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HYR-PB21 is a new sustained-release formulation of bupivacaine indicated for controlling postoperative pain. The objectives of this study were to investigate the analgesic efficacy and safety profile of HYR-PB21 in patients after haemorrhoidectomy.This was a multicentre, randomised, double-blind, positive-controlled trial. Patients were assigned randomly to receive a single dose of HYR-PB21 (150 mg or 300 mg) or bupivacaine HCl (75 mg) after surgery for prolapsing haemorrhoids. Postoperative pain was evaluated using a numeric rating scale at rest to calculate a cumulative pain score. Total rescue opioid usage and the proportion of subjects receiving rescue opioid were also assessed.We enrolled 72 patients with haemorrhoidectomy, and 71 patients completed the study. The average cumulative pain score through 72 h after surgery in the 300 mg HYR-PB21 group (87 scores) was lower than in the bupivacaine HCl group (166 scores) in an intention-to-treat analysis (P0.001). There was a dose-response effect in reducing total opioid usage and the proportion of rescue opioid use between the 150 mg and 300 mg HYR-PB21 groups, with bupivacaine HCl as a reference group. The HYR-PB21 groups did not show more adverse effects than the bupivacaine HCl group.Local infiltration of a single dose of HYR-PB21 sustained-release bupivacaine had better efficacy in controlling postoperative pain, with similar adverse effects, compared with a single dose of bupivacaine HCl in patients after haemorrhoidectomy.ChiCTR2000041318 (Chinese Clinical Trial Registry).

In this study, a 100-kHz narrow-linewidth burst-mode laser system combined with a master oscillator power amplifier (MOPA) structure was reported with a stable pulse burst profile over 2 ms duration. A theoretical model was established to characterize and compensate the variation characteristics of coefficient of variation (COV) within a burst envelope for the double-pass three-stage amplification system, in terms of different parameter factors. Simulated results yielded similar tendency with the measured ones. For a stable burst envelope with a COV of 2.72% and 2.93%, output pulse energy at a 100 kHz repetition rate was scaled up to 1.08 and 4.38 mJ in the case of an input average pulse energy of 8.6 and 116.51 nJ, respectively. Corresponding Mx2 and My2 values with 2.2 and 2.4 were endowed with 1.08 mJ output single-pulse energy and 2.7 and 2.1 for 4.38 mJ pulse energy. The spectral linewidth of amplified pulses was measured to be less than 83.1 and 67.9 MHz, with respect to output pulse duration of 10.3 and 96.1 ns, respectively.

A temporal pre-shaped burst-mode hybrid fiber-bulk laser system was illustrated at a 10 kHz rate with a narrow spectral linewidth. A theoretical model was proposed to counteract the temporal profile distortion and compensate for the desired one, based on reverse process of amplification. For uniformly modulated injection, amplified shapes were recorded and investigated in series for their varied pulse duration, envelope width and amplification delay, respectively. The pre-shaped output effectively realized a uniform distribution on a time scale for both the burst envelope and pulse shape under the action of the established theoretical method. Compared with previous amplification delay methods, this model possesses the capacity to extend itself for applications in burst-mode shaping with variable parameters and characteristics. The maximum pulse energy was enlarged up to 9.68 mJ, 8.94 mJ and 6.57 mJ with a 300 ns pulse duration over envelope widths of 2 ms to 4 ms. Moreover, the time-averaged spectral bandwidths were measured and characterized with Lonrentz fits of 68.3 MHz, 67.2 MHz and 67.7 MHz when the pulse duration varied from 100 ns to 300 ns.

In order to obtain a 1053 nm output laser with a high beam quality, the mode distribution of the YLF solid laser with a plane-plane resonator is studied. According to the Collins theory, the influences of the position and size parameters of a Gaussian aperture on the mode of the output beam is simulated and analyzed. Compared with the simulation results without a Gaussian aperture, the Gaussian aperture in the cavity can significantly improve the quality of the output laser. Based on the theoretical simulations, a laser with optimal structural parameters is built. The profiles and mode distributions of the laser output beams with a Gaussian aperture and without a Gaussian aperture in the cavity are measured, respectively. When the radius of the light spot on the film of the Gaussian aperture is 4 mm and the distance between the Gaussian aperture and total-reflection mirror is 30 mm, a 1053 nm laser output with the values of M2 in the x and y directions of 1.9 and 1.8, and maximum output power of 9.7 W is obtained. The experimental results demonstrate that the Gaussian aperture in the cavity can improve the mode distribution of the cavity and obtain the laser output with a higher beam quality, which is basically consistent with the results of theoretical simulations.

PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10–1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory.

Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFRα kinase inhibitor 15i (CHMFL-PDGFRα-159), which exhibited strong potency against purified PDGFRα (IC50: 132 nM) but not structurally similar PDGFRβ, ABL, c-KIT and VEGFR2 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 μM among 468 kinases/mutants in the KINOMEscan profiling. X-ray crystal structure of 15i in complex with PDGFRα revealed a distinct binding feature in the allosteric hydrophobic pocket which might help to expand the diversity of type II kinase inhibitors. Compound 15i potently inhibited the proliferation of PDGFRα driving Chronic Eosinophilic Leukemia (CEL) cell line EOL-1 through strong blockage of PDGFRα mediated signaling pathways, arresting cell cycle progression, and induction of apoptosis. Furthermore, compound 15i effectively suppressed the EOL-1 tumor progression in the xenograft model and increased the survival rate in the engraftment tumor model.

In this paper, a continuous wave (CW) and rhenium disulphide (ReS2) passively Q-switched Nd:GdTaO4 laser under the pump at 879 nm was firstly reported. CW output characteristics under indirect 808 nm pumping and direct 879 nm pumping were investigated, respectively. By comparison with indirect pumping, the direct pump at 879 nm effectively relieved thermal lenses effect. Under direct pumping, the maximum CW output power was 5.1 W with slope efficiencies (ηs) of 48.6%. In the indirect pumping a maximum CW output power of 4.3 W was obtained, corresponding to ηs of 41.2%. A ReS2 nanosheet was utilized to achieve the pulsed laser output. At absorbed pump power of 7.1 W, the highest repetition rate, narrowest pulse width, maximum average output power, single pulse energy, and peak power reached 67 kHz, 230 ns, 1 W, 14.93 μJ, and 64.9 W, respectively.

A self-assembled ZnO tail-like cluster (TC) had been successfully synthesized by a simple chemical vapor deposition method. Scanning electron microscopy observations show that ZnO TC is composed of bushy ZnO microwires with flower-shaped cross sections. Long and narrow furrows can be clearly observed on the surface of the ZnO TC. A possible growth model is proposed to discuss the formation mechanism. The analytical result indicates that the flower-shaped ZnO microwires are formed by the lateral coalescence of ZnO wires at high temperature. The room temperature PL spectrum shows a prominent UV emission band around 380 nm, and no green emission is found, implying that the unique flower-shaped ZnO microwires have high optical quality. This controlled growth of ZnO TC may have implication for potential applications in novel optoelectronic micro/nanodevices in the near future.

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3-ITD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavailability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg-1 day-1, TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-ITD positive AML.

// Chen Hu 1, 2, * , Aoli Wang 1, 2, * , Hong Wu 1, 3, * , Ziping Qi 1, 3, * , Xixiang Li 1, 3, * , Xiao-E Yan 4, * , Cheng Chen 1, 2 , Kailin Yu 1, 2 , Fengming Zou 1, 3 , Wenchao Wang 1, 3 , Wei Wang 1, 3 , Jiaxin Wu 1, 2 , Juan Liu 1, 2 , Beilei Wang 1, 2 , Li Wang 1, 2 , Tao Ren 5 , Shanchun Zhang 3, 6 , Cai-Hong Yun 4 , Jing Liu 1, 3 , Qingsong Liu 1, 2, 3, 5 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China 2 University of Science and Technology of China, Hefei, Anhui 230036, P. R. China 3 CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui 230031, P. R. China 4 Institute of Systems Biomedicine, Department of Biophysics, Beijing Key Laboratory of Tumor Systems Biology and Center for Molecular and Translational Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China 5 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China 6 Hefei Cosource Medicine Technology Co. LTD., Hefei, Anhui 230031, P. R. China * These authors have contributed equally to this work Correspondence to: Cai-Hong Yun, email: yunch@hsc.pku.edu.cn Jing Liu, email: jingliu@hmfl.ac.cn Qingsong Liu, email: qsliu97@hmfl.ac.cn Keywords: EGFR, EGFRT790M, NSCLC, kinase inhibitors, drug resistance Received: December 09, 2016 Accepted: January 23, 2017 Published: February 17, 2017 ABSTRACT EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct “DFG-in” and “cHelix-out” inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose.

In this paper, a continuous wave (CW) and two-dimensional (2D) tin diselenide (SnSe2) and palladium diselenide (PdSe2) passively Q-switched Nd:GdNbO4 laser under direct pumping was demonstrated for the first time. The CW laser performance under the pump at 879 nm was compared to that using traditional 808 nm pumping. The 2D SnSe2 and PdSe2 nanosheets were synthesized by chemical vapor deposition (CVD) technique. The optical properties and microstructures of two nanosheets were investigated. In the passively Q-switched operation, the highest repetition rate, narrowest pulse width, maximum pulse energy and peak power of SnSe2/Nd:GdNbO4 laser were 160 kHz, 555 ns, 2.3 μJ and 4.2 W, respectively. And for PdSe2/Nd:GdNbO4 laser, the corresponding values were 143 kHz, 530 ns, 3.7 μJ and 7.0 W, respectively.

The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC50: 46 nM) and c-KIT kinase (IC50: 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 μM among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors d...

// Xiaochuan Liu 1, 2, * , Aoli Wang 2, 3, * , Xiaofei Liang 2, 4, * , Juanjuan Liu 2, 3, * , Fengming Zou 2, 4, * , Cheng Chen 2, 4, * , Zheng Zhao 2, 4 , Yuanxin Deng 2, 3 , Hong Wu 2, 3 , Ziping Qi 2, 4 , Beilei Wang 2, 4 , Li Wang 2, 4 , Feiyang Liu 2, 3 , Yunhe Xu 1 , Wenchao Wang 2, 4 , Stacey M. Fernandes 5 , Richard M. Stone 5 , Ilene A. Galinsky 5 , Jennifer R. Brown 5 , Teckpeng Loh 1 , James. D. Griffin 5 , Shanchun Zhang 4, 6 , Ellen L. Weisberg 5 , Xin Zhang 2 , Jing Liu 2, 4 , Qingsong Liu 2, 3, 7 1 Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China 2 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China 3 University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China 4 CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA 6 Hefei Cosource Medicine Technology Co. LTD. Hefei, 230031, Anhui, P.R.China 7 Hefei Science Center, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China * These authors have contributed equally to this work Correspondence to: Ellen L. Weisberg, email: Ellen_weisberg@dfci.harvard.edu Xin Zhang, email: xinzhang@hmfl.ac.cn Jing Liu, email: jingliu@hmfl.ac.cn Qingsong Liu, email: qsliu97@hmfl.ac.cn Keywords: PI3Kδ, Vps34, combination, chronic lymphatic leukemia, acute myeloid leukemia Received: April 19, 2016 Accepted: June 03, 2016 Published: July 18, 2016 ABSTRACT PI3Kδ has been found to be over-expressed in B-Cell-related malignancies. Despite the clinical success of the first selective PI3Kδ inhibitor, CAL-101, inhibition of PI3Kδ itself did not show too much cytotoxic efficacy against cancer cells. One possible reason is that PI3Kδ inhibition induced autophagy that protects the cells from death. Since class III PI3K isoform PIK3C3/Vps34 participates in autophagy initiation and progression, we predicted that a PI3Kδ and Vps34 dual inhibitor might improve the anti-proliferative activity observed for PI3Kδ-targeted inhibitors. We discovered a highly potent ATP-competitive PI3Kδ/Vps34 dual inhibitor, PI3KD/V-IN-01, which displayed 10-1500 fold selectivity over other PI3K isoforms and did not inhibit any other kinases in the kinome. In cells, PI3KD/V-IN-01 showed 30-300 fold selectivity between PI3Kδ and other class I PI3K isoforms. PI3KD/V-IN-01 exhibited better anti-proliferative activity against AML, CLL and Burkitt lymphoma cell lines than known selective PI3Kδ and Vps34 inhibitors. Interestingly, we observed FLT3-ITD AML cells are more sensitive to PI3KD/V-IN-01 than the FLT3 wt expressing cells. In AML cell inoculated xenograft mouse model, PI3KD/V-IN-01 exhibited dose-dependent anti-tumor growth efficacies. These results suggest that dual inhibition of PI3Kδ and Vps34 might be a useful approach to improve the PI3Kδ inhibitor’s anti-tumor efficacy.

// Su Hang 1, 2 , Agnes F.Y. Tiwari 1 , Hextan Y.S. Ngan 3 , Yim-Ling Yip 4 , Annie L.M. Cheung 4 , Sai Wah Tsao 4 , Wen Deng 1 1 School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China 2 College of Forensic Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shanxi Province, P.R. China 3 Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, SAR, China 4 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China Correspondence to: Wen Deng, email: wdeng@hku.hk Keywords: cervical epithelial cells, immortalization, p16 INK4a , telomerase, HPV-negative Received: March 13, 2016 Accepted: May 29, 2016 Published: June 17, 2016 ABSTRACT Cervical epithelial cell immortalization with defined genetic factors without viral oncogenes has never been reported. Here we report that HPV-negative cervical epithelial cells failed to be immortalized by telomerase activation or the combination of p53 knockdown and telomerase activation. Under those conditions, p16 INK4a expression was always elevated during the late stage of limited cell lifespan, suggesting that cervical epithelial cells possess an intrinsic property of uniquely stringent activation of p16 INK4a , which may offer an explanation for the rarity of HPV-negative cervical cancer. Combining p16 INK4a knockdown with telomerase activation resulted in efficient immortalization of HPV-negative cervical epithelial cells under ordinary culture conditions. Compared with the HPV16-E6E7-immortalized cell lines derived from the same primary cell sources, the novel HPV-negative immortalized cell lines had lower degrees of chromosomal instability, maintained more sensitive p53/p21 response to DNA damage, exhibited more stringent G2 checkpoint function, and were more resistant to replication-stress-induced genomic instability. The newly immortalized HPV-negative cervical epithelial cell lines were non-tumorigenic in nude mice. The cell lines can be used not only as much-needed HPV-negative non-malignant cell models but also as starting models that can be genetically manipulated in a stepwise fashion to investigate the roles of defined genetic alterations in the development of HPV-negative cervical cancer.

c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.

// Xiaochuan Liu 1, 2, * , Aoli Wang 2, 3, * , Xiaofei Liang 2, 4, * , Cheng Chen 2, 4, * , Juanjuan Liu 2, 3 , Zheng Zhao 2, 4 , Hong Wu 2, 3 , Yuanxin Deng 2, 3 , Li Wang 2, 4 , Beilei Wang 2, 4 , Jiaxin Wu 2, 3 , Feiyang Liu 2, 3 , Stacey M. Fernandes 5 , Sophia Adamia 5 , Richard M. Stone 5 , Ilene A. Galinsky 5 , Jennifer R. Brown 5 , James D. Griffin 5 , Shanchun Zhang 4, 6 , Teckpeng Loh 1 , Xin Zhang 2 , Wenchao Wang 2, 4 , Ellen L. Weisberg 5 , Jing Liu 2, 4 , Qingsong Liu 2, 4, 7 1 Department of Chemistry, University of Science and Technology of China, Hefei 230036, Anhui, P. R. China 2 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China 3 University of Science and Technology of China, Hefei 230036, Anhui, P. R. China 4 CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China 5 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA 6 Hefei Cosource Medicine Technology Co. LTD., Hefei 230031, Anhui, P. R. China 7 Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China * These authors have contributed equally to this work Correspondence to: Wenchao Wang, email: wwcbo@hmfl.cas.cn Ellen L. Weisberg, email: Ellen_weisberg@dfci.harvard.edu Jing Liu, email: jingliu@hmfl.ac.cn Qingsong Liu, email: qsliu97@hmfl.ac.cn Keywords: PI3Kδ, leukemia, B-cell malignances, PI3K, kinase inhibitors Received: January 14, 2016 Accepted: March 28, 2016 Published: April 12, 2016 ABSTRACT PI3Kδ is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KD-IN-015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate anti-proliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.

The FLT3-ITD mutation is one of the most prevalent oncogenic mutations in AML. Several FLT3 kinase inhibitors have shown impressive activity in clinical evaluation, however clinical responses are usually transient and clinical effects are rapidly lost due to drug resistance. One of the resistance mechanisms in the AML refractory patients involves FLT3-ligand induced reactivation of AKT and/or ERK signaling via FLT3 wt kinase. Via a screen of numerous AKT kinase inhibitors, we identified the well-established orally available AKT inhibitor, A674563, as a dual suppressor of AKT and FLT3-ITD. A674563 suppressed FLT3-ITD positive AML both in vitro and in vivo. More importantly, compared to other FLT3 inhibitors, A674563 is able to overcome FLT3 ligand-induced drug resistance through simultaneous inhibition of FLT3-ITD- and AKT-mediated signaling. Our findings suggest that A674563 might be a potential drug candidate for overcoming FLT3 ligand-mediated drug resistance in FLT3-ITD positive AML.

Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

A continuous wave (CW) and passively Q-switched 1 . 06 μ m Nd:GdLaNbO4 laser under direct 879 nm pumping is firstly reported in this paper. The CW output power and slope efficiency varied from 4.50 W and 45.6% to 6.55 W and 50.0% when the indirect pumping of 808 nm was changed to the direct pumping of 879 nm. Furthermore, the beam quality was also improved significantly. For the CW Nd:GdLaNbO4 laser, as is known to all that the highest output power with excellent beam quality was obtained. In the Q-switched operation, rhenium disulfide (ReS2) synthetized by chemical vapor deposition (CVD) method was employed as a saturable absorber (SA). The optical properties and atom force microscope (AFM) image of ReS2 were measured and recorded to characterize it. A maximum average output power with 312 mW, a narrowest pulse width with 400 ns, and a highest repetition rate with 147 kHz were obtained under the direct 879 nm pumping.

A comparison of the pulsed laser performances of 2 μm passively Q-switched Tm:YAlO3 (YAP) lasers based on the use of tungsten disulfide (WS2) and molybdenum disulfide (MoS2) two-dimensional (2D) nanosheets as saturable absorbers is reported. The novel nanosheets were prepared by chemical vapor deposition (CVD) technology. The microstructure and optical characteristics of the nanosheets were investigated experimentally. In a continuous-wave (CW) operation, the maximum output power of 2.8 W was obtained at an absorbed pump power of 6.9 W, with a corresponding slope efficiency of 46.4%. In a passively Q-switched operation at a pump power of 1.45 W, the average output power, pulse width, repetition rate, pulse energy, and peak power for the Tm:YAP/WS2 laser were 0.11 W, 2.65 μs, 34.7 kHz, 2.9 μJ, and 1.23 W, respectively. As for the Tm:YAP/MoS2 laser, the corresponding values were 0.10 W, 2.5 μs, 24.0 kHz, 3.8 μJ, and 1.55 W.

In this work, a novel two-dimensional palladium diselenide (PdSe2) nanosheet was synthesized by chemical vapour deposition method and used as a saturable absorber (SA) for generation of Q-switched laser pulses. The microstructure and optical properties of PdSe2 nanosheet were investigated. For laser emission, a newly developed Nd:GdLaNbO4 mixed crystal was used as the gain medium, while the pump was done with fiber-coupled diode laser at 879 nm, directly into the 4F3/2 emitting level. The Q-switched Nd:GdLaNbO4/PdSe2 laser yielded 405 mW average output power for 8.8 W absorbed pump power at 879 nm. The laser runs at 164 kHz with 2.47 μJ energy per pulse; pulse duration was 340 ns, indicating a pulse peak power of 7.26 W. These first results prove that PdSe2 nanosheet can be used as SA in passively Q-switch laser devices.

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI50 = 22 nM), MOLM13/14 (GI50 = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.

Objective To investigate ethnic difference in the associations of BMI with comorbidity, mortality, and body composition between mainland Chinese and U.S. whites. Methods Ethnic-comparison study using data from China Health and Nutrition Survey, U.S. National Health and Nutrition Examination Survey, and data from Zhejiang University (China) and Columbia University (U.S.). Results Chinese people experienced greater odds of comorbidities than whites for a given BMI after standardizing for age and sex: 43% for diabetes, 30% for dyslipidemia, 28% for hypertension, 38% for metabolic syndrome, and 48% for hyperuricemia. Comparisons of BMI-mortality associations found that the U-shaped BMI-mortality curve shifted 1-2 kg m(-2) to the left in Chinese compared to whites. Compared to whites at BMIs of 25 and 30 kg m(-2), corresponding cutoffs in Chinese were 22.5 and 25.9 kg m(-2) in men, and 22.8 and 26.6 kg m(-2) in women after both fat and fat distribution were taken into account. Conclusions Comorbidity, mortality, and body composition data consistently support the use of lower BMI cutoffs in Chinese than those in whites.

Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy. Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC.

On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.

Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC50: 7 nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35) = 0.00) among 468 kinases/mutants at the concentration of 1 μM. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited BTK Y223 auto-phosphorylation (EC50

The purpose of this study was to examine whether social relationships were associated with sleep status in Chinese undergraduate students. A cross-sectional questionnaire survey was conducted in November 2012 at Huzhou Teachers College, China. The questionnaire involved demographic characteristics, personal lifestyle habits, social relationships and Pittsburgh Sleep Quality Index (PSQI). The associations between social relationships and sleep status were analyzed by using regression models after adjustment for potential factors. Poor sleep quality was prevalent among Chinese undergraduate students. Men tended to have better sleep than women. Lower social stress, better management of stress and good social support were correlated with better sleep status, and stress or support from friends, family and classmates were all related with sleep variables. While only weak associations between number of friends and sleep were detected. The results were consistent in men and women. Educators and instructors should be aware of the importance of social relationships as well as healthy sleep in undergraduates.

Objectives As the primary cause of lung cancer, whether smoking confers the same risk of lung cancer for women as men is unclear. Therefore, we aimed to compare male and female susceptibility for cigarette smoking-attributable lung cancer. Methods A systematic review and meta-analysis was conducted by searching articles published up to July 2013 in three online databases (MEDLINE, EMBASE, and Cochrane Database). All studies estimated the association of cigarette smoking with the risk of lung cancer between men and women, respectively. A random effects model with inverse variance weighting was used to pool data. Male to female ratio of relative risk (RRR) was calculated to compare male and female susceptibility for cigarette smoking-attributable lung cancer. Results 47 articles containing 404,874 individuals were included in the final analysis. Compared with non-smokers, male to female RRR was 1.61 (95%CI: 1.37, 1.89) among current smokers. Based on pathological type, adenocarcinoma had the highest RRR (1.42; 95%CI: 0.86, 2.35), followed by squamous cancer and small cell lung cancer. Furthermore, compared with non-smoking men, current smoking men had higher risk of lung cancer than women in spite of smoking quantity, smoking duration or years since quitting. Conclusions These findings indicated that males had higher susceptibility for cigarette smoking-attributable lung cancer than females. It is contradicted with traditional opinion that females would be more easily suffered from cigarette smoking-attributable health problems than males. Hence, tobacco control is very crucial in both males and females.

A novel pulsed 1065 nm Nd:GdLaNbO4 laser using 2D material molybdenum disulfide (MoS2) as saturable absorber was demonstrated for the first time to our best knowledge. The characteristic of 2D MoS2 nanosheet was examined firstly. Then, the continuous wave output power was tested and corresponding intensity distribution and beam quality factors were measured and calculated, respectively. Through adding of MoS2 nanosheet, the obtained shortest pulse duration, highest repetition rate and peak power were 0.59 μs, 112 kHz and 1.90 W, respectively.

BACKGROUND Hypertensive disorders of pregnant women are one of the important causes of maternal and perinatal morbidity and mortality. Evidence showed mental stress might be a risk factor of gestational hypertensive disorders. OBJECTIVE The objective of this study was to evaluate the relationships between mental stress and gestational hypertension/preeclampsia in pregnant women. METHODS Relevant studies were identified by PubMed, Cochrane, Chinese medical datasets (Wanfang, CNKI, and VIP Database). Only case-control or cohort studies evaluating an association of preeclampsia or gestational hypertension with mental stress were included in the present meta-analysis. Essential information was extracted from the qualified studies. Odds ratio (OR) was used as a pooled effect size. Potential heterogeneity and publication bias were detected as well. RESULTS Thirteen studies were included in the final analyses, which totally recruited 668,005 pregnant women. The results indicated that mental stress was associated with an increased risk of gestational hypertension (OR, 1.26; 95% confidence interval [CI], 1.00-1.59; P = 0.047) and preeclampsia (OR, 1.49; 95%CI, 1.27-1.74; P < 0.001). Meanwhile, work stress (OR, 1.50; 95% CI, 1.15-1.97; P = 0.003) and anxiety or depression (OR, 1.88; 95%CI, 1.08-3.25; P = 0.02)were positively associated with risk of preeclampsia. CONCLUSIONS Mental stress during life or pregnancy may be a risk factor for gestational hypertension and preeclampsia among pregnant women.

Maternal obesity is associated with a variety of common diseases in the offspring. One possible underlying mechanism could be maternal obesity induced alterations in DNA methylation. However, this hypothesis is yet to be tested. We performed epigenomic mapping of cord blood among 308 Black mother-infant pairs delivered at term at the Boston Medical Center using the Illumina HumanMethylation27 BeadChip. Linear regression and pathway analyses were conducted to evaluate the associations between DNA methylation levels and prepregnancy maternal BMI (

The initiators caspase-9 (CASP9) and caspase-10 (CASP10) are two key controllers of apoptosis and play important roles in carcinogenesis. This study aims to explore the association between CASPs gene polymorphisms and colorectal cancer (CRC) susceptibility in a population-based study. A two-stage designed population-based case-control study was carried out, including a testing set with 300 cases and 296 controls and a validation set with 206 cases and 845 controls. A total of eight tag selected single nucleotide polymorphisms (SNPs) in CASP9 and CASP10 were chosen based on HapMap and the National Center of Biotechnology Information (NCBI) datasets and genotyped by restriction fragment length polymorphism (RFLP) assay. Multivariate logistic regression models were applied to evaluate the association of SNPs with CRC risk. In the first stage, from eight tag SNPs, three polymorphisms rs4646077 (odds ratio (OR)(AA+AG): 0.654, 95% confidence interval (CI): 0.406-1.055; P=0.082), rs4233532 (OR(CC): 1.667, 95% CI: 0.967-2.876; OR(CT): 1.435, 95% CI: 0.998-2.063; P=0.077), and rs2881930 (OR(CC): 0.263, 95% CI: 0.095-0.728, P=0.036) showed possible association with CRC risk. However, none of the three SNPs, rs4646077 (OR(AA+AG): 1.233, 95% CI: 0.903-1.683), rs4233532 (OR(CC): 0.892, 95% CI: 0.640-1.243; OR(CT): 1.134, 95% CI: 0.897-1.433), and rs2881930 (OR(CC): 1.096, 95% CI: 0.620-1.938; OR(CT): 1.009, 95% CI: 0.801-1.271), remained significant with CRC risk in the validation set, even after stratification for different tumor locations (colon or rectum). In addition, never tea drinking was associated with a significantly increased risk of CRC in testing set together with validation set (OR: 1.755, 95% CI: 1.319-2.334). Our results found that polymorphisms of CASP9 and CASP10 genes may not contribute to CRC risk in Chinese population and thereby the large-scale case-control studies might be in consideration. In addition, tea drinking was a protective factor for CRC.

cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.

This study aims to explore the associations of polymorphisms in tachykinin, precursor 1 (TAC1), tachykinin receptor 1 (TACR1), and tachykinin receptor 2 (TACR2) genes and their interactions with the risk of colorectal cancer (CRC) among Chinese population.A population-based case-control study which included 394 cases and 393 cancer-free controls was carried out. A total of 19 tagSNPs in the three genes were chosen based on HapMap and NCBI datasets and genotyped by SNPshot assay. Multiple logistic regression models were applied to evaluate the associations of SNPs with CRC after adjustment for potential covariates. Furthermore, generalized multifactor dimensionality reduction (GMDR) method was used to test the interactive effect among three genes on CRC.Compared with those carrying rs3755457 CC/CT or rs12477554 TT/CT genotype, individuals carrying homozygous variants had higher risk of colorectal cancer (adjusted OR = 1.80, 95 % CI = 1.03-3.13, P = 0.039 for rs3755457; adjusted OR = 1.73, 95 % CI = 1.07-2.79, P = 0.024 for rs12477554). As for rs10198644, GG genotype was associated with a 1.72-fold (95 % CI = 0.37-0.88) decreased risk when compared with the common CC genotype. Moreover, the GMDR analysis indicated that the best interactive model included five polymorphisms: rs2072100 (TAC1), rs10198644 (TACR1), rs2193409 (TACR1), rs3771810 (TACR1), and rs4644560 (TACR2).Our study suggests that tachykinins pathway genes may participate in the development of CRC and the potential interactions among the three genes on CRC may exist, which has to be confirmed in future larger studies.

OBJECTIVE To evaluate associations between adiposity trajectories over time and insulin sensitivity and glucose deterioration in a Chinese twin cohort. RESEARCH DESIGN AND METHODS This study focused on 341 males and 292 females aged 20–50 years at baseline who had physical clinical examinations and oral glucose tolerance test at two time points with an average of 6 years apart. BMI, waist circumference, percent body fat (PBF), and percent trunk fat (PTF) trajectories were classified into five track groups based on age- and sex-specific tertiles at each visit. We calculated the odds of the insulin sensitivity index(0,120) [ISI(0,120)] or glycemic deterioration at follow-up among five defined trajectories (tertilebaseline → tertilefollow-up) using generalized estimate equation models. Additionally, we applied structural equation models to examine genetic and environmental influences on adiposity, adiposity change over time (ACO), ISI(0,120), and the interrelationships among them. RESULTS Participants with stable adiposity (BMI, waist circumference, PBF, and PTF) in the highest tertile or shifting to the highest tertile tended to have the lowest ISI(0,120) at follow-up or experience glycemic deterioration. Genetic factors exerted the major influence on adiposity, but environmental factors unique to each twin contributed more strongly to ISI and ACO. Correlations between adiposity/ACO and insulin sensitivity were mainly due to environmental influences. CONCLUSIONS When adiposity stays or becomes high, insulin sensitivity falls and risk of glycemic deterioration rises. Additionally, we found that genetic factors exerted the major influence on adiposity, while environmental factors played the principal role for ACO and insulin sensitivity.

Summary Due to the high morbidity and mortality of colorectal cancer (CRC), this study aims to determine the joint association of RE-1-silencing transcription factor (REST) and nuclear factor-κB 1 (NFKB1) genes with CRC in a population-based study. A well-matched case-control study including 390 controls and 388 patients with CRC was enrolled in China. The selected single nucleotide polymorphisms (SNPs) in the REST and NFKB1 genes were genotyped by Illumina SnapShot Chip. After adjustment for important covariates, the associations of SNPs and joint association of REST and NFKB1 with CRC were evaluated by multiple logistic regression models. The subjects with the rs2228991 AA genotype of the REST gene had a decreased risk for CRC (OR = 0.38; 95%CI: 0.19–0.74), compared with the GG genotype. There were no significant associations between three SNPs in the NFKB1 gene, their haplotype and CRC risk. However, a significant combined effect of rs3774959 and rs3774964 in the NFKB1 gene with rs2228991 in the REST gene on CRC risk was observed. In conclusion, the present study found that mutation in the REST gene rather than the NFKB1 gene was associated with the risk of CRC. Furthermore, significant REST-NFKB1 joint association was observed for CRC, colon cancer and rectal cancer risk.

Objective: Xeroderma pigmentosum complementation group C (XPC) participates in the initial recognition of DNA damage during nucleotide excision repair process in global genomic repair. Our meta-analysis was performed to evaluate the association between three polymorphisms (Lys939Gln, PAT+/– and Ala499Val) of XPC gene and risk of digestive system cancers. Methods: All the relevant case-control studies published to April 2011 were identified through searching PubMed. Digestive system cancer risk with the three polymorphisms was estimated for each study by odds ratio (OR) with its 95% confidence interval (95% CI). Results: We found an increased overall risk for digestive system cancers in all three models of Lys939Gln A>C (AC/CC vs. AA: OR, 1.20; 95% CI, 1.11–1.30; CC vs. AC/AA: OR, 1.24; 95% CI, 1.11–1.39; CC vs. AA: OR, 1.36; 95% CI, 1.21–1.53). When stratified by ethnicity, results remained significant in Asian population (AC/CC vs. AA: OR, 1.18; 95% CI, 1.02–1.37; CC vs. AC/AA: OR, 1.32; 95% CI, 1.1–1.51; CC vs. AA: OR, 1.35; 95% CI, 1.08–1.70), but not for Caucasians. However for Ala499Val C>T, a significant protective effect of T allele was only observed in the dominant model. Otherwise, no significant results were observed for PAT+/–. Conclusion: XPC Lys939Gln A>C polymorphism may play an important role in digestive system cancer susceptibility.

Objective To investigate the association between sleep duration and insulin resistance in rural Chinese adults and examine whether any such associations are independent of adiposity. Methods This is a cross-sectional analysis of 854 men and 640 women aged 20 to 70 years from the Anqing Twin Cohort. The following measures were obtained for each subject: Body mass index (BMI) and percentage of trunk fat (%TF), fasting plasma glucose, homeostatic model assessment of insulin resistance index (HOMA-IR), self-reported sleep duration and measures of snoring and sleep disturbance from the Pittsburgh Sleep Quality Indices (PSQI) questionnaire were modified for a Chinese population. Multivariate linear regressions were applied to examine the association of sleep duration with HOMA-IR, with and without adjustment for adiposity variables, along with other relevant covariates. Results In this sample of relatively lean rural Chinese adults, short sleep duration was associated with HOMA-IR in women but not in men. In women, short (⩽7 h/night) sleep duration was associated with a higher HOMA-IR ( p = 0.003) compared with normal sleep duration (>7 to ⩽8 h/night) after adjustment for all the covariates except adiposity. Further adjustment for BMI or %TF attenuated the sleep-HOMA-IR association, but the association remained significant upon adjustment for BMI ( p = 0.013); and upon adjustment for %TF ( p = 0.026). Long sleep duration (>8 h/night) was not significantly associated with HOMA-IR. Conclusion In this rural Chinese cohort, short sleep duration is independently associated with increased insulin resistance among women only, even after adjusting for adiposity and other potential confounders.

To cite this article: Liu X, Wang G, Hong X, Wang D, Tsai H-J, Zhang S, Arguelles L, Kumar R, Wang H, Liu R, Zhou Y, Pearson C, Ortiz K, Schleimer R, Holt P, Pongracic J, Price HE, Langman C, Wang X. Gene–vitamin D interactions on food sensitization: a prospective birth cohort study. Allergy 2011; 66: 1442–1448. Abstract Background: It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine whether cord blood VDD is associated with FS and whether such association can be modified by genetic variants in a prospective birth cohort. Methods: This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D

We conducted cross-sectional and longitudinal twin analysis to explore genetic and environmental contribution to serum lipid tracking during childhood and adolescence. The study sample was part of a population-based twin cohort that was recruited in the rural areas of the Anhui Province of China. The baseline recruitment of twins was carried out from 1998 through 2000 and the follow-up from 2005 through 2007. Serum lipids showed significant tracking during childhood and adolescence. Participants with lipids at the highest tertile at the baseline tended to remain high at follow-up across ages and Tanner stages, whereas subjects with lipids at the lowest tertile at the baseline tended to remain low at follow-up. Using twin modeling, we showed that genetic and environmental factors contributed to individual variations in lipid levels and tracking from the baseline to the follow-up visit. The estimated tracking correlations for total cholesterol, triglyceride, and LDL cholesterol were in the range of 0.25-0.53 and were predominantly influenced by genetic factors. In contrast, the phenotypic tracking of HDL cholesterol was influenced by both genetic and environmental factors. Our study underscores the importance of considering both environmental and genetic factors in studying the etiology of dyslipidemia.

Context: Adipokines have been linked to bone phenotypes recently, but with conflicting results. Few such studies have been conducted in adolescents.Objective: The aim of the study was to examine the associations of adiponectin and leptin with multiple bone phenotypes in Chinese adolescents and estimate the genetic contribution to these associations.Design and Setting: This was a cross-sectional study conducted in rural China.Participants: A total of 675 males and 575 females aged 13–21 yr were included.Outcome Measures: Fat mass (FM), lean mass (LM), bone area (BA), bone mineral content (BMC), cross-sectional area (CSA), and section modulus (SM) were measured by dual-energy x-ray absorptiometry. Plasma adipokine concentration was determined using sandwich immunoassays.Results: Adiponectin was inversely associated with all BMCs in males (P < 0.01), but not in females, after adjusting for LM, body weight, or BMI singly, or for LM and FM simultaneously. No such relationships were observed for CSA or SM in both genders. Leptin was inversely associated with all BAs, total-hip BMC, CSA, and SM in both genders, when adjusting for body weight or BMI. These associations, except for whole-body BA and lumbar spine BA in females, disappeared when simultaneously adjusting for LM and FM. By Cholesky decomposition models using twin design, significant genetic correlations were detected between adiponectin and total-hip BMC in males and between leptin and total-hip BMC in both genders.Conclusions: We demonstrated that adiponectin and leptin were inversely associated with adolescent bone phenotypes but showed differential associations by gender, type of bone phenotypes, and adjustment of FM. This study also suggested that adipokines and bone phenotypes may share a common set of genes.

Background: Adolescence is a critical period for rising adiposity and falling insulin sensitivity (IS), but the independent relation between adiposity and IS remains understudied. Objective: The objective was to examine which adiposity measures are most strongly associated with IS in nondiabetic adolescents, whether sex-difference exists, and to what degree genetic or environmental factors affect the adiposity-IS relation. Design: The study included 1613 rural Chinese adolescents (888 males) aged 13–20 y from a population-based twin cohort. We used graphic plots and linear mixed models to examine the relation of anthropometric and dual-energy X-ray absorptiometry–based measures of adiposity with IS [QUantitative Insulin-sensitivity ChecK Index (QUICKI), fasting serum insulin (FSI), homeostasis model assessment of insulin resistance (HOMA-IR)] and structural equation models to estimate genetic/environmental influences on these associations. Results: In graphic analyses, participants in the highest quintile (quintile 5) of waist circumference (WC) and percentage body fat (%BF) had the lowest QUICKI and the highest FSI and HOMA-IR values for all age-sex groups. In regression models adjusted for age, Tanner stage, zygosity, and physical activity, all adiposity measures showed inverse associations with IS in both sexes, but WC explained the largest fraction of variance in IS measures (10–14%). Of the phenotypic correlations between adiposity measures and IS (−0.28 to −0.38), 74–85% were attributed to shared genetic factors and 15–26% to common unique environmental factors in both sexes. Conclusions: In these relatively lean Chinese adolescents, WC and %BF (quintile 5) are the adiposity measures most consistently and strongly associated with decreased IS in both sexes. To a large degree, shared genetic factors contribute to this association.

Context: Factors associated with the high prevalence of vitamin D deficiency in China are not well described, especially among Chinese adolescents. Objectives: The aim of the study was to examine important environmental or sociodemographic factors influencing 25-hydroxyvitamin D [25(OH)D] levels and estimate its heritability. Design: A sample of 226 male and female adolescent twins aged 13–20 yr from a large prospective twin cohort of rural Chinese children and adolescents that has been followed for 6 yr were evaluated. Main Outcome Measure(s): Blood level of 25(OH)D was measured using tandem mass spectrometry methodology. Results: The overall mean (sd) 25(OH)D level was 18.0 (9.4) ng/ml, with wide variation by gender and season. In males (47.4% of subjects), the mean (sd) 25(OH)D level was 12.1 (4.2) ng/ml in non-summer and 27.4 (8.8) ng/ml in summer; in females, it was 10.1 (4.1) ng/ml in non-summer and 19.5 (6.3) ng/ml in summer. A multivariate model that included gender, age, season, physical activity, and student status demonstrated that male gender, summer season, and high physical activity significantly increased 25(OH)D levels. Summer season and male gender also significantly decreased the risk of being in the lowest 25(OH)D tertile. Overall, 68.9% of the variability in 25(OH)D level was attributable to additive genetic influence. Stratification by gender found that in males, 85.9% of the variability in 25(OH)D level was attributable to such influence, but in females, it was only 17%. Conclusion: In this sample of rural Chinese adolescents, 25(OH)D level was influenced by gender, season, and physical activity level. There was a strong genetic influence on 25(OH)D level in males only.

Objective We compared the efficacy of folic acid (FA) plus enalapril with enalapril alone on the reduction of blood pressure (BP) and fasting plasma glucose (FPG) in adult Chinese hypertensive patients. Methods Four hundred eighty subjects with mild to moderate BP were randomly assigned to one of three treatment groups: 1) 10 mg of enalapril (control group), 2) 10 mg of enalapril plus 0.4 mg of FA (low-FA group), or 3) 10 mg of enalapril plus 0.8 mg of FA (high-FA group) daily for 8 wk. Generalized linear mixed models were used to compare the reduction in BP and FPG level from baseline to week 8 of the treatment and the difference among the three treatment groups, adjusting for pertinent covariates. Results Four hundred forty-three subjects (57.3% women, 27–75 y of age) successfully completed the trial. After the 8-wk treatment, compared with baseline, all treatment groups showed significant reduction of BP but not of FPG. There was no significant difference in BP or FPG reduction among the three treatment groups. In subgroup analysis, we found that in subjects with hyperglycemia (FPG ≥6.1 mmol/L) at baseline, FPG reduction was significantly greater in the high-FA group (−0.80 ± 1.20 mmol/L) than in the low-FA group (−0.39 ± 1.44 mmol/L) and the control group (−0.23 ± 1.30 mmol/L). Regression analysis further confirmed that FPG reduction in the high-FA group was −0.68 ± 0.28 mmol/L greater than in the control group (P = 0.015), even after adjustment for important covariates. A dose–response trend was evident (P for trend = 0.025) and the test for an interaction between treatment group and baseline FPG was significant (P Conclusion In this sample of adult Chinese hypertensive patients, FA combined with enalapril showed a greater beneficial effect on reduction of FPG in a dose-related fashion than did enalapril alone among subjects with hyperglycemia.

Preterm delivery (PTD

The purpose of the present study was to investigate the interactions between brain microvascular endothelial cells (BMEC) and mesenchymal stem cells (MSC) under hypoxic conditions. Primary cultured human bone marrow MSC and rat BMEC were isolated, cultured and identified. Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were detected in the conditioned media of BMEC and MSC under normal and hypoxic conditions using ELISA. MSC differentiation was analyzed using flow cytometry and fluorescence immunocytochemistry. Transendothelial electrical resistance (TEER) techniques were employed to measure changes in permeability across the BMEC monolayer. Under hypoxic conditions, the concentration of VEGF and MMP-9 in the conditioned media increased significantly, with greater levels in the MSC than the BMEC media. Primary MSC did not express vWF and Flk-1. MSC were co-cultured with BMEC under hypoxic conditions 5 days later. MSC expressing Flk-1 accounted for 23.64+/-2.50% (n=6, P

Aromatase-dependent biosynthesis of estrogen plays an important role in maintenance of the male skeleton, and Cytochrome p450 aromatase is the key enzyme to catalyze the conversion of androgen precursors to estrogens. We investigated the association of polymorphisms in the CYP19A1 gene and bone mineral density in a Chinese cohort. 2392 extreme low femoral neck BMD cases or extreme high femoral neck BMD controls were selected from a population-based cohort and genotyped for eight SNPs in the CYP19A1 gene. Significant associations for rs17703883, rs12594287 and rs16964201 SNPs with BMD were found in men only. Men with TC/CC genotypes in the rs17703883 SNP had a 1.5 times higher risk of having extreme low femoral neck BMD (P = 0.003, empirical P value = 0.05), and decreased BMDs at total body (P = 0.004, empirical P value = 0.07) and total hip (P = 0.003, empirical P value = 0.05). Men carrying AA/AG genotypes in the rs12594287 SNP had a 30% reduced risk of having extreme low femoral neck BMD (P = 0.007, empirical P value = 0.12), and increased BMDs at total body (P = 0.0009, empirical P value = 0.018) and total hip (P = 0.001, empirical P value = 0.02). Men carrying TT/TC genotypes in the rs16964201 SNP had a 40% reduced risk of having extreme low femoral neck BMD (P = 0.005, empirical P value = 0.087), and increased BMDs at total body (P = 0.0001, empirical P value = 0.002) and total hip (P = 0.0006, empirical P value = 0.012). Haplotype analysis showed that the G-C-T-A-T haplotype was significantly related to higher BMD. Our finding suggests that genetic variations in the CYP19A1 gene are significantly associated with BMD at different skeletal sites in adult men, but not in women.

In the present study, we aimed to establish a rabbit atherosclerosis model and examine atherosclerotic plaques by using optical coherence tomography (OCT) and intravascular ultrasonography (IVUS) to evaluate the clinical usefulness of these diagnostic tools in the detection of atherosclerotic plaques. Twenty healthy New Zealand rabbits were fed on a high-fat diet for 4 weeks and then subjected to abdominal aortic intimal injury. The OCT and IVUS were performed after 8 weeks. The distal and proximal plaque images were marked to observe the plaque thickness and features of the lesions at the tunica intima and tunica media. Moreover, a pathological examination was performed to evaluate the efficacies of OCT and IVUS. The mean (SD) plaque thickness on OCT and IVUS images was 386.5 (125.3) μm and 412.7 (165.8) μm, respectively. Pathological examinations indicated a mean (SD) plaque thickness of 360.2 (98.l) μm (P > 0.05). No significant differences were noted between the 2 methods. The intimal and medial thickness measured with OCT showed greater correlation with pathologically measured thickness (r = 0.95, P < 0.001 for OCT; r = 0.88, P < 0.001 for IVUS); in particular, the intimal thickness measurements on OCT showed a higher correlation (r = 0.98, P < 0.001). However, the measurements obtained using IVUS were not accurate. Thus, compared with IVUS, OCT was more accurate in determining the nature and thickness of vascular plaques.

Several studies have found that body adiposity index (BAI) is a better index of body adiposity than body mass index (BMI) in African and Mexican American adults. This study aims to evaluate the ability of BAI to predict body adiposity in Chinese children and adults.In total, 2425 children and 5726 adults were recruited from rural China. All participants completed whole-body dual-energy X-ray absorptiometry (DXA) and anthropometric measures. The correlation of BMI, BAI, and waist circumference (WC) to DXA adiposity indexes was performed across sex-specific adult and age- and sex-specific child cohorts, using Spearman correlation and linear regression models, respectively.Both BMI and WC had a higher correlation with all adiposity indexes (whole body fat, percent body fat [Bfat%], trunk fat, and percent trunk fat [Tfat%]) measured by DXA than did BAI in both adults and children. Meanwhile, most of the linear regression model associations for BMI with Bfat% and Tfat% had a greater adjusted R(2) than those for BAI among both children and adults.This study indicates that BMI and WC are better tools than BAI for estimating whole body fat and central body fat in a Chinese population.