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The emergence of acquired drug resistance through therapeutic treatment remains a critical threat to efficient chemotherapy, target therapy, or immune therapy. These resistant cancer cells most often lead to relapse or metastasis. The development of drug resistance is a multi-step evolutionary adaptation for cancer cells. Tumor heterogeneity, cancer cells’ plasticity, and microenvironment contribute to the resistant clone’s formation. Therefore, a time-lapse adaptation model is critical to define the mechanism of drug resistance evolution. Recently, several studies have revealed that the initial acquired drug resistance might be conferred by transient events, such as drug-tolerant persisters (DTP) that might occur in a subpopulation of the cancer cells at the early stage of the treatment, which were then followed by the transcriptomic reprogramming and secondary-wave genetic mutations in the progression of resistance development. In the clinic, chemotherapy is still the mainstream treatment for TNBC, and one of the primary chemo agents is doxorubicin. Although the initial responsive rate of doxorubicin-based chemotherapy is up to 70%, it is well recognized that TNBC cells usually generate an evolutionary adaptive response that can result in the acquired drug-resistance and multi-drug resistant phenotypes. To date, numerous different mechanisms of acquired chemo-resistance have been reported, but the vast majority of these results have been derived from the continuous-high-dose-exposure acquired resistant cell line models. Since the chemo-treatment dosage in these artificial models is well above what is physiologically achievable in patients, few of them can mimic the actual situation of resistance development or improve the clinical trial outcomes. Moreover, most of these studies only characterized the terminal resistant cells, which are challenging to be resensitized because of their dominant genetic mutations. In this study, we hypothesize that the TNBC chemo-resistant cells may derive from the early-stage reversible chemo-tolerant “DTP-like” (CTP) cells, and early-stage epigenetic landscape perturbation might determine the progression of chemo-resistance development. To test the hypothesis and overcome the previous model limitations, based on the clinical drug exposure kinetics for doxorubicin, we developed an in vitro “pulsing-treatment CTPs regrowth” model (referred to as CTP model), which could mimic the clinical treatment and provide therapeutically relevant insights into the initial drug-induced stress response and resistance development. Leveraging this CTP model, we are able to define the early event for drug response, in which the doxorubicin-treated cells showed a senescence-like phenotype, and the interferon alpha (type I) pathway was activated. Furthermore, unexpectedly, we found that the expression of HERVs was significantly activated but LINE1s not. To further explore the TEs reactivation, we did the single cell RNA-seq for 0h, 2h, and 4 days samples. With a novel bioinformatic workflow, we integrated the TE expression information with coding genes mRNA profiling from the same single cell RNA-seq dataset and identified the IFN-enriched cluster had higher expression of HERVs. Herein, a subpopulation of HERVhigh cells with IFN activation was identified as a “hot-cluster” which might be the early determinant in the resistance evolution. Citation Format: Zijian Zhang, Yiyang Wang, Xinluo Luo, Xuwen Li, Xiaomei Zhan, Yumin Zheng, Jun Ding, Tao Wu. The Aberrant Activity of Retrotransposon Elements Mediates the Chemo-tolerant Persister Cells Relapse in TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-02.

Background. Immune checkpoint inhibitors (ICIs) have changed the situation of tumor therapy in recent years. However, for security reasons, those special populations are often excluded from clinical trials, such as infected hepatitis B or hepatitis C patients. ICIs are systematically reviewed and meta-analyzed for the first time in patients infected with hepatitis B or C in this paper. Methods. The relevant studies were searched in PubMed, EMBASE, Cochrane Library, and Web of Science until October 2022. Trials and observational studies meeting the inclusion criteria were included. The outcomes included the effectiveness of ICIs in patients with HBC/HCV (ORR, DCR, mOS, and mPFS), the incidence of adverse reactions, high-grade adverse reactions, and abnormal liver enzymes. At the same time, these indexes were compared with those of uninfected patients. Results. A total of 2,625 patients were enrolled, involving 1,179 patients with hepatitis (HBV or HCV). We found that ICIs showed higher ORR (25.80% vs. 18.10%) and DCR (66.22% vs. 58.74%) in patients with hepatitis B/C than those without infection. In terms of survival time, patients with hepatitis virus infection showed longer mOS (15.44 m vs. 13.30 m) but shorter mPFS (4.94 m vs. 5.01 m) than uninfected patients. As for safety data, patients with hepatitis showed a lower incidence of all-grade irAEs (68.02% vs. 70.43%) than uninfected patients, while that of 3-4 irAEs (21.27% vs. 21.79%) was similar in the two groups. However, hepatic dysfunction was more common and serious in hepatitis patients. Four HBVr and no HCVr were observed. Conclusion. According to this meta-analysis, ICIs are effective and safe for patients with hepatitis B or C, but basic liver enzymes have to be evaluated before treatment to avoid liver adverse events.

The aim of this prospective multi-center study was to investigate the diagnostic value of myocardial blood flow (MBF) quantification using NaI(Tl)-based single-photon emission computed tomography (SPECT) for determining coronary artery disease (CAD) defined by quantitative coronary angiography (QCA).Absolute quantitation of MBF and myocardial flow reserve (MFR) using SPECT is clinically feasible; however, whether flow quantification using NaI(Tl) SPECT is superior to commonly performed SPECT myocardial perfusion imaging (MPI) in determining CAD has not been evaluated.Patients with suspected or known CAD underwent pharmacological stress/rest dynamic SPECT imaging and routine SPECT MPI followed by QCA. Obstructive disease was defined as ≥ 50% reduction in luminal diameter on QCA.One hundred fifty-four patients (462 vessels) were included in the analysis. Obstructive CAD was detected in 76/154 patients (49.4%) and 112/462 vessels (24.2%). Optimal cut-off values were 1.86 mL/min/g for stress MBF and 1.95 for MFR, respectively. Stress MBF and MFR were more sensitive than MPI in both individual patients (stress MBF vs MPI: 81.6% vs 51.3%; MFR vs MPI: 72.4% vs 51.3%) and in coronary vascular regions (stress MBF vs MPI: 78.6% vs 31.3%; MFR vs MPI: 75.9% vs 31.3%; all P .01). In receiver operating characteristic curve analysis, quantification revealed a significantly greater area under the curve than MPI at the patient (stress MBF vs MPI: 0.761 vs 0.641; MFR vs MPI: 0.770 vs 0.641) and the vessel (stress MBF vs MPI: 0.745 vs 0.613; MFR vs MPI: 0.756 vs 0.613; all P .05) levels. Integrating quantitative SPECT measures with MPI significantly increased the area under the curve and improved the discriminatory and reclassification capacity.Flow quantification using NaI(Tl) SPECT provides superior sensitivity and discriminatory capacity to MPI in detecting significant stenosis. Clinical trial registration NCT03637725.

This work focused on the exploration of NEAT1 in Parkinson's disease (PD) and aimed to explore its effects on PD and related molecular mechanisms. Two experimental models were initially constructed, including MPTP-induced mice in vivo and the MPP+-induced SH-SY5Y cell line in vitro. Immunofluorescence assays were conducted to determine the TH+ positive cell rate. Pole tests and rotarod tests were also performed for the visualization of behavioral changes in mice. Cellular apoptosis was determined using MTT and flow cytometry assays. Changes in the number of autophagosomes were obtained under a transmission electron microscope. The content of dopamine was confirmed by high performance liquid chromatography. The targeted interrelationship between miR-107-5p and NEAT1 was clarified via dual-luciferase reporter gene assays. Meanwhile, mRNA and protein expressions were also detected using qRT-PCR and Western blot respectively. Furthermore, the level of NEAT1 was positively correlated with MPP+ concentration. Interfering with NEAT1 in the present study promoted cellular proliferation and mediated SH-SY5Y cell apoptosis and autophagy treated with MPP+. An increase was discovered in TH positive neurons and suppressive autophagy in PD mice. miR-107-5p was then considered as a NEAT1 putative target involving apoptosis and autophagy of SH-SY5Y cells. Interfering with NEAT1 efficiently facilitated the viability of SH-SY5Y cells and drastically suppressed autophagy and apoptosis of PD mice induced by MPTP- via elevating miR-107-5p level, which indicated that lncRNA NEAT1 acted as a latent therapeutic factor for PD treatment.

Li Dong,1 Yu-Min Zheng,2 Xiao-Guang Luo,3 Zhi-Yi He2 1Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of South University of Science and Technology, The Second Clinical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, People’s Republic of ChinaCorrespondence: Xiao-Guang LuoDepartment of Neurology, The First Affiliated Hospital of South University of Science and Technology, The Second Clinical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, People’s Republic of ChinaEmail guanche537@126.comZhi-Yi HeDepartment of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of ChinaEmail yizizhan40559@163.comBackground: Parkinson’s disease is a common neurodegenerative disease in the elderly. The incidence of various cancers in Parkinson’s disease patients is significantly lower than in healthy people. Parkinson’s disease patients are individuals with a high tendency for inflammation, whose peripheral immune system is represented in an activated state. We hypothesized that the hyperinflammatory predisposition of Parkinson’s disease patients is pathogenic.Methods: DBA/1 mice were used to simulate “highly inflammatory individuals”, and the carcinogen DEN was used to induce malignancy. Hematoxylin & eosin (H&E) staining was used to observe the formation of lung tumors. Apoptosis of neurons was observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Immunohistochemistry and flow cytometry were used to observe CD4, CD28, major histocompatibility complex II (MHCII), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and programmed death 1 (PD-1). The ionized calcium binding adaptor molecule-1 (IBA-1) + inducible nitric oxide synthase (iNOS) was used to label M1 microglia, and IBA-1 + arginase 1 (Arg1) was used to label M2 microglia by immunofluorescence. The expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and anti-inflammatory cytokines IL-10 and IL-4 was detected by ELISA.Results: DBA/1 mice with high inflammatory tendency showed a continuous increase of peripheral inflammation, promoting intracranial inflammation, decreasing the tumor incidence and increasing the neurodegeneration under induction of malignant change. CD28 and CTLA-4/PD-1 reduced the T-cell-dominated inflammatory response, reduced the intracerebral inflammatory response, protected from neurodegeneration, and increased the incidence of tumor. Combination of CTLA-4 and PD-1 blocker can overactivate T cells, worsen peripheral and intracranial inflammation, reduce the incidence of tumor, cause damage to dopamine neurons, and promote the occurrence of neurodegeneration.Conclusion: High inflammatory tendency induced by malignant stimulation through the imbalance of CD28 and CTLA-4/PD-1 leads to dopamine neuron injury.Keywords: high inflammatory tendency, malignant stimulation, CD28, CTLA-4/PD-1, dopamine neuron injury

ObjectiveThe aim of the study was to investigate the clinical, neuropsychological, and regional cerebral blood flow (rCBF) perfusion changes in patients with neuropsychiatric symptoms caused by nitrous oxide (N2O) abuse.MethodsA total of 16 patients with neuropsychiatric symptoms caused by nitrous oxide abuse were recruited for this study. The study was carried out in the withdrawal phase of N2O abuse. A 925–1110 MBq 99mTc-ECD was administered intravenously. SPECT/CT images were collected with a low-energy and high-resolution collimator. The region uptake statistics of different brain regions of interest between patients with N2O abuse and normal people of the databases for younger subjects from the Scenium DB Comparison software were calculated automatically.ResultsThe clinical manifestations of the 16 patients with neuropsychiatric symptoms were mood lability, anxiety, hallucination, delusion, agitation, confusion, and other psychiatric symptoms. In addition, 15 of the patients also complained of memory decline; 14 patients manifested numbness or paresthesia; 14 patients developed limb weakness, and their motor impairments were more severe in the lower limbs than in the upper limbs; and eight patients had urinary and defecation disturbances. In the neuropsychological examination, the BPRS score was 54.69 ± 11.48, the HAMD score was 30.00 ± 11.06, the HAMA score was 18.06 ± 5.77, the MMSE score was 28.06 ± 2.29, and the MoCA score was 25.06 ± 3.40. SPECT showed hypoperfusion in the frontal and temporal lobes, which is consistent with the clinical findings.ConclusionThis was the first study to demonstrate the obvious effect of N2O abuse on CBF in patients with neuropsychiatric symptoms. CBF perfusion imaging is helpful to detect the changes in the local brain functional activity in patients with N2O abuse.

Background Lipid metabolism alternations reprogrammed tumor microenvironment (TME) to participate in clinical response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Body mass index (BMI), clinically used to assess body fat, has been positively correlated with ICIs monotherapy response. Circulating cholesterol is mainly packaged into apolipoproteins B (apoB) in the form of apoB containing lipoproteins, including low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC), which have been regarded as risk factors of tumorigenesis. The association between BMI, lipoproteins, and clinical outcome of ICIs is far from clear. Methods We performed a retrospective case-control analysis of 99 NSCLC patients treated with chemotherapy plus ICIs regimens in the department of oncology and lung cancer center of China-Japan Friendship Hospital between January 2019 to December 2021 and assessed the prognostic value of the BMI, serum lipids, lipoproteins, and apolipoproteins. Efficacy was assessed by response evaluation criteria in solid tumors (RECIST) version 1.1 and evaluated by the ICIs response (durable clinical benefit [DCB] / non-durable benefit [NDB]), best response (active/ non-active) and progression-free survival (PFS). The validation test and the mechanism exploration were performed with public data using bioinformatic methods. Results The contrary results to the ICIs single agents were obtained. BMI ≥ 25 kg/m2 was a risk indicator for NDB, non-active response to ICIs, shorter PFS with the confounders adjusted (OR = 6.06, 95% CI 2.05–19.89, p.val = 0.002; OR = 4.37, 95% CI 1.64–12.43, p.val = 0.004; HR = 3.08, 95% CI 1.63–5.82, p.val 2, the elevated cholesterol-riched apoB containing lipoproteins are promise indicators for the poor ICIs response. Further large-scale validations and experimental explorations are needed.

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy, presenting both structural and metabolic abnormalities in the ipsilateral mesial temporal lobe. While it has been demonstrated that the metabolic abnormalities in MTLE actually extend beyond the epileptogenic zone, how such multidimensional information is associated with the diagnosis of MTLE remains to be tested. Here, we explore the whole-brain metabolic patterns in 23 patients with MTLE and 24 healthy controls using [18 F]fluorodeoxyglucose PET imaging. Based on a multivariate machine learning approach, we demonstrate that the brain metabolic patterns can discriminate patients with MTLE from controls with a superior accuracy (>95%). Importantly, voxels showing the most extreme contributing weights to the classification (i.e., the most important regional predictors) distribute across both hemispheres, involving both ipsilateral negative weights over the anterior part of lateral and medial temporal lobe, posterior insula, and lateral orbital frontal gyrus, and contralateral positive weights over the anterior frontal lobe, temporal lobe, and lingual gyrus. Through region-of-interest analyses, we verify that in patients with MTLE, the negatively weighted regions are hypometabolic, and the positively weighted regions are hypermetabolic, compared to controls. Interestingly, despite that both hypo- and hypermetabolism have mutually contributed to our model, they may reflect different pathological and/or compensative responses. For instance, patients with earlier age at epilepsy onset present greater hypometabolism in the ipsilateral inferior temporal gyrus, while we find no evidence of such association with hypermetabolism. In summary, quantitative models utilizing multidimensional brain metabolic information may provide additional assistance to presurgical workups in TLE.

This pilot study aimed to prove the complementary value of a novel Gallium-labeled heterodimeric peptide, Ga-NOTA-3P-TATE-RGD, in detection and evaluation of tumors with somatostatin receptor subtype 2 or integrin αvβ3 overexpression, including non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), neuroendocrine tumor (NET), and neuroendocrine carcinoma (NEC).With institute review board approval and written informed consent, 32 patients with pathologically diagnosed lung cancer (18 NSCLC, 14 SCLC) and 12 patients with neuroendocrine neoplasm (8 NET, 4 NEC) patients were recruited to undergo Ga-NOTA-3P-TATE-RGD PET/CT. For comparison, the NSCLC patients also underwent Ga-NOTA-TATE PET/CT, the SCLC patients underwent Ga-NOTA-RGD PET/CT, and the neuroendocrine neoplasm patients underwent F-FDG PET/CT within 3 days. The maximum standardized uptake value (SUV) of the primary tumor (T) and mean SUV of the blood pool (B) were measured, and the T/B ratios were calculated for comparison.In the primary tumors of NSCLC, the T/B ratios of Ga-NOTA-3P-TATE-RGD were significantly higher than those of Ga-NOTA-TATE (4.54 ± 3.00 versus 4.10 ± 2.83, P = 0.0058). In SCLC, the T/B ratios of Ga-NOTA-3P-TATE-RGD were significantly higher than those of Ga-NOTA-RGD (6.06 ± 6.09 versus 2.65 ± 1.19, P = 0.0344). In NET, the T/B ratios of Ga-NOTA-3P-TATE-RGD were 36.13 ± 33.84, significantly higher than those of F-FDG (2.91 ± 1.71, P = 0.0234). In NEC, there were no significant difference between the T/B ratios of Ga-NOTA-3P-TATE-RGD (4.80 ± 0.85) and those of F-FDG (3.56 ± 0.74, P = 0.1833).This proof-of-concept study preliminarily demonstrates the efficacy of the dual targeting Ga-NOTA-3P-TATE-RGD PET/CT in the evaluation of lung cancer and neuroendocrine neoplasm in a single scan.

Eating abnormalities are one of the core symptoms of frontotemporal dementia (FTD), especially for behavioral variant FTD (bvFTD), and semantic variant primary progressive aphasia (svPPA). A group of FTD patients (43 bvFTD, 29 svPPA) underwent single-photon emission CT (SPECT) to measure the region cerebral blood flow (rCBF). The Cambridge Behavioral Inventory (CBI) was used to measure the eating abnormalities. A whole-brain voxel-based correlation between eating abnormalities and rCBF was investigated. In bvFTD, the sweet preference was correlated with decreased rCBF in the bilateral gyrus rectus and temporal pole, and eating the same food was correlated with the left ventral anterior cingulate cortex. In svPPA, decreased rCBF in the left inferior temporal gyrus was correlated with eating the same food. These findings showed that either different symptoms in the same subtype or the same symptom in different subtypes of FTD may be correlated with different regions, indicating different neural mechanisms behind them.

e21036 Background: Non-small cell lung cancer(NSCLC) patients(pts) with epidermal growth factor receptor (EGFR) exon 19 deletion have more benefit from EGFR-tyrosine kinase inhibitors(EGFR-TKIs) compared to pts with EGFR exon 21 L858R mutation. Icotinib, which is a first-generation EGFR-TKI had been approved for use in EGFR-positive advanced NSCLC pts. A phase II trial(INCREASE trial) showed that high-dose icotinib 250mg tid(ico250) can effectively prolong the progression-free survival(PFS) of NSCLC pts with exon 21 L858R mutation without increased toxicity. However, the RW evidence is lacking. Methods: In this single-center, single-arm study, data were retrospectively collected from China-Japan Friendship Hospital. Pts with advanced LUAD, harboring EGFR exon 21 L858R mutation, and who received ico250 for more than 20 days without chemotherapy or immunotherapy were reviewed. Clinical data were analyzed for PFS, objective response rate(ORR), disease control rate(DCR), overall survival(OS), duration of treatment(DoT) and adverse events(AEs). Survival factors were evaluated by univariate and multivariate Cox regression analysis. Results: In total 40 pts(14M,26F; median age 67[46-86]; smoker:20.0%; ECOG performance status 0-1/2-3: 33/7) who received ico250 between 4/2019-11/2021 were analyzed. The median line of pre-ico therapies was 1(range 0-2). At the cut-off day, 29(72.5%) pts had discontinued ico250, and 7(17.5%) pts died. Overall, ORR was 30.0%, DCR was 80.0%, median DoT was 8.0mos (95%CI, 3.4-12.6), median PFS was 12.9mos (95%CI, 8.2-17.6) and median OS was not reached. The univariate and multivariate analysis showed that there was no significant and independent factor associated with PFS(all P> 0.05). 30(75.0%) pts experienced AEs, while the most common AEs were rash(24,60.0%), dry skin(9,22.5%), paronychia(8,20.0%) and diarrhea(6,15.0%). Grade 3/4 AEs in 6(15.0%) pts included AST/ALT elevation(3,7.5%), rash(2,5%), diarrhea(1,2.5%) and mucositis(1,2.5%)(1 suffered both rash and mucositis). 5(12.5%) pts discontinued high-dose icotinib due to AEs. Conclusions: These data add to the RW evidence that the efficacy and tolerability of ico250 in advanced LUAD pts harboring EGFR exon 21 L858R mutation. The efficacy results are consistent with the previous INCREASE trial. High-dose icotinib could be considered whatever the previous treatment and basic characteristics of LUAD pts with exon 21 L858R mutation. However, the higher incidence of grade3/4 AEs deserves special attention.

Background Parkinson's Disease is a common neurodegenerative disease in elderly. Parkinson's Disease patients were supposed to have a higher risk of malignant transformation, however, actually the incidence of various cancers in Parkinson's Disease patients is significantly lower than common people.Parkinson's Disease patients are individuals with a high tendency of inflammation, whose peripheral immune represented in an activated state. The secretion of inflammatory factors in peripheral blood of Parkinson's Disease patients is significantly increased. We hypothesized that the hyperinflammatory predisposition of Parkinson's Disease patients is one of pathogenesis. Method: DBA/1 mice were used to simulate highly inflammatory individuals, and the carcinogen DEN was treated for malignant stimulation.HE staining was used to observe the formation of lung tumors.Apoptosis of neurons was observed by TUNEL staining.Immunohistochemical and Flow cytometrywere used to observed the expression of CD4, CD28, MHCII, CTLA-4 and PD-1. IBA-1 + iNOS was used to label M1 type microglias, and IBA-1 + Arg1 was used to label M2 type microglias by immunofluorescence. The contents of pro-inflammatory cytokines TNF-α, IL-1β and anti-inflammatory cytokines IL-10 and IL-4 in serum and brain tissues of mice in each group were detected by ELISA. Results DBA/1 mice with high inflammatory tendency showed continuous increasing of peripheral inflammation, promoting of intracranial inflammation, decreasing the tumor incidence and increasing the neurodegeneration under induction of malignant change.CD28 and CTLA-4/PD-1 reduced the T-cell-dominated inflammatory response, reduce intracerebral inflammatory response, protected the neurodegeneration, and increased the incidence of tumor.Combination of CTLA-4 and PD-1 blocker can over-activate T cells, worsen peripheral and intracranial inflammation, reduce the incidence of tumor, and cause damage to dopamine neurons, promotethe occurrence of neurodegeneration. Conclusions High inflammatory tendency induced by malignant stimulation through imbalance of CD28 and CTLA-4 / PD-1 leading to dopamine neuron injury.

A 34-year-old man suffered intermittent abdominal pain for 1 month, especially after drinking or eating. Enhancement CT was performed to determine the cause, which detected a soft tissue mass in the gastric antrum, suggestive of possible malignancy. FDG PET/CT scan was undertaken for staging, which showed increased metabolism in the known gastric mass, also suggestive of malignancy. However, this lesion was confirmed as ectopic pancreatitis pathologically.

Long non-coding RNAs (lncRNAs) play biological roles in brain disorder and neurodegenerative diseases. As the functions of lncRNA NEAT1 in Parkinson's disease (PD) remain unknown, in the present study, we aimed to explore the roles and underlying molecular mechanisms of NEAT1 in PD. A PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and a cell model of SH-SY5Y induced by N-methyl-4-phenylpyridinium (MPP+) were established. The ratio of tyrosine hydroxylase (TH+) cells was determined by immunofluorescence assay, and the behavioral changes in mice were observed using pole tests and rotarod tests. The cellular viability and apoptosis of SH-SY5Y were detected by MTT assay and flow cytometric analysis, respectively, and the number of autophagosomes was subsequently measured by transmission electron microscopy. High-performance liquid chromatography was performed to detect the content of dopamine, and a dual-luciferase reporter assay was used to clarify the target of NEAT1 simultaneously. The results demonstrated that the level of NEAT1 was upregulated in the MPTP-induced PD mice, dopamine neurons, and the SH-SY5Y cells treated with MPP+, whereas the level of miR-374c-5p was downregulated. NEAT1 level was positively correlated with MPP+ in a concentration-dependent manner. NEAT1 inhibition efficiently facilitated cell proliferation but inhibited apoptosis and autophagy in the MPP+-treated SH-SY5Y cells. Additionally, silencing of NEAT1 increased the TH+ rate of neurons and suppressed autophagy greatly in PD mice. As a possible target of NEAT1, miR-374c-5p could impact on the apoptosis and autophagy of the SH-SY5Y cells. NEAT1 inhibition upregulated the expression of miR-374c-5p, enhanced SH-SY5Y cell viability, and repressed autophagy and apoptosis in MPTP-induced PD mice. These findings indicated a potential therapeutic role of NEAT1 in treating PD.

In eukaryotes, polyadenylation (poly(A)) is an essential process during mRNA maturation. Identifying the cis-determinants of poly(A) signal (PAS) on the DNA sequence is the key to understand the mechanism of translation regulation and mRNA metabolism. Although machine learning methods were widely used in computationally identifying PAS, the need for tremendous amounts of annotation data hinder applications of existing methods in species without experimental data on PAS. Therefore, cross-species PAS identification, which enables the possibility to predict PAS from untrained species, naturally becomes a promising direction. In our works, we propose a novel deep learning method named Poly(A)-DG for cross-species PAS identification. Poly(A)-DG consists of a Convolution Neural Network-Multilayer Perceptron (CNN-MLP) network and a domain generalization technique. It learns PAS patterns from the training species and identifies PAS in target species without re-training. To test our method, we use four species and build cross-species training sets with two of them and evaluate the performance of the remaining ones. Moreover, we test our method against insufficient data and imbalanced data issues and demonstrate that Poly(A)-DG not only outperforms state-of-the-art methods but also maintains relatively high accuracy when it comes to a smaller or imbalanced training set., Author summary The key to understanding the mechanism of translation regulation and mRNA metabolism is to identify the cis-determinants of PAS on the DNA sequence. PAS leads to correct identification of Poly(A) sites which play an essential role in understanding human diseases. While many researchers have employed deep learning methods to improve the performance of PAS identification, an underlying problem is the expensive and time-consuming nature of PAS data collection, which makes the application of deep learning models for identifying PAS from a broad range of species a tough task. We attempt to use domain generalization methods, inspired by its thrive in the field of computer vision, to overcome the insufficient annotation data challenge in PAS data. Here, empirical results suggest that our proposed model Poly(A)-DG can extract species-invariant features from multiple training species and be directly applied to the target species without fine-tuning. Furthermore, Poly(A)-DG is a promising practical tool for PAS identification with its stable performance on insufficient or species-imbalanced training data. We share the implementation of our proposed model on the GitHub. (https://github.com/Szym29/PolyADG).

Vascular cognitive impairment (VCI) refers to the entire form of cognitive decline (from subjective cognitive decline to dementia) caused by the brain vascular pathology. Neuroimaging plays an important role in the diagnosis of VCI. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are widely used in the evaluation of the metabolism and perfusion change in VCI. Recent advancements in molecular imaging allow the in vivo visualization of deposition of abnormal proteins, including amyloid β and tau. In this chapter, we will briefly describe the characteristics of commonly used radio ligand tracers in VCI. And we will discuss the utility of PET and SPECT in the clinical and research field of VCI.

Objectives. Parkinson’s disease (PD) is a common neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons in the substantia nigra. The present study investigated miR-141-3p/sirtuin1 (SIRT1) activity in a 1-methyl-4-phenylpyridinium- (MPP+-) induced PC12-cell model of PD. Methods. PC12 cells were exposed to MMP+ following induction of differentiation by nerve growth factor (NGF). miR-141-3p and SIRT1 expressions were examined using RT-qPCR and western blot. Cell viability was evaluated using the MTT assay. Apoptosis percentage, reactive oxygen species (ROS) production, and mitochondrial membrane potential (Δψm) were evaluated using flow cytometry. Expression of Nuclear factor-kappa B- (NF-κB-) related proteins was determined by western blot. Bioinformatic analysis, RT-qPCR, and luciferase reporter assay were used to confirm the interaction between miR-141-3p and SIRT1. Results. miR-141-3p was upregulated, and SIRT1 was downregulated in MPP+-treated PC12 cells. MPP+ treatment also upregulated nitric oxide synthase 1 (Nos1) and α-synuclein. miR-141-3p induced apoptosis, oxidative stress, mitochondrial dysfunction, and downregulated the SIRT1 mRNA expression. The luciferase reporter assay showed that SIRT1 was the target of miR-141-3p. SIRT1 transfection attenuated apoptosis, ROS production and maintained Δψm. SIRT1 also downregulated Nos1, tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), interleukin 6(IL-6) and upregulated B cell lymphoma 2 (Bcl-2) protein. In addition, SIRT1 activator resveratrol blocked the effects of miR-141-3p mimic on Nos1, α-synuclein, and mitochondrial membrane potential. SIRT1 inhibitor sirtinol reversed the biological effects of miR-141-3p. Conclusion. Increased miR-141-3p induced apoptosis, oxidative stress, and mitochondrial dysfunction in MPP+-treated PC12 cells by directly targeting the SIRT1 expression. Our study provided a potential therapeutic strategy for PD.

Objective Autism is a neurodevelopmental disorder which significantly impacts the quality of people’s life. Oxytocin is a hormone impacting the social cognition and interpersonal trust. In this study, we aimed to explore the role of oxytocin in autism. Methods Autistic mice models were established by valproate. Animal behaviors were assessed by open field test, tail suspension test, marble burying test and three-chamber social interaction test. Oxidative stress was evaluated by the levels or activities of malondialdehyde, superoxide dismutase, glutathion peroxidase, reduced glutathione and reactive oxygen species. Inflammation was assessed by the levels of tumor necrosis factor-α, interleukin-1β and interleukin-6. The number of activated microglia was detected by immunofluorescence with an Iba-1 antibody. Results Our results showed that oxytocin improved the behaviors of autistic mice, with less anxiety, depression and repetitive behavior, and ameliorated social interaction. Further study showed that the elevated oxidative stress and inflammation in autistic mice were alleviated after treatment of oxytocin. Conclusion Our study demonstrates that oxytocin treatment ameliorates autism in a mouse model, maybe through its modulation on oxidative stress and inflammation. It is indicated that oxytocin may beneficial to autism.

Here, we report the diagnosis and treatment of a very rare case of malignant insulinoma derived from ectopic pancreas. A middle-aged woman presented with a 6-year history of recurrent hypoglycemia with multiple lesions in liver. Admission workup revealed elevated serum insulin and C-peptide, as well as multiple lesions in the liver (largest being 4.3 cm), enlarged lymph nodes around the pancreas, and a lesion (of 3.5 cm) at the proximal jejunum, as shown by contrast computed tomography (CT). Liver biopsy showed the lesions to be well-differentiated neuroendocrine tumors, grade G1. 68Gallium-exendin-4 positron emission tomography/CT confirmed the origin as the lesion located at the jejunum. The combination treatment of everolimus plus long-acting octreotide relieved symptoms and achieved a partial tumor response. Maintenance treatment of the somatostatin analog (ie, octreotide) alone was administered. Three years of follow-up, up to the writing of this report, showed good survival, with the patient remaining asymptomatic and euglycemic without disease progression. This case shows that 68Gallium-exendin-4 positron emission tomography/CT is useful for locating insulinoma, especially for insulinoma derived from ectopic pancreas, and that everolimus plus octreotide with maintenance somatostatin analog alone is an effective drug strategy for treating inoperable malignant insulinoma.

In this paper, we address the problem of multi-class semantic segmentation of high resolution aerial imagery with a deep-convolutional-neural-network-based model named D-LinkNet, which was initially designed for the task of road extraction. D-LinkNet extends LinkNet, which is considered as an efficient method for semantic segmentation and adopts encoder-decoder architecture, by inserting dilated convolution layers between LinkNets encoder and decoder to enlarge the receptive field of kernel without reducing the resolution of the feature maps. Besides, we use the multi-class form of the original loss function combined by Dice loss and Binary Cross Entropy loss, which has proven to be effective in classification tasks with imbalanced class distribution that is prevalent for aerial imagery. Experimental results on public available Potsdam dataset demonstrate that D-LinkNet obtains an overall accuracy of 86.1%, which outperforms state-of-the-art methods. Moreover, D-LinkNet achieves a competitive speed in the experiment so it can produce relatively accurate predictions more efficiently.

Apathy is one of the core symptoms in behavioral variant of frontotemporal dementia (bvFTD), and increases patient's morbidity and caregiver's distress. In this study, we applied a graph theoretical analysis (GTA) to analyze the topological properties of cerebral blood flow (CBF) network in 64 bvFTD patients with and without apathy (47 bvFTD-apathy and 17 bvFTD-woapathy, respectively), and 20 normal controls (NCs) based on single photon emission tomography (SPECT). Compared with the NCs, both the bvFTD groups preserved global function and typical features of small-worldness, but exhibited the loss of hubs mainly distributed in the prefrontal cortex (PFC). Compared with bvFTD-woapathy, the bvFTD-apathy group exhibited additional loss of hubs in the ventral PFC areas, middle cingulate cortex, limbic and paralimbic system, and subcortical regions, but recruited hubs in the areas of angular gyrus, precuneus and posterior cingulate cortex. Overall, our findings support the hypothesis that the disruption of frontostriatal circuit is associated with apathy in bvFTD.

Introduction In this study, novel 99m Tc(III)-azide complexes [ 99m Tc(N 3 )(CDO)(CDOH) 2 B-R] ( 99m Tc-ISboroxime-N 3 : R=IS; 99m Tc-MPboroxime-N 3 : R=MP; 99m Tc-PAboroxime-N 3 : R=PA; 99m Tc-PYboroxime-N 3 : R=PY; and 99m Tc-Uboroxime-N 3 : R=5U) were evaluated as heart imaging agents. Methods Complexes [ 99m Tc(N 3 )(CDO)(CDOH) 2 B-R] (R=IS, MP, PA, PY and 5U) were prepared by ligand exchange between NaN 3 and [ 99m TcCl(CDO)(CDOH) 2 B-R]. Biodistribution and imaging studies were carried out in Sprague–Dawley rats. Image quantification was performed to compare their initial heart uptake and myocardial retention. Results 99m Tc-ISboroxime-N 3 , 99m Tc-PYboroxime-N 3 and 99m Tc-Uboroxime-N 3 were prepared with high RCP (93–98%) while the RCP of 99m Tc-MPboroxime-N 3 and 99m Tc-PAboroxime-N 3 was 80–85%. The myocardial retention curves of 99m Tc-ISboroxime-N 3 , 99m Tc-PYboroxime-N 3 and 99m Tc-Uboroxime-N 3 were best fitted to the bi-exponential decay function. The half-time of the fast component was 1.6±0.4min for 99m Tc-ISboroxime-N 3 , 0.7±0.1min for 99m Tc-PYboroxime-N 3 and 0.9±0.4min for 99m Tc-Uboroxime-N 3 . The 2-min heart uptake from biodistribution studies followed the ranking order of 99m Tc-ISboroxime-N 3 (3.60±0.68%ID/g)> 99m Tc-PYboroxime-N 3 (2.35±0.37%ID/g)≫ 99m Tc-Uboroxime-N 3 (1.29±0.06%ID/g). 99m Tc-ISboroxime-N 3 had the highest 2-min heart uptake among 99m Tc radiotracers revaluated in SD rats. High quality SPECT images were obtained with the right and left ventricular walls being clearly delineated. The best image acquisition window was 0–5min for 99m Tc-ISboroxime-N 3 . Conclusion Both azide coligand and boronate caps had significant impact on the heart uptake and myocardial retention of complexes [ 99m Tc(N 3 )(CDO)(CDOH) 2 B-R]. Among the radiotracers evaluated in SD rats, 99m Tc-ISboroxime-N 3 has the highest initial heart uptake with the heart retention comparable to that of 99m Tc-Teboroxime. 99m Tc-ISboroxime-N 3 is a promising alternative to 99m Tc-Teboroxime for SPECT MPI.

Introduction In this study two 111 In-labeled dimeric cyclic RGD peptides, 111 In(DOTA-Galacto-RGD 2 ) and 111 In(DOTA-3P-RGD 2 ), were evaluated as radiotracers for breast tumor imaging. The objective was to evaluate the impact of SAA, PEG 2 and 1,2,3-triazole linkers as compare to PEG 4 on the tumor uptake and excretion kinetics of 111 In radiotracers. Methods DOTA-Galacto-RGD 2 was prepared by conjugation of Galacto-RGD 2 with DOTA-OSu in the presence of diisopropylethylamine. Its integrin α v β 3 binding affinity was determined using a whole-cell displacement assay against 125 I-echistatin bound to U87MG glioma cells, and was compared with those of c(RGDfK), DOTA-3P-RGD 2 and DOTA-3P-RGK 2 (a nonsense peptide conjugate with "scrambled" RGK sequences). 111 In(DOTA-Galacto-RGD 2 ) and 111 In(DOTA-3P-RGD 2 ) were prepared and evaluated for their tumor-targeting capability and biodistribution properties in athymic nude mice bearing MDA-MB-435 breast tumor xenografts. Planar imaging studies were performed to demonstrate the utility of 111 In(DOTA-Galacto-RGD 2 ) and 111 In(DOTA-3P-RGD 2 ) for breast tumor imaging. Results IC 50 values of DOTA-Galacto-RGD 2 , DOTA-3P-RGD 2 , and DOTA-3P-RGK 2 were calculated to be 27±2, 29±4, 596±48nM, respectively. The tumor uptake values of 111 In(DOTA-Galacto-RGD 2 ) (6.79±0.98, 6.56±0.56, 4.17±0.61 and 1.09±0.13 %ID/g at 1, 4, 24 and 72hours p.i., respectively) were almost identical to those of 111 In(DOTA-3P-RGD 2 ) (6.17±1.65, 5.94±0.84, 3.40±0.50 and 0.99±0.20 %ID/g, respectively). 111 In(DOTA-Galacto-RGD 2 ) had a faster clearance from blood and muscle than 111 In(DOTA-3P-RGD 2 ), leading to higher tumor/blood and tumor/muscle ratios. 111 In(DOTA-3P-RGD 2 ) had lower liver uptake and better tumor/liver ratios than 111 In(DOTA-Galacto-RGD 2 ). The tumor uptake of 111 In(DOTA-Galacto-RGD 2 ) and 111 In(DOTA-3P-RGD 2 ) was both integrin α v β 3 and RGD-specific. Imaging data suggest that 111 In(DOTA-Galacto-RGD 2 ) and 111 In(DOTA-3P-RGD 2 ) are useful as radiotracers for imaging integrin α v β 3 -positive breast tumors. Conclusion The results from this study suggest that replacing PEG 4 linkers between two RGD moieties with a pair of SAA, PEG 2 and 1,2,3-triazole groups has little impact on integrin α v β 3 binding affinity and tumor uptake of 111 In-labeled dimeric cyclic RGD peptides. Despite the subtle differences in their excretion kinetics from noncancerous tissues, 111 In(DOTA-Galacto-RGD 2 ) and 111 In(DOTA-3P-RGD 2 ) are useful radiotracers for imaging integrin α v β 3 -positive breast tumors.

This study sought to evaluate FITC-conjugated cyclic RGD peptides (FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2) as fluorescent probes for in vitro assays of integrin αvβ3/αvβ5 expression in tumor tissues. FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2 were prepared, and their integrin αvβ3/αvβ5 binding affinity was determined using the displacement assay against (125)I-echistatin bound to U87MG glioma cells. IC50 values of FITC-Galacto-RGD2, FITC-3P-RGD2, and FITC-RGD2 were calculated to be 28 ± 8, 32 ± 7, and 89 ± 17 nM, respectively. The integrin αvβ3/αvβ5 binding affinity followed a general trend: FITC-Galacto-RGD2 ∼ FITC-3P-RGD2 > FITC-RGD2. The xenografted tumor-bearing models were established by subcutaneous injection of 5 × 10(6) tumor cells into shoulder flank (U87MG, A549, HT29, and PC-3) or mammary fat pad (MDA-MB-435) of each athymic nude mouse. Three to six weeks after inoculation, the tumor size was 0.1-0.3 g. Tumors were harvested for integrin αvβ3/αvβ5 staining, as well as hematoxylin and eosin (H&E) staining. Six human carcinoma tissues (colon cancer, pancreatic cancer, lung adenocarcinoma, squamous cell lung cancer, gastric cancer, and esophageal cancer) were obtained from recently diagnosed cancer patients. Human carcinoma slides were deparaffinized in xylene, rehydrated with ethanol, and then used for integrin αvβ3/αvβ5 staining, as well as H&E staining. It was found that the tumor staining procedures with FITC-conjugated cyclic RGD peptides were much simpler than those with the fluorescence-labeled integrin αvβ3 antibodies. Since FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2 were able to co-localize with the fluorescence-labeled integrin β3 antibody, their tumor localization and tumor cell binding are integrin αvβ3-specific. Quantification of the fluorescent intensity in five xenografted tumors (U87MG, MDA-MB-435, A549, HT29, and PC-3) and six human carcinoma tissues revealed an excellent linear relationship between the relative integrin αvβ3/αvβ5 expression levels determined with FITC-Galacto-RGD2 and those obtained with the fluorescence-labeled anti-human integrin β3 antibody. There was also an excellent linear relationship between the tumor uptake (%ID/g) of (99m)Tc-3P-RGD2 (an integrin αvβ3/αvβ5-targeted radiotracer) and the relative integrin αvβ3/αvβ5 expression levels from the quantification of fluorescent intensity in the tumor tissues stained with FITC-Galacto-RGD2. These results suggest that FITC-conjugated cyclic RGD peptides might be useful to correlate the in vitro findings with the in vivo imaging data from an integrin αvβ3/αvβ5-targeted radiotracer. The results from this study clearly showed that the FITC-conjugated cyclic RGD peptides (particularly FITC-3P-RGD2 and FITC-Galacto-RGD2) are useful fluorescent probes for assaying relative integrin αvβ3/αvβ5 expression levels in tumor tissues.

The objective of this study was to develop a kit formulation for [(99m) TcN(mpo)(PNP5)](+) (MPO = 2-mercaptopyridine oxide), ((99m) TcN-MPO) to support its clinical evaluations as a SPECT radiotracer. Radiolabeling studies were performed using three different formulations (two-vial formulation and single-vial formulations with/without SnCl2 ) to explore the factors influencing radiochemical purity (RCP) of (99m) TcN-MPO. We found that the most important factor affecting the RCP of (99m) TcN-MPO was the purity of PNP5. (99m) TcN-MPO was prepared >98% RCP (n = 20) using the two-vial formulation. For single-vial formulations with/without SnCl2 , β-cyclodextrin (β-CD) is particularly useful as a stabilizer for PNP5. The RCP of (99m) TcN-MPO was 95-98% using β-CD, but its RCP was only 90-93% with γ-cyclodextrin (γ-CD). It seems that PNP5 fits better into the inner cavity of β-CD, which forms more stable inclusion complex than γ-CD in the single-vial formulations. The results from biodistribution and imaging studies in Sprague-Dawley rats clearly demonstrated biological equivalence of three different formulations. Single photon-emission computed tomography data suggested that high quality images could be obtained at 0-30-min post-injection without significant interference from the liver radioactivity. Considering the ease for (99m) Tc-labeling and high RCP of (99m) TcN-MPO, the non-SnCl2 single-vial formulation is an attractive choice for future clinical studies.

Purpose: 99mTc-3P-RGD2 is a 99mTc-labeled dimeric cyclic RGD peptide that binds to integrin αvβ3 with high affinity and specificity. The purpose of this study was to demonstrate the utility of 99mTc-3P-RGD2 SPECT/CT (single photon emission computed tomography/computed tomography) as a molecular imaging tool for noninvasive monitoring breast tumor early response to antiangiogenesis therapy with linifanib, and to illustrate its limitations in monitoring the efficacy of anti-αvβ3 treatment. Methods: To support SPECT/CT imaging, biodistribution and therapy studies, the xenografted breast cancer model was established by subcutaneous injection of 5 × 106 MDA-MB-435 cells into the fat pad of each athymic nude mouse. Linifanib (ABT-869) was used as antiangiogenesis agent. The tumor volume was 180 ± 90 mm3 on the day (-1 day) before baseline SPECT/CT. Each animal was treated twice daily with vehicle or 12.5 mg/kg linifanib. Longitudinal 99mTc-3P-RGD2 SPECT/CT imaging was performed on days -1, 1, 4 and 11. Tumors were harvested at each time point for pathological analysis of hematoxylin and eosin (H&E) and immunohistochemistry (IHC). Tumor uptake of 99mTc-3P-RGD2 was calculated from SPECT/CT quantification. When cyclic peptide E[c(RGDfK)]2 (RGD2) was used as the anti-αvβ3 agent, SPECT/CT images were obtained only at 7 and 21 days after last RGD2 dose. Results: The tumor uptake of 99mTc-3P-RGD2 from SPECT/CT quantification was almost identical to that from biodistribution. There was a dramatic reduction in both %ID and %ID/cm3 tumor uptake of 99mTc-3P-RGD2 during the first 24 hours of linifanib therapy. The therapeutic effect of linifanib was on both tumor cells and vasculature, as determined by IHC analysis of integrin αvβ3 and CD31. Changes in tumor vasculature were further confirmed by pathological H&E analysis of tumor tissues. While its %ID tumor uptake increased steadily in vehicle-treated group, the %ID tumor uptake of 99mTc-3P-RGD2 decreased in linifanib-treated group slowly over the 11-day study period. The degree of tumor response to linifanib therapy correlated well to the integrin αvβ3 expression levels before linifanib therapy. Conclusion: 99mTc-3P-RGD2 is an excellent radiotracer for monitoring integrin αvβ3 expression during and after linifanib therapy. 99mTc-3P-RGD2 SPECT/CT is an useful molecular imaging tool for patient selection before antiangiogenic and anti-αvβ3 therapy; but it would be difficult to use 99mTc-3P-RGD2 for accurate and noninvasive monitoring of early tumor response to anti-αvβ3 therapy.

Peripheral inflammation is known to trigger neuroinflammation and neurodegenerative disease. However, the key components during the propagation of inflammation from the periphery to the central nervous system (CNS) remain unclear. Lipopolysaccharide (LPS) was administered to Sprague-Dawley rats to induce peripheral inflammation. An intravenous injection and an intranigral injection of clodronate liposomes were given to deplete monocytes and microglia, respectively. Recombinant CD200 fusion protein (CD200Fc) or an anti-CD200R1 antibody was injected into the substantia nigra to manipulate the involvement of CD200 and CD200R1. Immunohistochemistry and immunofluorescence staining were used to measure microglial activation and dopaminergic neuronal loss. The expression of brain pro-inflammatory cytokines (i.e., tumor necrosis factor alpha, IL-1β) and CD200-CD200R1 signaling were measured by quantitative RT-PCR. Our data showed that the peripheral LPS injection activated the microglia and induced an increase in the levels of pro-inflammatory cytokines (i.e., tumor necrosis factor alpha, IL-1β). The depletion of either monocytes or microglia suppressed these inflammatory effects that were induced by peripheral LPS administration. The peripheral LPS injection increased the expression of CD200 and CD200R1 in the substantia nigra. Dopaminergic neuronal loss induced by the peripheral LPS injection was accelerated by the blockade of CD200-CD200R1 signaling with an anti-CD200R1 antibody and attenuated by intensifying the signaling with CD200Fc. These results highlight the importance of monocytes, microglia, and CD200-CD200R1 signaling in the transmission of inflammation from the periphery to the CNS.

In this study, novelComplexes [Both azide coligand and boronate caps had significant impact on the heart uptake and myocardial retention of complexes [

This study sought to explore the impact of boronate groups on the heart uptake and myocardial retention of novel (99m)Tc(III) complexes [(99m)TcCl(CDO)(CDOH)2B-R] ((99m)Tc-ISboroxime: R = isoxazol-4-yl (IS); (99m)Tc-MPboroxime: R = N-methylpyridinium (MP); (99m)Tc-PAboroxime: R = pyrazol-3-yl (PA); (99m)Tc-PYboroxime: R = pyridin-3-yl (PY); and (99m)Tc-5Uboroxime: R = uracil-5-yl (5U)). All five new (99m)Tc(III) radiotracers were prepared in high yield and high radiochemical purity (RCP = 90-98%), and they remained stable in the kit mixture for6 h. Biodistribution and imaging (planar and SPECT) studies were carried out using Sprague-Dawley (SD) rats. Planar image quantification was performed to compare their myocardial retention and liver clearance kinetics. It was found that their heart retention and liver clearance curves were best fitted to the biexponential decay function. The initial heart uptake at 0-1 min after injection followed the general ranking order of (99m)Tc-ISboroxime (4.98 ± 1.05%ID) ∼ (99m)Tc-Teboroxime (4.56 ± 0.91%ID) ∼ (99m)Tc-PAboroxime (4.03 ± 1.23%ID) ∼ (99m)Tc-PYboroxime (4.07 ± 0.80%ID)(99m)Tc-5Uboroxime (3.24 ± 0.67%ID)(99m)Tc-MPboroxime (2.53 ± 0.65%ID). The fast-phase myocardial retention time followed the general order of (99m)Tc-PAboroxime (3.21 ± 0.29 min)(99m)Tc-Teboroxime (1.63 ± 0.40 min) ∼ (99m)Tc-PYboroxime (1.57 ± 0.29 min) ∼ (99m)Tc-ISboroxime (1.55 ± 0.32 min)(99m)Tc-MPboroxime (0.68 ± 0.16 min)(99m)Tc-5Uboroxime (0.33 ± 0.11 min). (99m)Tc-PAboroxime (3.05 ± 1.10%ID/g) and (99m)Tc-ISboroxime (3.75 ± 0.68%ID/g) had the 2 min initial heart uptake very close to that of (99m)Tc-Teboroxime (3.30 ± 0.50%ID/g). However, the myocardial retention time of (99m)Tc-PAboroxime was significantly longer than that of (99m)Tc-ISboroxime and (99m)Tc-Teboroxime. Even though the best time window is 0-5 min for SPECT image acquisition, high quality SPECT images could be obtained during the first 30 min postinjection of (99m)Tc-PAboroxime in SD rats. This statement was supported by the SPECT/CT studies in normal pigs. On the basis of results from this study, it was concluded that boronate groups had significant impact on the heart uptake, myocardial retention, and liver clearance kinetics of (99m)Tc(III) complexes [(99m)TcCl(CDO)(CDOH)2B-R]. The combination of high initial heart uptake with longer myocardial retention makes it possible to image the heart with (99m)Tc-PAboroxime during the first 30 min using both standard and specialized cardiac SPECT cameras.

Based on the surveying of condition based maintenance technology organized by China Three Gorges Project Company, the condition-based maintenance system for hydroelectric generating unit and its application environment are discussed in this paper. Its function, structure characters and research hotspots are summarized also, combining with some instances applied in practice. The advice for application of condition-based maintenance for hydroelectric generating unit is given at the same time.