A bis-boron boramino acid PET tracer for brain tumor diagnosis.

PURPOSE: Boramino acids are a class of amino acid biomimics that replace the carboxylate group with trifluoroborate and can achieve the 18F-labeled positron emission tomography (PET) and boron neutron capture therapy (BNCT) with identical chemical structure. METHODS: This study reports a trifluoroborate-derived boronophenylalanine (BBPA), a derived boronophenylalanine (BPA) for BNCT, as a promising PET tracer for tumor imaging. RESULTS: Competition inhibition assays in cancer cells suggested the cell accumulation of [18F]BBPA is through large neutral amino acid transporter type-1 (LAT-1). Of note, [18F]BBPA is a pan-cancer probe that shows notable tumor uptake in B16-F10 tumor-bearing mice. In the patients with gliomas and metastatic brain tumors, [18F]BBPA-PET shows good tumor uptake and notable tumor-to-normal brain ratio (T/N ratio, 18.7 ± 5.5, n = 11), higher than common amino acid PET tracers. The [18F]BBPA-PET quantitative parameters exhibited no difference in diverse contrast-enhanced status (P = 0.115-0.687) suggesting the [18F]BBPA uptake was independent from MRI contrast-enhancement. CONCLUSION: This study outlines a clinical trial with [18F]BBPA to achieve higher tumor-specific accumulation for PET, provides a potential technique for brain tumor diagnosis, and might facilitate the BNCT of brain tumors.

Photocatalytic direct borylation of carboxylic acids.

The preparation of high value-added boronic acids from cheap and plentiful carboxylic acids is desirable. To date, the decarboxylative borylation of carboxylic acids is generally realized through the extra step synthesized redox-active ester intermediate or in situ generated carboxylic acid covalent derivatives above 150 °C reaction temperature. Here, we report a direct decarboxylative borylation method of carboxylic acids enabled by visible-light catalysis and that does not require any extra stoichiometric additives or synthesis steps. This operationally simple process produces CO2 and proceeds under mild reaction conditions, in terms of high step economy and good functional group compatibility. A guanidine-based biomimetic active decarboxylative mechanism is proposed and rationalized by mechanistic studies. The methodology reported herein should see broad application extending beyond borylation.

Me2(CH2Cl)SiCF3 Facilitated Tandem Synthesis of Oxasilacycles Featuring a Trifluoromethyl Group.

An unprecedented tandem trifluoromethylsilylation/intramolecular SN2 substitution sequence was realized by using bifunctional reagent Me2(CH2Cl)SiCF3, allowing efficient construction of valuable trifluoromethylated oxasilacyclohexanes that are difficult to access by known methods. Initial attempts into developing asymmetric variant reveal that using cinchonine-derived dimeric PTC catalyst could afford chiral oxasilacyclohexanes in up to 92% enantiomeric excess.

The Bifunctional Silyl Reagent Me2 (CH2 Cl)SiCF3 Enables Highly Enantioselective Ketone Trifluoromethylation and Related Tandem Processes.

We report the development of bifunctional trifluoromethylsilyl reagents for selective trifluoromethylation. The newly developed reagent, Me2 (CH2 Cl)SiCF3 , allows highly enantioselective trifluoromethylations of ketones with broad scope. Notably, by taking advantage of the chloromethyl group, a tandem synthesis of chiral trifluoromethylated oxasilacyclopentanes is developed, paving way to α-CF3 tertiary alcohols with vicinal tertiary or quaternary stereocenters. Theoretical studies revealed the important role of nonclassical C-H⋅⋅⋅F-C interactions in stabilizing the transition state, and that the presence of the chlorine atom enhances such interactions for better enantiofacial control.

Me2(CH2[double bond, length as m-dash]CH)SiCN: a bifunctional ethylene equivalent for Diels-Alder reaction based controllable tandem synthesis.

A bifunctional silyl reagent Me2(CH2[double bond, length as m-dash]CH)SiCN has been developed as a novel ethylene equivalent for the Diels-Alder (DA) reaction. The use of this reagent enables the controllable synthesis of value-added cyclohexenyl ketones or 2-acyl cyclohexancarbonitrile derivatives through a five- or six-step tandem sequence based on a Wittig/cyanosilylation/DA reaction/retro-cyanosilylation/isomerization sequence that involves a temporary silicon-tethered intramolecular DA reaction.

Organocatalytic enantioselective reactions involving prochiral carbocationic intermediates.

Since the discovery of carbocations in 1901, the past 120 years have witnessed many marvelous advances in the chemistry of carbocations. The state-of-the-art research in this field is to overcome the intrinsic instability and high reactivity of the prochiral carbocationic intermediates to develop catalytic asymmetric reactions. Such transformations enable the facile synthesis of structurally diverse value-added products from readily available starting materials such as alkenes, alcohols, and carbonyl derivatives, and enjoy high and even perfect atom-economy in most cases. Notably, such allows catalytic stereoconvergent synthesis from racemic substrates and can realize regioselectivity in olefin functionalization reactions complementary to radical processes. With the rapid developments in modern asymmetric organocatalysis, a variety of highly enantioselective protocols evolving prochiral carbocationic intermediates have been achieved by employing three strategies, namely chiral ion-pairing, chiral nucleophile, or chiral carbenium ion strategy. This feature article aims to summarize the exciting advances in this emerging area and briefly showcase the possible mechanisms. The advantages and limitations of each strategy are presented as well as their synthetic applications in the synthesis of natural products or bioactive compounds.

Catalyst-Free and Solvent-Controlled Divergent Synthesis of Difluoromethylene-Containing S-Heterocycles.

An unprecedented catalyst-free reaction of benzo[b]thiophene-2,3-diones with difluoroenoxysilanes has been developed using either MeOH or H2O as the solvent, which constitutes a facile and efficient protocol for the solvent-controlled divergent synthesis of five- and seven-membered S-heterocycles featuring a gem-difluoromethylene group. A gram-scale synthesis and the diversification of the product transformations to other difluorinated S-heterocycles further highlight its utility.

Modular synthesis of chiral 1,2-dihydropyridines via Mannich/Wittig/cycloisomerization sequence that internally reuses waste.

1,2-Dihydropyridines are valuable and reactive synthons, and particularly useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals. However, the catalytic enantioselective synthesis of structurally diverse 1,2-dihydropyridines is limited to enantioselective addition of nucleophiles to activated pyridines. Here, we report a modular organocatalytic Mannich/Wittig/cycloisomerization sequence as a flexible strategy to access chiral 1,2-dihydropyridines from N-Boc aldimines, aldehydes, and phosphoranes, using a chiral amine catalyst. The key step in this protocol, cycloisomerization of chiral N-Boc δ-amino α,ß-unsaturated ketones recycles the waste to improve the yield. Specifically, recycling by-product water from imine formation to gradually release the true catalyst HCl via hydrolysis of SiCl4, whilst maintaining a low concentration of HCl to suppress side reactions, and reusing waste Ph3PO from the Wittig step to modulate the acidity of HCl. This approach allows facile access to enantioenriched 2-substituted, 2,3- or 2,6-cis-disubstituted, and 2,3,6-cis-trisubstituted piperidines.

Multiple imaging modality-guided radiofrequency ablation combined with transarterial chemoembolization for hepatocellular carcinoma in special locations.

PURPOSE: We aimed to evaluate the safety and effectiveness of radiofrequency ablation (RFA) combined with transarterial chemoembolization (TACE) guided by multiple imaging modalities for hepatocellular carcinomas (HCCs) in special (i.e., high-risk or unfavorable) locations compared with those in conventional locations. METHODS: A total of 122 HCC patients were enrolled, including 85 patients (69.7%) with HCC in conventional locations and 37 (30.3%) with HCC in special locations. The clinical data, overall survival (OS), progression-free survival (PFS), and procedure-related adverse events were analyzed. RESULTS: RFA combined with TACE was successfully performed in all patients. Three complications (2.5%) occurred, with no significant difference between the conventional (n=1, 1.2%) and special (n=2, 5.4%) locations (P = 0.218). Complete tumor necrosis rate was not significantly different between the conventional (n=73, 85.9%) and special (n=34, 91.9%) locations at one-month imaging (P = 0.353). After a follow-up of 3-48 months, the PFS was 17 months for patients with HCC in conventional locations and 14 months for patients with HCC in special locations; one-year PFS rate was 68.1% in the conventional location group, not significantly (P = 0.741) different from 59.1% in the special location group. The OS was 28 months in the conventional location group while 32 months in the special location group. The cumulative one- and two-year OS rates were 89.9% and 63.3%, respectively, in the conventional location group, not significantly different from 96.3% and 65% in the special location group (P = 0.273). Age (P = 0.043) and tumor size (P < 0.001) were significant prognostic factors for OS, and tumor size (P < 0.001) was the only significant prognostic factor for PFS. CONCLUSION: RFA guided by multiple imaging modalities combined with TACE may be safe and effective for treating HCCs in special locations.

Positive Effects of Qing'e Pill () on Trabecular Microarchitecture and its Mechanical Properties in Osteopenic Ovariectomised Mice / 中国结合医学杂志

OBJECTIVE@#To investigate the impact of Qing'e Pill (, QEP) on the cancellous bone microstructure and its effect on the level of β-catenin in a mouse model of postmenopausal osteoporosis.@*METHODS@#Ninety-six 8-week-old specific pathogen free C57BL/6 mice were randomly divided into 4 groups (24/group): sham, ovariectomised osteoporosis model, oestradiol-treated, and QEP-treated groups. Three months after surgery, the third lumbar vertebra and left femur of the animals were dissected and scanned using micro-computed tomography (micro-CT) to acquire three-dimensional (3D) parameters of their cancellous bone microstructure. The impact of ovariectomy, the effect of oestradiol and QEP intervention on cancellous bone microstructure, and the expression of β-catenin were evaluated.@*RESULTS@#The oestradioland the QEP-treated groups exhibited a significant increase in the bone volume fraction, trabecular number, trabecular thickneßs, bone surface to bone volume ratio (BS/BV), and β-catenin expression compared with those of the model group (P <0.05). In contrast, the structure model index, trabecular separation, and BS/BV were significantly decreased compared with those of the ovariectomised osteoporosis model group (P <0.05). No differences were observed in the above parameters between animals of the QEP- and oestradiol-treated groups.@*CONCLUSIONS@#The increased β-catenin expression may be the mechanism underlying QEP's improvement of the cancellous bone microstructure in ovariectomised mice. Our findings provide a scientific rationale for using QEP as a dietary supplement to prevent bone loss in postmenopausal women.

Effects of Modified Qing'e Pill () on expression of adiponectin, bone morphogenetic protein 2 and coagulation-related factors in patients with nontraumatic osteonecrosis of femoral head / 中国结合医学杂志

<p><b>OBJECTIVES</b>To observe the regulation of Chinese herbal medicine, Modifified Qing'e Pill (, MQEP), on the expression of adiponectin, bone morphogenetic protein 2 (BMP2), osteoprotegerin (OPG) and other potentially relevant risk factors in patients with nontraumatic osteonecrosis of the femoral head (ONFH).</p><p><b>METHODS</b>A total of 96 patients with nontraumatic ONFH were unequal randomly divided into treatment group (60 cases) and control group (36 cases). The treatment group were treated with MQEP while the control group were treated with simulated pills. Both groups were given caltrate D. Six months were taken as a treatment course. Patients were followed up every 2 months. The levels of plasma adiponectin, BMP2, OPG, von Willebrand factor (vWF), von Willebrand factor cleaving protease (vWF-cp), plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), C-reactive protein (CRP), blood rheology, bone mineral density (BMD) of the femoral head and Harris Hip Score were measured before and after treatment.</p><p><b>RESULTS</b>After 6 months of treatment, compared with the control group, patients in the treatment group had signifificantly higher adiponectin and BMP2 levels (P<0.01 and P=0.013, respectively), lower vWF, PAI-1 and CRP levels (P=0.019, P<0.01 and P<0.01, respectively), and lower blood rheology parameters. BMD of the femoral neck, triangle area and Harris Hip Score in the treatment group were signifificantly higher than those in the control group. Moreover, plasma adiponectin showed a positive association with BMP2 (r=0.231, P=0.003) and a negative association with PAI-1 (r=-0.159, P<0.05).</p><p><b>CONCLUSION</b>MQEP may play a protective role against nontraumatic ONFH by increasing the expression of adiponectin, regulating bone metabolism and improving the hypercoagulation state, which may provide an experimental base for its clinical effects.</p>

Association of serum Dkk-1 levels with β-catenin in patients with postmenopausal osteoporosis / 华中科技大学学报（医学）（英德文版）

Wnt signaling plays an important role in the bone development and remodeling. The Wnt antagonist Dkk-1 is a potent inhibitor of bone formation. The aims of this study were firstly to compare the serum Dkk-1 levels in postmenopausal osteoporosis patients with age-matched healthy controls, and secondly, to assess the possible relationship between Dkk-1 and β-catenin, sclerostin, or bone turnover markers [CTX, PINP, N-MID-OT and 25(OH)D] in the setting of postmenopausal osteoporosis. A total of 350 patients with postmenopausal osteoporosis and 150 age-matched healthy controls were enrolled, and the serum levels of Dkk-1, β-catenin, sclerostin, OPG, and RANKL were detected by ELISA, and bone turnover markers [CTX, PINP, N-MID-OT and 25(OH)D] were measured by Roche electrochemiluminescence system in two groups. Serum Dkk-1 levels were significantly higher in postmenopausal osteoporosis group than in control group (P<0.001). Univariate analyses revealed that serum Dkk-1 levels were weakly negatively correlated to β-catenin (r=-0.161, P=0.003) and OPG (r=-0.106, P=0.047), while multiple regression analysis showed a negative correlation between serum Dkk-1 levels with β-catenin (β=-0.165, P=0.009) and BMD (β=-0.139, P=0.027), and a positive correlation between serum Dkk-1 levels and CTX (β=0.122, P=0.040) in postmenopausal osteoporosis group. No similar correlations ware observed in control group. The results provided evidence for the role of Dkk-1 in bone metabolism and demonstrated the link of Dkk-1 and Wnt/β-catenin in some ways.

Effect of Qing'e formula on circulating sclerostin levels in patients with postmenopausal osteoporosis / 华中科技大学学报（医学）（英德文版）

Serum sclerostin is positively associated with serum 25 hydroxyvitamin D concentration. Our preliminary studies confirmed that Qing'e formula (QEF) could effectively increase serum 25 hydroxyvitamin D concentration in patients with postmenopausal osteoporosis (PMOP), but the effect of supplementation with QEF on serum sclerostin is unknown. This study investigated the effects of supplementation of QEF on serum sclerostin levels in patients with PMOP. Totally 120 outpatients and inpatients with PMOP treated in our hospital between January and October 2012 were randomly divided into QEF+calcium group, alfacalcidol+calcium group, and placebo+calcium group (n=40 each), with a follow-up period of 2 years. The serum levels of sclerostin, 25 hydroxyvitamin D, and bone turnover markers (β-CTX, N-MID and T-PINP) at baseline and at the 6th month, 1st year, 1.5th year, and 2nd year after treatment were measured. The results showed that the levels of circulating sclerostin were increased significantly at the 6th month after treatment in QEF+calcium group and alfacalcidol+calcium group as compared with placebo+calcium group (P<0.05), but there was no significant difference between the former two groups (P>0.05). The levels of β-CTX, N-MID and T-PINP in serum were decreased in both QEF+calcium group and alfacalcidol+calcium group at the 6th month after treatment, without significant difference between the two groups (P>0.05). But the levels were significantly lower than that in placebo+calcium group (P<0.05). These results suggest that the mechanism by which QEF modulates bone metabolism in patients with PMOP might be related with the effect of QEF in increasing sclerostin expression. Our findings provide a scientific rationale for using QEF as an effective drug to prevent bone loss in PMOP.

Association of serum Dkk-1 levels with β-catenin in patients with postmenopausal osteoporosis / 华中科技大学学报（医学）（英德文版）

Wnt signaling plays an important role in the bone development and remodeling. The Wnt antagonist Dkk-1 is a potent inhibitor of bone formation. The aims of this study were firstly to compare the serum Dkk-1 levels in postmenopausal osteoporosis patients with age-matched healthy controls, and secondly, to assess the possible relationship between Dkk-1 and β-catenin, sclerostin, or bone turnover markers [CTX, PINP, N-MID-OT and 25(OH)D] in the setting of postmenopausal osteoporosis. A total of 350 patients with postmenopausal osteoporosis and 150 age-matched healthy controls were enrolled, and the serum levels of Dkk-1, β-catenin, sclerostin, OPG, and RANKL were detected by ELISA, and bone turnover markers [CTX, PINP, N-MID-OT and 25(OH)D] were measured by Roche electrochemiluminescence system in two groups. Serum Dkk-1 levels were significantly higher in postmenopausal osteoporosis group than in control group (P<0.001). Univariate analyses revealed that serum Dkk-1 levels were weakly negatively correlated to β-catenin (r=-0.161, P=0.003) and OPG (r=-0.106, P=0.047), while multiple regression analysis showed a negative correlation between serum Dkk-1 levels with β-catenin (β=-0.165, P=0.009) and BMD (β=-0.139, P=0.027), and a positive correlation between serum Dkk-1 levels and CTX (β=0.122, P=0.040) in postmenopausal osteoporosis group. No similar correlations ware observed in control group. The results provided evidence for the role of Dkk-1 in bone metabolism and demonstrated the link of Dkk-1 and Wnt/β-catenin in some ways.

[Ameliorated effects of cyclovirobuxine D on oxidative stress and energy metabolism in experimental cardiac injured rats induced by sympathetic overactivity in vivo].

OBJECTIVE: To investigate the ameliorated effect of CVB-D on oxidative stress and energy metabolism in experimental cardiac injuried rats induced by sympathetic overactivity in vivo. METHODS: SD rats were randomly divided into five groups as following: control group, model group, Vitamin E 150 mg/kg group, CVB-D low dose and high dose groups, respectively. The rat experimental cardiac injury model was established by exposed to norepinephrine (NE) 3 mg/kg by ip for 16 d. The drugs were administrated to rat for 16 d by ig. The body weight of rats were monitored during all of the experimental period. At the designing ending-time point the indexes were assayed as following: cardiac index, hydroxyproline, histopathologically examination, oxidative stress ( MDA, SOD, CAT, GSH-Px and T-AOC) and energy metabolism indicatricle ( Na+, K(+) -ATPase, and Ca2+, Mg(2+) -ATPase). RESULTS: After exposed with NE for 16 d, the rats of model group was appeared dysfunction of oxidative stress and energy metabolism such as decreasing body weight, increasing cardiac index and hydroxyproline in cardiac tissue, decreasing Na+, K(+) -ATPase and Ca(2+), Mg(2+) -ATPase activities, and deteriorating the oxidative stress. Treated with CVB-D could ameliorate all of the exacerbated indexes. CONCLUSION: CVB-D has protective effect against oxidative stress and energy metabolism in rats of experimental myocardial injury induced by sympathetic overactivity.

[Protective effects of CVB-D on cardiac myocytes injury induced by high sympathesis activity in vitro].

OBJECTIVE: To investigate the protective effect of CVB-D on cardiac myocytes injury induced by high sympathesis activity and its relationship with oxidative stress. METHODS: Primary culture cardiac myocyte of new-born rat was injuried by NE and then incubated with VE and CVB-D (10 and 50 micromol/L). Indexes of cardiac myoctye injury were assayed by morphologic change, MTT, and LDH leakage ratio. The activity of SOD and the content of MDA were investigated to identify oxidation and antioxygen. RESULTS: CVB-D (10 and 50 micromol/L) significantly increased the cell survival rate,and reduced the LDH leakage rate. CVE-D (50 micromol/L) significantly increased the activity of SOD, and decreased content of MDA in injuried cell. CONCLUSION: CVB-D has protective effect against myocardial injury induced by high sympathesis activity, the mechanism involves in ameliorating oxidative stress.

Serum sclerostin levels associated with lumbar spine bone mineral density and bone turnover markers in patients with postmenopausal osteoporosis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Sclerostin, expressed exclusively by osteocytes, is a negative regulator of bone formation. To gain insights into the action of sclerostin in postmenopausal osteoporosis, we evaluated serum sclerostin levels in postmenopausal women and investigated its possible associations with bone turnover markers in patients with postmenopausal osteoporosis.</p><p><b>METHODS</b>We detected serum sclerostin, and measured lumbar spine bone mineral density in 650 Chinese postmenopausal women. We also assessed serum levels of β-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin, 25-hydroxyvitamin D, and estradiol.</p><p><b>RESULTS</b>Serum sclerostin levels were lower in postmenopausal osteoporotic women compared with non-osteoporotic postmenopausal women ((38.79 ± 7.43) vs. (52.86 ± 6.69) pmol/L, P < 0.001). Serum sclerostin was positively correlated with lumbar spine bone mineral density (r = 0.391, P < 0.001) and weakly negatively correlated with β-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin (r = -0.225, P < 0.001; r = -0.091, P = 0.046; r = -0.108, P = 0.018; respectively) in postmenopausal osteoporosis. There was no significant association of serum sclerostin with age, body mass index, 25-hydroxyvitamin D, and estradiol (r = -0.004, P = 0.926; r = 0.067, P = 0.143; r = 0.063, P = 0.165; r = -0.045, P = 0.324; respectively).</p><p><b>CONCLUSION</b>Sclerostin may be involved in the pathogenesis of postmenopausal osteoporosis and may play a role in bone turnover.</p>

Effects of Bushen Huogu decoction on bone metabolism of ovariectomized osteoporotic rats / 中国组织工程研究

BACKGROUND: Bushen Huogu decoction can effectively prevent and treat osteoporosis, but the concrete mechanism of pharmacology is still not clear. 25-hydroxy vitamin D3 and 1, 25-dihydroxyvitamin D3 are important coupling factors, which can regulate bone resorption and formation.OBJECTIVE: To investigate the curative effects of Bushen Huogu decoction on the bone mineral density, bone biomechanics, and level of 25-hydroxy vitamin D3 and 1, 25-dihydroxyvitamin D3 in blood serum, liver and kidney in the ovariectomized osteoporotic rats.METHODS: Totally 108 healthy female Sprague-Dawley rats were randomly divided into model group, sham-operated group, andtreatment group. All rats had been ovariectomized to induce estrogen absence and further establish osteoporotic models, except those in sham-operated group. Treatment group of rats were intragastrically administrated with 2 mL Bushen Huogu decoction,twice a day.RESULTS AND CONCLUSION: Compared with model group, the bone mineral density in the rat femur was significantly increased in the treatment group (P 0.05). In the early period of estrogenic hormone absence, the Chinese kidney-tonifying drugs could activate bone metabolism, raise bone mineral density and reinforce quality of bone through up-regulating expression of 25-hydroxy vitamin D3 and 1,25-dihydroxyvitamin D3.

[Analysis of risk factors for urinary continence after radical prostatectomy].

OBJECTIVE: There are many causative factors for the occurrence of post-prostatectomy incontinence. Objective clinical characteristics, surgical techniques and pelvic floor muscle therapy are the most important ones. The present study was to identify the risk factors associated with urinary incontinence after radical retropubic prostatectomy (RRP). METHODS: A total of 263 patients were recruited for this multivariate analysis. After a close follow-up, a series of pre-, peri- and post-operative factors were recorded and analyzed. RESULTS: Urinary continence after radical prostatectomy was 14.8% at 4 weeks and 94.7% at 16 weeks. The most important recovery interval for urinary continence was 4 - 16 weeks post-operation. Multivariate analysis revealed that age (P = 0.015), blood transfusion (P = 0.017), previous TURP (transurethral resection of the prostate) (P = 0.006) and neoadjuvant hormonal therapy (P = 0.005) were the important risk factors for urinary incontinence. CONCLUSION: During RRP, optimized preservation of urethral rhabdosphincter length, nerve sparing and early postoperative functional exercises can improve the recovery of urinary continence. Age, blood transfusion and previous TURP are the independent prognostic factors. Neoadjuvant hormonal therapy may improve urinary continence through increasing the preoperative length of membranous urethra.