δψm) while suppressed mitochondrial swelling in isolated myocardial mitochondria. DT-018 increased the expression of MEF2D and PGC-1α as well as Nrf2 and Tfam in H9c2 cells. Transfection of MEF2D-siRNA and PGC-1α-siRNA down-regulated the protein expression of PGC-1α and partially abolished the cardioprotection of DT-018 in t-BHP injured cells. For the in vivo studies, administration of DT-018 significantly alleviated infarct area induced by ischemia and reperfusion injury. These observations demonstrated that the cardioprotective effect of DT-018 is mediated, at least in part, by preservation of mitochondrial integrity through up-regulation of MEF2D/PGC-1α pathway.

Comparison between technetium-99m methoxyisobutylisonitrile scintigraphy and ultrasound in the diagnosis of parathyroid adenoma and parathyroid hyperplasia.

OBJECTIVE: The aim of this study was to evaluate the value of technetium-99m methoxyisobutylisonitrile (Tc-MIBI) imaging and ultrasound in preoperative localization of parathyroid adenoma (PA) and parathyroid hyperplasia (PH). PARTICIPANTS AND METHODS: A retrospective study of Tc-MIBI double-phase scintigraphy (DPS) was performed in 187 hyperparathyroidism cases with pathologically diagnosed PA or PH. Of these patients, 167 cases underwent ultrasound, and 146 cases underwent Tc-MIBI single-photon emission computed tomography/computed tomography (SPECT/CT). The sensitivity and diagnostic accuracy of ultrasound, Tc-MIBI DPS, and SPECT/CT were compared between PA and PH. Differences in Tc-MIBI DPS, serum parathyroid hormone (PTH), serum calcium and phosphorus, as well as the weight and longest diameter of lesion between PA and PH were also compared. RESULTS: As per patient-based analysis, the sensitivity of ultrasound, Tc-MIBI DPS, and SPECT/CT was 90.70% (39/43), 95.56% (43/45), and 100.00% (30/30), respectively, for PA, and 93.55% (116/124), 90.85% (129/142), and 93.10% (108/116), respectively, for PH. There were no significant differences in sensitivity of these three imaging methods between PA and PH. However, per lesion-based analysis, the accuracy of ultrasound, Tc-MIBI DPS, and SPECT/CT in detecting PA was 78.43% (40/51), 86.79% (46/53) and 96.88% (31/32), respectively, and the accuracy of Tc-MIBI DPS was higher than that of ultrasound (χ=6.507, P=0.011), and for PH, it was 49.69% (160/322), 40.71% (171/420), and 43.80% (152/347), respectively. The accuracy of ultrasound was higher than that of Tc-MIBI DPS (χ=5.940, P=0.015). The accuracy of a combination of all three examinations of ultrasound+Tc-MIBI DPS, ultrasound+Tc-MIBI SPECT/CT, Tc-MIBI DPS+SPECT/CT, and ultrasound+Tc-MIBI DPS+Tc-MIBI SPECT/CT was 51.51% (154/299), 53.85% (161/299), 50.17% (150/299), and 54.18% (162/299), respectively, which was higher than that of ultrasound (χ=5.273, P=0.022; χ=8.226, P=0.004; χ=3.880, P=0.049; χ=8.702, P=0.003, respectively). Serum levels of PTH and phosphorus were lower in patients with PA than in patients with PH (P<0.001), and serum calcium level, the weight, and the longest diameter of lesion and early uptake rate of Tc-MIBI DPS were higher in patients with PA than in patients with PH (P<0.01). Serum PTH level is often less than 1000 pg/ml in PA, but usually more than 1000 pg/ml in PH. CONCLUSION: Ultrasound, Tc-MIBI DPS, and SPECT/CT all have a higher value in the diagnosis of PA than PH. Tc-MIBI SPECT/CT should be optimal for detecting PA, and early SPECT/CT scan might be better than delayed scan. Compared with Tc-MIBI DPS and SPECT/CT, ultrasound has a slight advantage in localization of PH lesions. The combination of ultrasound and Tc-MIBI DPS or SPECT/CT imaging could improve the accuracy in localization of PH lesions and should be considered as the first-line method for detecting PH.

Experimental and clinical observations of 99mTc-MIBI uptake correlate with P-glycoprotein expression in lung cancer.

BACKGROUND: 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) has been used as a tumour positive scintigraphic agent for diagnostic purposes. However, the pharmaceutical kinetics and accumulation patterns of 99mTc-MIBI in tumour tissues (both in vitro and in vivo) remained poorly understood. Using human embryonic lung fibroblasts (HLFs) as a control, we investigated the kinetics of 99mTc-MIBI accumulation in four human cancer cell lines. RESULTS: We found that, among the tested groups, the uptake rate (UR) of 99mTc-MIBI in normal lung fibroblast cells was the lowest at 90 min after injection, while the UR of four groups of carcinoma cells increased significantly. A significant change of the UR value was observed under cellular depolarization and hyperpolarization. Interestingly, we found that malonic acid, a respiratory chain inhibitor, could inhibit UR rates by 27% from the lowered level in hyper-potassium condition. We also used a semi-quantitative method to analyse 99mTc-MIBI imaging results from 93 clinical cases of pathologically or cytologically confirmed lung cancer lesions. We found that the UR value of a lung benign lesion group was significantly lower than that of a malignant lesion group. We conclude that the sensitivity, specificity and accuracy of 99mTc-MIBI imaging for the lung occupied cancer lesions were 89.83%, 79.41% and 86.02%, respectively. We also investigated the relationship between P-gp expression and MIBI uptake in 25 clinical cases. CONCLUSION: These observations demonstrate a close relationship between the state of 99mTc-MIBI accumulation and the metabolic level of tumour cells and the P-gp expression. Our data suggest that 99mTcc-MIBI semi-quantitative imaging is useful for the qualitative diagnosis of lung-occupied cancer lesions and may be a potential predictor of the P-gp expression in the clinic.

Establishing a new formula for estimating renal depth in a Chinese adult population.

We aimed to establish a new formula for estimating renal depth, based on anthropometric variables, and to compare the estimates with actual data from a group of living kidney donors undergoing computed tomography angiography (CTA).Renal depths in 167 living kidney donors were measured by CTA. Regression analysis was used to derive the formulae for estimation of renal depth of both kidneys based on patient age, sex, body height, body weight, and body mass index (BMI). The results of the renal depth estimation from the derived formulae were compared with those using existing formulae.Using regression analysis, we derived 2 new formulae as follows; for left kidney, renal depth (cm) = 0.083 × W - 0.058 × H + 11.541 (male) or 10.89 (female), for right kidney, renal depth (cm) = 13.498 × W/H + 2.141 (male) or 1.816 (female), in which W represents the weight (kg) and H represents the height (cm). The correlation coefficients between our left or right renal depth estimates and those obtained from other formulae in another 271 kidney donors were 0.864 (left) or 0.893 (right) by the Tønnesen, 0.937 (left) or 0.97 (right) by the Taylor, 0.937 (left) or 0.97 (right) by the Itoh, 0.927 (left) or 0.951 (right) by the Li-qian, and 0.937 (left) or 0.97 (right) by the Inoue formula.Our formula may be more precise than the Tønnesen formula in estimating the renal depth. Estimating formulae based on CT findings might be useful in clinical practice.

[Diagnostic efficacy of 99Tcm-MIBI SPECT/CT and 18F-FDG coincidence SPECT/CT for solitary pulmonary nodules: a comparative study].

OBJECTIVE: To compare the diagnostic accuracy of (99)Tc(m)-MIBI SPECT/CT and (18)F-FDG coincidence SPECT/CT for solitary pulmonary nodules. METHODS: A total of 88 cases suspected of solitary pulmonary nodules were analyzed retrospectively, of whom 36 were examined with (18)F-FDG coincidence SPECT/CT and 52 with (99)Tc(m)-MIBI SPECT/CT. The nature of the solitary pulmonary nodules (malignant or benign) were determined according to the pathological or follow-up (>2 years) results. The diagnostic accuracy of the two modalities for solitary pulmonary nodules was evaluated by ROC curve. The correlation of the lesion size and pathological grade determined by the two modalities with the L/N ratio was assessed using Spearman correlation analysis. RESULTS: (18)F-FDG coincidence SPECT/CT and (99)Tc(m)-MIBI SPECT/CT showed a similar area under curve (AUC) of the L/N ratio (0.92 vs 0.88, P=0.565) with diagnostic sensitivities of 76.92% (20/26) and 80.77% (21/26) and specificities of 100% (10/10) and 88.46% (23/26), respectively. For solitary pulmonary nodules with lesion diameter ≤2 cm, the AUC was 1.00 with (18)F-FDG coincidence SPECT/CT and 0.90 with (99)Tc(m)-MIBI SPECT/CT (P=0.746), while for nodules beyond 2 cm but below 3 cm, the AUCs were 0.79 and 0.89, respectively (P<0.001). In either of the two modalities, correlation analysis revealed no correlation of the L/N ratio with the pathological grade of the malignant lesions (P=0.771 and 0.077, respectively). The L/N ratio was not correlated with the size of the malignant lesion detected by (99)Tc(m)-MIBI SPECT/CT (P=0.516) but was significantly correlated with the size of the malignant lesions detected by (18)F-FDG coincidence SPECT/CT (P=0.016). CONCLUSION: (99)Tc(m)-MIBI SPECT/CT has a greater diagnostic accuracy than (18)F-FDG coincidence SPECT/CT for solitary pulmonary nodules with lesion a diameter beyond 2 cm, and is therefore the primary choice for low-income patients.

Effects of GM-CSF on the stem cells mobilization and plasma C-reactive protein levels in patients with acute myocardial infarction.

BACKGROUND: Stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) has been proposed to improve cardiac function and prevent ventricular remodeling after acute myocardial infarction (AMI) in preclinical and clinical studies. It has been demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) can improve collateral flow in patients with coronary artery disease. In this study, we used GM-CSF to mobilize the bone marrow stem cells (BMSCs) in patients with AMI and assessed the safety, feasibility and efficacy of this treatment. METHODS: Twenty patients with AMI were randomly divided into GM-CSF group (10 microg/kg body weight, for 7 days) and control group (saline). The absolute counts of CD34 positive cells in peripheral blood were enumerated with flow cytometry. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrotic factor-alpha (TNF-alpha) were measured on days 1, 3, 7, 10 and 14. Echocardiography (UCG) was done on day 7 and after 12 months. RESULTS: Peripheral CD34 positive cells in GM-CSF patients obviously increased shortly after using GM-CSF and peaked on day 7 (p<0.01 versus controls). GM-CSF group had significantly higher mean level of plasma CRP than controls on day 10 (p<0.05). The levels of IL-6 and TNF-alpha in therapy patients were as same as in controls. Left ventricular ejection fraction (EF) at 12 months was significantly greater than that on day 7 in GM-CSF patients (p<0.05). The EF in controls had no obvious differences in follow-up. There were no statistically differences regarding the left ventricular end-systolic volume (LVESV), the left ventricular end-diastolic volume (LVEDV) and the resting wall thickening (WT) in the infarct zone in two groups in follow-up. CONCLUSIONS: Our results demonstrate that GM-CSF can effectively mobilize the CD34 positive cells and at the same time may increase the levels of plasma CRP in patients with AMI. The remote effects of this drug need to be further defined.