[Mechanism of Qingluo Tongbi Formula for regulating immune-bone erosion in rheumatoid arthritis].

OBJECTIVE: To explore the mechanism of Qingluo Tongbi formula for regulating "immune-bone erosion" in rheumatoid arthritis (RA). METHODS: Sixty-four RA patients were randomized into two groups to receive treatment with oral methotrexate or Qingluo Tongbi Formula for 12 weeks. Flow cytometry was used to analyze the changes in the percentages of CD3-CD19+, CD19+CD27 and CD19+BAFFR+B cell subpopulations in peripheral blood of the patients, and serum levels of B cell activating factor (BAFF), RANKL, RANK and osteoprotegerin (OPG) levels were detected using ELISA. Before and after the treatment, serum levels of ß-CTX, TRACP-5b, BGP, BALP, and PINP were measured with ELISA, and bone mineral density was determined with DXEA dual-energy X-ray absorptiometry. In the cell experiment, RAW264.7 cells were induced to differentiated into osteoclasts and treated with Qingluo Tongbi Formula at low-, moderate and high doses (125, 250 and 500 µg/mL, respectively) or with methotrexate (2 µg/mL) for 48 h, and the changes in the expression levels of RANKL, RANK, OPG and c-Fos were detected using Western blotting. RESULTS: The B cell subgroups in RA patients were correlated with the RANKL/RANK/OPG system. Treatment with Qingluo Tongbi Formula obviously down-regulated the percentages of the B cell subgroups, lowered serum levels of BAFF, ß-CTX and TRACP-5b, increased the levels of BGP, BALP and PINP, and improved lumbar bone density of RA patients (P<0.05); All these changes were significantly correlated with the regulation of B cell expressions (P<0.05). In RAW264.7 cells-derived osteoclasts, Qingluo Tongbi Formula significantly decreased the expressions of RANKL, RANK and c-Fos and increased the expression of OPG (P<0.05). CONCLUSION: Qingluo Tongbi Formula inhibits bone erosion in RA possibly by regulating B cell subset percentages and BAFF expression and inhibiting osteoclast differentiation via the RANKL/RANK/OPG pathway.

[The value of a nomogram based on clinical data and contrast enhanced CT radiomics in the preoperative prediction of Epstein-Barr virus-associated gastric carcinoma].

Objective: To explore the value of a nomogram based on clinical data and enhanced CT radiomics in the prediction of Epstein-Barr virus-associated gastric carcinoma(EBVaGC). Methods: The data of 136 patients, including 100 males and 36 females, aged [M (Q1, Q3)] 65 (53, 71) years, with gastric cancer confirmed by surgery and pathology were retrospectively analyzed. According to Epstein-Barr virus-encoded small RNA (EBER) in situ hybridization, those patients were divided into Epstein-Barr virus (EBV) positive group (n=32) and EBV negative group (n=104). All patients underwent multi-phase enhanced CT scanning before surgery and randomly assigned to the training group (n=95) and validation group (n=41) in a ratio of 7︰3. MaZda software was used to extract radiomics features of enhanced CT images. The intra-group correlation coefficient (ICC), variance analysis and minimum absolute shrinkage and selection algorithm (LASSO) regression were used to reduce the dimensionality of the radiomics features, and then the radiomics score (Radscore) was calculated. The nomogram model was based on combined clinical data, morphological features and Radscore. The predictive power of the nomogram was evaluated according to the area under the receiver operating characteristic curve (AUC), and the net clinical benefit of the nomogram was evaluated by the decision curve and calibration curves were drawn according to the data of the training group and the validation group to analyze the consistency of the nomogram model. Results: After selection, six optimal radiomics features were obtained, including Mean, Skewness, S(1, 0) Sum entropy, S(1, 1) Contrast, 99% percentile and S(2, 2)Angular second moment. Radscore of EBV positive group were higher than that of the EBV negative group (training group: 3.78±0.83 vs 2.80±0.98; validation group: 3.81±0.47 vs 2.94±0.95) (both P<0.05) both in the training group and validation group. The AUC of the radiomics model in training group and validation group were 0.773(95%CI:0.612-0.962)and 0.792(95%CI:0.597-0.927)respectively,and the sensitivity and specificity were 63.6% and 93.1%, 70.0% and 87.1%, respectively. The AUC of the nomogram model based on clinical data and radiomics in the training group and the validation group were 0.883(95%CI:0.644-0.984) and 0.851(95%CI:0.715-0.996), respectively. The nomogram model showed superior predictive performance (both P<0.05). Conclusion: The nomogram model based on clinical data and radiomics has better efficacy in the prediction of Epstein-Barr virus associated gastric cancer.

Sodium MRI at 7T for Early Response Evaluation of Intracranial Tumors following Stereotactic Radiotherapy Using the CyberKnife.

BACKGROUND AND PURPOSE: Conventionally, early treatment response to stereotactic radiotherapy in intracranial tumors is often determined by structural MR imaging. Tissue sodium concentration is altered by cellular integrity and energy status in cells. In this study, we aimed to investigate the feasibility of sodium MR imaging at 7T for the preliminary evaluation of radiotherapeutic efficacy for intracranial tumors. MATERIALS AND METHODS: Data were collected from 16 patients (12 men and 4 women, 24-75 years of age) with 22 intracranial tumors who were treated with stereotactic radiation therapy using CyberKnife at our institution between December 1, 2016, and August 15, 2019. Sodium MR imaging was performed at 7T before and 48 hours, 1 week, and 1 month after CyberKnife radiation therapy. Tissue sodium concentration (TSC) was calculated and analyzed based on manually labeled regions of tumors. RESULTS: Ultra-high-field sodium MR imaging clearly showed the intratumoral signal, which is significantly higher than that of normal tissue (t = 5.250, P <.001)., but the edema zone has some influence. The average TSC ratios of tumor to CSF in the 22 tumors, contralateral normal tissues, edema zones, frontal cortex, and frontal white matter were 0.66 (range, 0.23-1.5), 0.30 (range, 0.15-0.43), 0.58 (range, 0.25-1.21), 0.25 (range, 0.17-0.42), and 0.30 (range, 0.19-0.49), respectively. A total of 12 tumors in 8 patients were scanned at 48 hours, 1 week, and 1 month after treatment. The average TSC at 48 hours after treatment was 0.06 higher than that before treatment and began to decrease at 1 week. The TSC ratios of 10 continued to decline and 2 tumors increased at 1 month, respectively. Tumor volume decreased by 2.4%-99% after 3 months. CONCLUSIONS: Changes in the TSC can be quantified by sodium MR imaging at 7T and used to detect radiobiologic alterations in intracranial tumors at early time points after CyberKnife radiation therapy.

Seasonal changes of rumen and intestine morphology of the Qinghai yak (Bos grunniens).

AIM: The aim of the current study was to investigate the effects of seasonal changes in grass quality on the ruminal and intestinal morphology of male Qinghai yaks. MATERIALS AND METHODS: A total of four male yaks with the same age of 4 years old from each season (summer and winter) were randomly selected and slaughtered to determine the effect of different season on intestinal morphology of yak in the Qinghai-Tibetan Plateau. RESULTS: The histological analysis shows that male yak has the longer and wider papillae in rumen in green season. The height of villi in duodenum and jejunum was significantly higher in green season, and the width of villi on duodenum, jejunum, ileum, and rectum was significantly wider in green season. Surface area of villi and crypt depth in duodenum, jejunum, and ileum was significantly larger and deeper in green season. Submucosa thickness of duodenum, jejunum, ileum, and rectum was significantly thicker in green season. The muscular thickness of jejunum, cecum, and rectum was significantly thicker in green season. CONCLUSION: According to this research, we found that the seasonal changes of ruminal and intestinal morphology of yak showed different length and width papillae, villi, crypt, and submucosa. This fact was confirmed the functional advantages resulting from the ability to successfully adapt to a dry climate and diets, flat, open, and cold grassland may allow yak to overcome both water shortage and energy deficiency in winter.

[Treatment of single one-stage posterior atlantoaxial fixation in Chiari malformation].

Objective: To explore the effects of surgical technique of single one-stage posterior C(1-2) screw rod fixation of Chiari malformation (CM) associated with occipitalization and without atlantoaxial dislocation. Methods: A total of 23 patients with CM treated between January 2014 and October 2015 in Department of Neurosurgery of Chinese People's Liberation Army General Hospital were retrospective reviewed. All of them were diagnosis with CM associated with occipitalization and without atlantoaxial dislocation, including 8 males and 15 females, aging from 11 to 57 years (mean (35.5±10.52) years). Single one-stage posterior C(1-2) screw rod fixation with bone grafting fusion was performed. Operation time and intraoperative blood loss were recorded. Japanese Orthopaedic Association (JOA) scores and Odom rating were used to evaluate the clinical effects at pre- and post-operative. Regression of the cerebellar tonsillar was measured by MRI. The results were analyzed by paired samples t test. Results: Twenty-three patients were implanted screws successfully, the vertebral artery injury and cerebrospinal fluid leakage were not found. The mean operation time was (172.7±19.9) minutes, the intraoperative blood loss was (153.9±49.3) ml. Compared to preoperative, the JOA score increased (13.7±1.6 vs. 11.5±1.4) and the tonsillar herniation decreased ((0.8±0.6)cm vs. (1.9±0.6) cm) in the last follow-up, there were statistical difference (t=13.386, P<0.01; t=17.995, P<0.01). The results of the postoperative Odom grading were as follows: 6 cases were perfect (26.1%), 13 cases were good (56.5%), 4 cases were moderate (17.4%) and no case was poor.No signs of instrument loosen or screw broken was noticed. 100% bony fusion rate was achieved. The follow-up time was 6 to 23 months (mean (10.5±3.2) months). One case developed internal fixator related discomfort, the symptom was relieved by internal fixator removal surgery performed 4 months after the operation when osseous fusion had already been achieved. No new neurologic symptoms were observed in other 22 patients. Conclusions: The results of the study substantiates the effectiveness of single one-stage posterior fixation strategy for CM, which is associated with occipitalization and without atlantoaxial dislocation. This technique could be an alternative choice for this type of CM.

[Copy number variants analysis in whole-genome of patients with lipoma tethered cord syndrome].

Objective: To explore the abnormality of chromosomes of patients with lipoma tethered cord syndrome and the probable association between Copy Number Variations (CNV) and lipoma tethered cord syndrome. Methods: By using the Agilent SurePrint G3 Human CGH 8×60K Microarray Kit, we performed genome-wide screening for CNV on 11 patients with lipoma tethered cord syndrome adopted by the Neurosurgery Department of Chinese PLA General Hospital and their healthy parents from March 2015 to May 2015. We analyze CNVs got by the kit against the gene databases. Unrelated confirmed polymorphisms contained in Database of Genomic Variants (DGV) were discarded. Database of Chromosomal Imbalance and Phenotype in Humans using Ensemble Resources (DECIPHER) helps us with similarity inquiry, and UCSC Genome Browser helps in identification of non-polymorphic CNV. Biological process, cellular component and molecular function enrichment of these genes were conducted to confirm the association between the CNV and lipoma tethered cord syndrome. Results: 17 CNV were discovered by aCGH in 11 patients. Chr8: 39258894-39386158 and Chr15: 20481702-22509254 showed a high frequency of 5/11. Angelman syndrome and Prader-Wolli syndrome were found to be associated with the CNV of Chr15. Gene function enrichment analysis revealed that ADAM5P and ADAM3A contained in CNV obtained from patients with lipoma tethered cord syndrome was also associated with orofacial clefts. Conclusions: CNV in Chr8 and Chr15 of patients with lipoma tethered cord syndrome had a higher frequency than that of common human. It revealed that there is probable association between these two pieces of CNV and lipoma tethered cord syndrome. To explorer related genes or CNV, focusing on certain type of NTDs may increase the research efficiency and get more accurate results.

[The research advances of microRNA-184 and related ocular diseases].

microRNA-184 (miR-184) is a small, non-coding, endogenic RNA molecule of 22 nucleotides in length. It is a highly conserved sequence throughout many different species. Multiple studies have demonstrated that miR-184 is an important factor in regulating gene expression at the post-transcriptional level. miR-184 plays vital roles in many biological processes, including development and differentiation in many tissues and organs. Meanwhile, the research on the physiological and pathological role of miR-184 in eyes draws more and more attention lately. Recent research indicates that miR-184 is highly expressed in the cornea and lens of mice. miR-184 plays crucial regulatory roles in several ocular diseases, such as neovascularization, keratoconus, endothelial dystrophy-iris hypoplasia-congenital cataract-stromal thinning syndrome, corneal squamous cell carcinoma, age-related macular degeneration and cataract. Here we summarize and discuss the recent findings of miR-184 in its gene structure, gene expression and regulation, biological function and its relevance with ocular diseases. (Chin J Ophthalmol, 2017, 53: 950-955).

Radiosynthesis of [18F] N-(3-Fluoropropyl)-2-beta-Carbomethoxy-3-beta-(4-Bromophenyl) Nortropane and the regional brain uptake in non human primate using PET.

A synthetic procedure for the preparation of [18F]FPCBT, an imaging agent for the dopamine transporter (DAT), has been developed. The radiosynthesis was carried out in a two step procedure. Even though the yield was low, we were able to prepare 20 to 30 mCi of the product, which was enough for two or three studies. The radiochemical purity was greater than 96%. The in vivo properties of this radiotracer were evaluated using baboon and it showed highest uptake in the striatum. The studies also revealed that the maximum uptake was reached within 7 to 10 minutes post injection. Plasma metabolite analysis indicated that there is only one metabolite and it is less lipophilic than the parent compound. [18F]FPCBT displayed good brain uptake and its high target to non target ratio indicate that it is a potential candidate for DAT imaging.

Synthesis and biological evaluation of a series of novel N- or O-fluoroalkyl derivatives of tropane: potential positron emission tomography (PET) imaging agents for the dopamine transporter.

A series of novel fluoroalkyl-containing tropane derivatives was synthesized, and their binding affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined via competitive binding assays. Among these derivatives, the fluoropropyl ester of beta-CIT (19), the fluoroethyl ester of beta-CIT (20), the N-fluoropropyl derivative of beta-CBT (12), and the fluoropropyl ester of beta-CMT (18) displayed higher affinity and greater selectivity for the DAT versus SERT and NET than FP-CIT, which indicates that they are attractive candidates for the development of (18)F-labeled PET imaging agents for the DAT.

Transcriptional activation by a matrix associating region-binding protein. contextual requirements for the function of bright.

Bright (B cell regulator of IgH transcription) is a B cell-specific, matrix associating region-binding protein that transactivates gene expression from the IgH intronic enhancer (E mu). We show here that Bright has multiple contextual requirements to function as a transcriptional activator. Bright cannot transactivate via out of context, concatenated binding sites. Transactivation is maximal on integrated substrates. Two of the three previously identified binding sites in E mu are required for full Bright transactivation. The Bright DNA binding domain defined a new family, which includes SWI1, a component of the SWI.SNF complex shown to have high mobility group-like DNA binding characteristics. Similar to one group of high mobility group box proteins, Bright distorts E mu binding site-containing DNA on binding, supporting the concept that it mediates E mu remodeling. Transfection studies further implicate Bright in facilitating spatially separated promoter-enhancer interactions in both transient and stable assays. Finally, we show that overexpression of Bright leads to enhanced DNase I sensitivity of the endogenous E mu matrix associating regions. These data further suggest that Bright may contribute to increased gene expression by remodeling the immunoglobulin locus during B cell development.

[Synthesis, characterization and fluorescence property of europium ternary complex p-nitrophenylacetic acid and 1, 10-phenanthroline].

The europium ternary solid complex containing p-nitrophenylacetic acid and 1, 10-phenanthroline was synthesized in this work, and the chemical formula of this compound was determined to be EuL3 phen by elemental analysis. The complex has been characterized by analysis of molar conductivity, TG-DTA, IR and UV. The fluorescence spectra of this Eu3+ complex has been investigated also in this paper.

Regulation of matrix attachment region-dependent, lymphocyte-restricted transcription through differential localization within promyelocytic leukemia nuclear bodies.

Bright (B cell regulator of IgH transcription) transactivates the immunoglobulin heavy chain (IgH) intronic enhancer, Emicro, by binding to matrix attachment regions (MARs), sites necessary for DNA attachment to the nuclear matrix. Here we report that Bright interacts with the ubiquitous autoantigen Sp100, a component of promyelocytic leukemia nuclear bodies (PML NBs), and with LYSp100B/Sp140, the lymphoid-restricted homolog of Sp100. Both in intact cells and in nuclear matrix preparations, the majority of Bright and Sp100 colocalize within PML NBs. In contrast, Bright colocalizes with only a small fraction of LYSp100B while inducing a redistribution of the majority of LYSp100B from its associated nuclear domains (LANDs) into nucleoplasm and cytoplasm. Sp100 represses the MAR-binding and transactivation activity of Bright. LYSp100B interacts more weakly with Bright but requires significantly higher levels than Sp100 to inhibit MAR binding. However, it strongly stimulates Bright transactivation through E mu. We suggest that Sp100 and LYSp100B interactions with Bright have different consequences for IgH transcription, potentially through differential association of E mu MARs with nuclear matrix- associated PML NBs and LANDs.

Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence.

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

Cux/CDP homeoprotein is a component of NF-muNR and represses the immunoglobulin heavy chain intronic enhancer by antagonizing the bright transcription activator.

Nuclear matrix attachment regions (MARs) flanking the immunoglobulin heavy chain intronic enhancer (Emu) are the targets of the negative regulator, NF-muNR, found in non-B and early pre-B cells. Expression library screening with NF-muNR binding sites yielded a cDNA clone encoding an alternatively spliced form of the Cux/CDP homeodomain protein. Cux/CDP fulfills criteria required for NF-muNR identity. It is expressed in non-B and early pre-B cells but not mature B cells. It binds to NF-muNR binding sites within Emu with appropriate differential affinities. Antiserum specific for Cux/CDP recognizes a polypeptide of the predicted size in affinity-purified NF-muNR preparations and binds NF-muNR complexed with DNA. Cotransfection with Cux/CDP represses the activity of Emu via the MAR sequences in both B and non-B cells. Cux/CDP antagonizes the effects of the Bright transcription activator at both the DNA binding and functional levels. We propose that Cux/CDP regulates cell-type-restricted, differentiation stage-specific Emu enhancer activity by interfering with the function of nuclear matrix-bound transcription activators.

Local injection of alkylating and nonalkylating dopamine receptor antagonists into rat basal forebrain: autoradiographic assessment of D2-like and D3 sites.

N-chloroethyl derivatives of 7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), or fluphenazine were microinjected into rat nucleus accumbens (Acc), and receptor binding quantified autoradiographically after 24 h. EEDQ reduced [3H]nemonapride (D2-like receptors) binding in Acc (by 84%) and islands of Calleja (IC; 44%), without affecting [3H](+)-7-OH-DPAT (D3); N-chloroethyl-7-OH-DPATs blocked both radioligands in Acc and IC (30%-70%); fluphenazine had no effect.

[Synthesis and spectroscopic properties of rare earth and p-anisic acid with 1, 10-phenanthroline].

The title complex with the formula EuL3 x phen x H2O (phen=1, 10-phenathroline, HL=p-anisic acid) were synthesized and characterized by elemental analysis, molar conductivity, IR, UV, NMR etc.

Mutually exclusive interaction of a novel matrix attachment region binding protein and the NF-muNR enhancer repressor. Implications for regulation of immunoglobulin heavy chain expression.

The immunoglobulin heavy chain (IgH) intronic enhancer stimulates transcription from functional promoters in B lymphocytes but not other cell types. The observation that binding sites for the nuclear factor-mu negative regulator (NF-muNR) enhancer repressor overlap nuclear matrix attachment regions (MARs) in this enhancer has lead to the hypothesis that the cell type specificity of the enhancer might be controlled by regulating nuclear matrix attachment (Scheuermann, R. H., and Chen, U. (1989) Genes & Dev. 3, 1255-1266). To understand the role of MARs in IgH enhancer regulation, we have identified a novel MAR-binding protein, MAR-BP1, from soluble nuclear matrix preparations based on its ability to bind to the MARs associated with the IgH enhancer. Purified MAR-BP1 migrates as a 33-kDa protein, and it can be found in nuclear matrix preparations from a number of different types of lymphoid cell lines. Although specific binding sites have been difficult to localize by chemical or enzymatic footprinting procedures, NF-muNR binding sites are critical for efficient MAR-BP1 binding. Indeed, binding of the IgH enhancer to either intact nuclear matrix preparations or to MAR-BP1 is mutually exclusive to NF-muNR binding. These results are consistent with a model for cell-type specific regulation in which binding of the NF-muNR repressor to the IgH enhancer prevents nuclear matrix attachment in inappropriate cells by interfering with MAR-BP1/enhancer interaction.

Effects of aporphine isomers on rat prolactin.

S(+)-aporphines are partial agonists at D2 dopamine receptors. High selectivity of anti-dopaminergic action in limbic vs. extrapyr amidal regions of rat brain and lack of induction of dopaminergic supersensitivity have suggested their potential as atypical antipsychotic drugs. Now, in testing for effects on circulating prolactin, a typical D2 antagonist haloperidol elevated, and potent agonist R(-)-11-hydroxy-N-propylnoraporphine lowered, serum prolactin levels in gentled male rats, while S(+)-N-propylnorapomorphine and its 11-monohydroxy analog had little or no effect, even at high doses. Lack of hyperprolactinemia adds to characteristics of S(+)-aporphines that are desirable in improved antipsychotics.

Receptor affinities of aporphine enantiomers in rat brain tissue.

R(-) and S(+) enantiomers of apomorphine, N-n-propylnorapomorphine and 11-hydroxy-N-n-propylnorapomorphine were screened for affinity at over 40 representative sites in rat brain tissue that included amine, purine, amino acid and peptide receptors, transporters, ion channels, and effector components; only dopamine receptors and alpha-adrenoceptors showed appreciable affinity that was quantified further. The aporphines showed R(-) > S(+) isomeric selectivity as well as D2 > D1 selectivity at dopamine receptors. While R(-) isomers preferred alpha 2-adrenoceptors, S(+)-aporphines were alpha 1-selective, with similar affinity at alpha 1-adrenoceptors and dopamine D2 receptors. Interactions of S(+)-aporphines at alpha 1-adrenoceptors as well as dopamine D2 receptors may contribute to their unusual behavioral properties.