Automatic synthesis of 18F-AV-45 and its clinical application in Alzheimer's disease.

OBJECTIVE: To investigate the automatic synthesis of ß-amyloid (Aß) positron emission tomography (PET) imaging agent (E) -4- (2- (6- (2- (2-18F fluoroethoxy) ethoxy) ethoxy) pyridine-3-yl) vinyl) - N-methylaniline (18F-AV-45) for the diagnosis of Alzheimer's disease (AD) and its clinical application in AD patients. MATERIALS AND METHODS: Fluorine-18-AV-45 was synthesized with AV-105 as the precursor, and the factors affecting the synthesis efficiency, such as the amount of precursor, nucleophilic reaction temperature were studied. At the same time, 18F-AV-45 PET/computed tomography (CT) brain scanning was performed in 15 patients with dementia to determine whether AD was the cause of the dementia. RESULTS: After optimizing the parameters, it was discovered that the highest synthesis efficiency was achieved with a AV-105 dosage of 2mg, a reaction temperature of 130oC, and 1mL of DMSO. The radiochemical yield (RCP) was greater than 98, and the uncorrected synthesis efficiency was about 31.0%±2.8%. Ten of the 15 patients with dementia showed positive Aß protein deposition, and the main deposition site of the imaging agent was the gray matter area of the brain, which was consistent with AD diagnosis, while the other 5 patients showed negative Aß protein deposition, suggesting non-AD dementia. CONCLUSION: ß-amyloid protein 18F-AV-45 imaging agent can be easily and quickly prepared by the All in One radiochemical synthesis module. Our preliminary results offer hope that it can effectively detect ß-amyloid deposition in the brain of AD patients in order to determine the etiology of dementia.

Prognostic value of secretory autophagosomes in patients with acute respiratory distress syndrome.

BACKGROUND: Growing evidence supports that extracellular vesicles (EVs) in blood plasma and other body fluids may function as biomarkers for disease. We previously found that secretory autophagosomes (SAPs), a kind of EV, could exacerbate lung injury in mice. However, the clinical value of SAPs in acute respiratory distress syndrome (ARDS), the most severe form of lung injury, remains unknown. Our study investigated the prognostic value of secretory autophagosomes in ARDS. METHODS: ARDS patients (n = 46) and controls (n = 8) were included in a prospective monocentric study. Bronchoalveolar lavage fluid (BALF) samples were collected from ARDS patients on the first day (Day 1) or the third day (Day 3) of enrollment and were collected from controls on Day 1. Gradient centrifugation was performed to isolate EVs. The size and concentration of EVs were characterized by nanoparticle tracking analysis (NTA). SAPs in EVs were characterized by flow cytometry, transmission electron microscopy, and western blot analysis, and the proportion of SAPs in EVs (PSV) was measured by flow cytometry. The association of SAPs with 28-day mortality was assessed. RESULTS: On Days 1 and 3, the proportion of SAPs (SAPs%) in BALF was higher in patients with ARDS than in controls. On Day 3, the SAPs% was significantly higher in nonsurvivors than in survivors. In particular, a high SAPs% was associated with poor overall survival in ARDS patients. Furthermore, the combination of SAPs% and SOFA obtained a higher predictive value of ARDS outcome than PSV or SOFA alone. CONCLUSION: SAPs% in BALF is elevated in patients with ARDS and is associated with the risk of death in ARDS, suggesting that SAPs% may be a novel prognostic biomarker in ARDS.

Plasma Core Alzheimer's Disease Biomarkers Predict Amyloid Deposition Burden by Positron Emission Tomography in Chinese Individuals with Cognitive Decline.

Blood-based biomarkers have been considered as a promising method for the diagnosis of Alzheimer's disease (AD). The reliability and accuracy of plasma core AD biomarkers, including phosphorylated tau (P-tau181), total tau (T-tau), Aß42, and Aß40, have also been confirmed in diagnosing AD and predicting cerebral ß-amyloid (Aß) deposition in Western populations, while fewer research studies have ever been conducted in China's Han population. In this study, we investigated the capability of plasma core AD biomarkers in predicting cerebral Aß deposition burden among the China Aging and Neurodegenerative Disorder Initiative (CANDI) cohort consisting of cognitively normal (CN), mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Body fluid (plasma and CSF) AD core biomarkers were measured via single-molecule array (Simoa) immunoassay. The global standard uptake value ratio (SUVR) was then calculated by 18F-florbetapir PET, which was divided into positive (+) and negative (-). The most significant correlation between plasma and CSF was plasma P-tau181 (r = 0.526, P < 0.0001). Plasma P-tau181 and P-tau181/T-tau ratio were positively correlated with global SUVR (r = 0.257, P < 0.0001; r = 0.263, P < 0.0001, respectively), while Aß42 and Aß42/Aß40 ratio were negatively correlated with global SUVR (r = -0.346, P < 0.0001; r = -0.407, P < 0.0001, respectively). Interestingly, voxel-wise analysis showed that plasma P-tau181 and P-tau181/T-tau ratio were negatively related to 18F-florbetapir PET in the hippocampus and parahippocampal cortex. The optimal predictive capability in distinguishing all Aß+ participants from Aß- participants and MCI+ from MCI- subgroups was the plasma P-tau181/T-tau ratio (AUC = 0.825 and 0.834, respectively). Our study suggested that plasma P-tau181 and P-tau181/T-tau ratio possessed better diagnostic and predictive values than plasma Aß42 and Aß42/Aß40 in this cohort, a finding that may be useful in clinical practices and trials in China.

Correlation between Cerebrospinal Fluid Core Alzheimer's Disease Biomarkers and ß-Amyloid PET in Chinese Dementia Population.

The current diagnoses of Alzheimer's disease (AD) mainly rely on such measures as amyloid-ß (Aß) and tau neuropathology biomarkers in vivo via cerebrospinal fluid (CSF) and positron emission tomography (PET) imaging, which had been systematically studied in Caucasian individuals, whereas diagnostic performances of these approaches in Chinese dementia population still remain unclear. This study investigated the associations between the levels of CSF core AD biomarkers, including phosphorylated tau (p-Tau181), total tau (t-Tau), Aß42, and Aß40 measured by the single-molecule array (Simoa) and cerebral Aß deposition status assessed by 18F-Florbetapir PET (Aß PET), and evaluated the predictive values of CSF core AD biomarkers in discriminating Aß PET status in a clinical dementia cohort of the Chinese population, which consisted of patients with mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Global standard uptake value ratios (SUVRs) were calculated by Aß PET, which was divided into positive (Aß+) and negative (Aß-) through visual analysis. CSF p-Tau181 and p-Tau181/t-Tau ratio were positively correlated with the global SUVR, while CSF Aß42 and Aß42/Aß40 ratio were negatively correlated with the global SUVR. CSF Aß40 has the highest predictive value in discriminating the MCI group from the AD group, while CSF p-Tau181 was applied to discriminate the AD group from the non-ADD group. CSF Aß42/Aß40 ratio, as the optimal predictive factor, was combined with APOE ε4 status rather than age and education, which could improve the predictive ability in differentiating the Aß+ group from the Aß- group. The results reveal the universal applicability of CSF core AD biomarkers and Aß PET imaging in Chinese dementia population, which is helpful in clinical practice and drug trials in China.

Efficient and automatic synthesis of TSPO PET ligand [18F]-GE-180 and its application in rheumatoid arthritis model.

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic synovial inflammation, which ultimately leads to joint deformity and dysfunction. [18F]-GE-180 is a specific PET tracer of the 18 kDa translocator protein (TSPO), which is overexpressed on activated macrophages, and proposed as a biomarker of inflammation. Our study addresses the need to streamline the automatic synthesis of [18F]-GE-180 to make it more accessible for routine production and widespread clinical evaluation and application. The nucleophilic radiofluorination was performed on an AllinOne synthesis module by SPE purification method, and the formulated [18F]-GE-180 was obtained in non-decay corrected radiochemical yields of 69 ± 1.8% in 32 min. PET/CT imaging in animal model showed that [18F]-GE-180 highly concentrated in joints from RA rats. This methodology facilitates efficient synthesis of [18F]-GE-180 in a commercially available synthesis module and shows potential diagnosis performance in RA models.

An automated radiosynthesis of (S)-[18F]28 for PET imaging of Alzheimer's disease.

18F-labeled 2-arylbenzoxazole derivative (S)-[18F]28 is potent and selective radiopharmaceutical Aß tracers for Alzheimer's disease positron-emission tomography (PET). Our study aimed to enable facile preparation of (S)-[18F]28 in commercially available PET tracer production facilities to promote the widespread application and clinical translation. Here, we successfully demonstrated an automated radiosynthesis of (S)-[18F]28 with high radiochemical yield and radiochemical purity by the AllinOne radiosynthesis module. The method developed here can facilitate extensive use of (S)-[18F]28 in large-scale clinical trials.

Electrochemical Trifluoromethylation of Thiophenols with Sodium Trifluoromethanesulfinate.

We developed an electrochemical trifluoromethylation of thiophenols without the use of metal catalysts and oxidants. This reaction features mild reaction conditions, readily available substrate, as well as moderate to good yields. In addition, this protocol can be easily scaled up with moderate efficiency.

Association between CD24 Ala/Val polymorphism and multiple sclerosis risk: A meta analysis.

BACKGROUND: The aim of this study was to explore the association between CD24 Ala/Val polymorphism and susceptibility of multiple sclerosis (MS). METHODS: A comprehensive literature search for relevant studies was performed on google scholar, PubMed, Web of science, Embase, the Chinese National Knowledge Infrastructure and the Chinese Biology Medicine. This meta-analysis was conducted using the STATA 11.0 software and the pooled odds ratio with 95% confidence interval was calculated. RESULTS: Seven case-control studies were included in this meta-analysis. The results showed significant association between CD24 Ala/Val polymorphism and susceptibility to MS. Stratified analysis by areas also showed significant association in Asians. However, no association was found in Europeans. CONCLUSION: This study suggested that the CD24 Val allele was associated with an increased risk of MS and larger-scale studies of populations are needed to explore the role of CD24 Ala/Val polymorphism during the pathogenesis of MS.

Effect of dexmedetomidine on postoperative cognitive dysfunction and inflammation in patients after general anaesthesia: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Neuroprotective effects of dexmedetomidine are reported in preclinical and clinical studies but evidence regarding the postoperative neurocognitive function is still unclear. This study performed a meta-analysis on outcomes of studies which examined neurocognitive performance and inflammatory factors to investigate the effects of dexmedetomidine on postoperative cognitive dysfunction (POCD) and inflammation in patients after general anaesthesia. METHODS: Literatures were searched in several electronic databases and studies were selected by following precise inclusion criteria. We searched PubMed, EMBASE, the Cochrane Library, China Academic Journals full-text database (CNKI), and Google Scholar to find randomized controlled trials (RCTs) of the influence of dexmedetomidine on POCD and inflammation in patients who had undergone general anaesthesia. Two researchers independently screened the literature, extracted data, and evaluated quality of methodology against inclusion and exclusion criteria. Meta-analyses of pooled ORs of POCD incidences and mean differences in neurocognitive assessment scores and inflammation levels were carried out and subgroup analyses were performed. Stata 12.0 was used to conduct our meta-analysis. RESULTS: Twenty-six RCTs were included. Compared with controls, perioperative dexmedetomidine treatment significantly reduced the incidence of POCD (pooled ORs = 0.59, 95% confidence interval (CI) 0.45-2.95) and improved Mini-Mental State Examination (MMSE) score (standardized mean difference (SMD) = 1.74, 95% CI 0.43-3.05) on the first postoperative day. Furthermore, perioperative dexmedetomidine treatment significantly decreased IL-6 (SMD = -1.31, 95% CI -1.87-0.75, P < .001) and TNF-α (SMD = -2.14, 95% CI -3.14-1.14, P < .001) compared to saline/comparators treatment. In the stratified analysis by surgical type, age, type of control, and study region, the differences were also significant between dexmedetomidine- and saline-treated patients. CONCLUSION: Perioperative dexmedetomidine treatment is associated with significantly reduced incidence of POCD and inflammation and better neurocognitive function postoperatively in comparison with both saline controls and comparator anaesthetics.

Silibinin: an old drug for hematological disorders.

INTRODUCTION: Silibinin (silybin), a non-toxic natural polyphenolic flavonoid, is the principal and the most biologically active component of silymarin. It is efficient in the treatment of acute and chronic liver disorders caused by toxins, drug, alcohol, hepatitis, and gall bladder disorders. Further, in our previous studies, we explored the anti-cancer efficacy in common cancers, such as lung, prostatic, colon, breast, bladder, as well as, hepatocellular carcinoma. Interestingly, silibinin is still not solely limited to the treatment of these diseases. Recent research endeavors suggest that silibinin may function diversely and serve as a novel therapy for hematological disorders. AREAS COVERED: It discovered several interesting viewpoints in the widely studied mechanisms of silibinin in the hematological disorders. EXPERT COMMENTARY: In this report, we review the up-to-date findings of more potency roles of silibinin in ß-thalassemia (ß-TM), acute myeloid leukemia (AML), anaplastic large cell lymphoma (ALCL) and multiple myelomas (MM) therapy and attempt to clarify the mechanisms underlying its effects. There are two viewpoints: First, The functional mechanisms of silibinin in AML cells via regulating cell differentiation to exert anti-cancer effect; Second, combination treatment strategy may be a good choice.

Transforming growth factor ß: A potential biomarker and therapeutic target of ventricular remodeling.

Transforming growth factor ß (TGF-ß) is a multifunctional cytokine that is synthesized by many types of cells and regulates the cell cycle. Increasing evidence has led to TGF-ß receiving increased and deserved attention in recent years because it may play a potentially novel and critical role in the development and progression of myocardial fibrosis and the subsequent progress of ventricular remodeling (VR). Numerous studies have highlighted a crucial role of TGF-ß in VR and suggest potential therapeutic targets of the TGF-ß signaling pathways for VR. Changes in TGF-ß activity may elicit anti-VR activity and may serve as a novel therapeutic target for VR therapy. This review we discusses the smad-dependent signaling pathway, such as TGF-ß/Smads, TGF-ß/Sirtuins, TGF-ß/BMP, TGF-ß/miRNAs, TGF-ß/MAPK, and Smad-independent signaling pathway of TGF-ß, such as TGF-ß/PI3K/Akt, TGF-ß/Rho/ROCK,TGF-ß/Wnt/ß-catenin in the cardiac fibrosis and subsequent progression of VR. Furthermore, agonists and antagonists of TGF-ß as potential therapeutic targets in VR are also described.

Trimetazidine in conditions other than coronary disease, old drug, new tricks?

Trimetazidine (TMZ) has traditionally been used as an anti-ischemic drug for coronary artery disease by selectively inhibiting the mitochondrial long-chain 3-ketoacyl-CoA thiolase. Recently, new applications for this therapy have been investigated. This article reviews alternative uses for TMZ in non-coronary artery diseases, such as non-ischemic cardiomyopathy, sepsis, myocardial dysfunction induced by anti-cancer drugs, diabetic cardiomyopathy and contrast-induced nephropathy.

Statins in conditions other than hypocholesterolemic effects for chronic subdural hematoma therapy, old drug, new tricks?

Chronic subdural hematoma (CSDH) is one of the most common intracranial hematomas worldwide with a high incidence in the general population. However, the optimum treatment for CSDH is Burr-hole drainage with or without rinse Considering the poor outcomes of CSDH in aged patients, and ambiguous prediction of recurrence in many sides of recurrent CSDHs who have been analyzed, new effective therapies are needed for those CSDHs who are predicated to have poor prognosis for surgery and/or have a higher risk of recurrence. Statins, which is the first-line treatment for patients with high cholesterol and coronary heart disease. However, statins are still not solely limited in the treatment of these diseases. It has been demonstrated that statins could improve CSDH due to its effect of regulation of angiogenesis and inflammation. In this review, in order to provide potential new treatment for CSDH we summarize the recent findings of statins in CSDH in order to try to clarify the mechanisms of this effect.

Expression and prognostic significance of unique ULBPs in pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide, due to the lack of efficient therapy and difficulty in early diagnosis. ULBPs have been shown to behave as important protectors with prognostic significance in various cancers. MATERIALS AND METHODS: Immunohistochemistry and enzyme-linked immunosorbent assays were used to explore the expression of ULBPs in cancer tissue and in serum, while survival analysis was used to evaluate the subsequent clinical value of ULBPs. RESULTS: Statistics showed that high expression of membrane ULBP1 was a good biomarker of overall survival (18 months vs 13 months), and a high level of soluble ULBP2 was deemed an independent poor indicator for both overall survival (P<0.001) and disease-free survival (P<0.001). CONCLUSION: ULBP1 provides additional information for early diagnosis, and soluble ULBP2 can be used as a novel tumor marker to evaluate the risk of pancreatic cancer patients.

Silibinin: a potential old drug for cancer therapy.

INTRODUCTION: Silibinin is mixture of flavonolignans extracted from milk thistle and often has been used in the treatment of acute and chronic liver disorders caused by toxins, drug, alcohol and hepatitis and gall bladder disorders for its antioxidant and hepatoprotective properties. Areas covered: However, increasing evidence suggest that silibinin is not solely limited in the treatment of these diseases. Further research suggests that silymarin may function diversely and may serve as a novel therapy for cancer therapy, such as lung cancer, prostatic cancer, colon cancer, breast cancer, bladder cancer and hepatocellular carcinoma by regulating cancer cells growth, proliferation, apoptosis, angiogenesis and many other mechanism. Expert commentary: In this review, in order to provide potential new treatment for these cancer, we summarize the recent anti-cancer findings of silibinin in these cancer and clarify the mechanisms of this effect.

Abnormal expression levels of sMICA and NKG2D are correlated with poor prognosis in pancreatic cancer.

Soluble major histocompatibility complex class I-related chain A molecules (sMICA) and natural-killer group 2 member D (NKG2D) not only correlate with tumorigenesis and progression, but also with tumor invasion and metastasis. In this study, we used immunohistochemistry to investigate the correlation and prognostic significance of the differential expression of sMICA and NKG2D in pancreatic carcinoma and paracarcinoma tissues from 70 patients with pancreatic carcinomas. The results showed that sMICA expression was significantly (P<0.05) higher in tumor tissues (67.1%) than that in adjacent nontumor tissues (31.4%), whereas NKG2D expression was significantly (P<0.001) lower in tumor tissues (32.9%) than that in adjacent nontumor tissues (60.0%). Spearman's rank correlation test showed a negative correlation between the expression of sMICA and that of NKG2D (r=-0.676, P<0.001). Kaplan-Meier survival analysis showed that a high sMICA expression was significantly correlated with decreased disease-free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001), while a high NKG2D expression was significantly associated with increased DFS (P=0.001) and OS (P=0.001) of the patients. Multivariate analysis showed that a high sMICA expression was an independent predictive factor for poor DFS (P<0.001) and OS (P=0.012); but low NKG2D expression was not an independent prognostic factor for poor DFS (P=0.238) and OS (P=0.574). In conclusion, our findings suggest that the expression levels of sMICA and NKG2D are abnormal and negatively correlated with one another in pancreatic carcinoma tissues; they may be considered as valuable biomarkers for the prognosis of pancreatic carcinoma.

DNT cell inhibits the growth of pancreatic carcinoma via abnormal expressions of NKG2D and MICA in vivo.

This research aimed to investigate the effects of natural killer group 2 member D (NKG2D) and its ligands major histocompatibility complex class I chain-related molecules A(MICA) in DNT cell killing pancreatic carcinoma. Antibodies adsorption was used to separate DNT cell from human peripheral blood. Human pancreatic tumor models were established via implanting BXPC-3 cells into nude mice. Then randomly divided mice into blank group, gemcitabine group and DNT group. Mice weights and mice tumor volumes were measured every 5 days. 50 days later mice were euthanized at cervical dislocation method. Tumor weights were measured. Relative tumor volume and tumor inhibition rate were calculated. Western blot and qPCR were used to detect the expressions of NKG2D and MICA in the transplanted tumors of the three groups. DNT cell significantly increased over time. The blank group tumor volume and weight were significantly larger than the other groups (p < 0.001, p < 0.001), but there were no significantly difference between DNT group and gemcitabine group (p > 0.05). Gemcitabine and DNT cell tumor inhibition rate were 40.4% and 35.5%. Western blot and qPCR showed that MICA mRNA and protein levels in blank group were significantly higher than DNT group (p = 0.001, p = 0.003). NKG2D mRNA and protein levels in blank group were significantly lower than DNT cells group (p < 0.001, p = 0.001). In conclusion DNT cell can significantly inhibit the growth of pancreatic carcinoma in vivo, and the mechanism may be involved in abnormal expressions of MICA and NKG2D.