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Purpose: Nowadays, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for treating metastatic breast cancer and have achieved inspiring curative effects. But some discoveries have indicated that CDK 4/6 are not the requisite factors in some cell types because CDK2 partly compensates for the inhibition of CDK4/6. Thus, it is urgent to design CDK2/4/6 inhibitors for significantly enhancing their potency. This study aims to explore the mechanism of the binding of CDK2/4/6 kinases and their inhibitors to design novel CDK2/4/6 inhibitors for significantly enhancing their potency in different kinds of cancers. Materials and methods: A series of 72 disparately functionalized 4-substituted N-phenylpyrimidin-2-amine derivatives exhibiting potent inhibitor activities against CDK2, CDK4 and CDK6 were collected to apply to this research. The total set of these derivatives was divided into a training set (54 compounds) and a test set (18 compounds). The derivatives were constructed through the sketch molecule module in SYBYL 6.9 software. A Powell gradient algorithm and Tripos force field were used to calculate the minimal structural energy and the minimized structure was used as the initial conformation for molecular docking. By the means of 3D-QSAR models, partial least squares (PLS) analysis, molecular dynamics (MD) simulations and binding free energy calculations, we can find the relationship between structure and biological activity. Results: In this study, we used molecular docking, 3D-QSAR and molecular dynamics simulation methods to comprehensively analyze the interaction and structure–activity relationships of 72 new CDK2/4/6 inhibitors. We used detailed statistical data to reasonably verify the constructed 3D-QSAR models for three receptors (q2 of CDK2 = 0.714, R2pred = 0.764, q2 = 0.815; R2pred of CDK4 = 0.681, q2 = 0.757; R2pred of CDK6 = 0.674). MD simulations and decomposition energy analysis validated the reasonability of the docking results and identified polar interactions as crucial factors that influence the different bioactivities of the studied inhibitors of CDK2/4/6 receptors, especially the electrostatic interactions of Lys33/35/43 and Asp145/158/163. The nonpolar interaction with Ile10/12/19 was also critical for the differing potencies of the CDK2/4/6 inhibitors. We concluded that the following probably enhanced the bioactivity against CDK2/4/6 kinases: (1) electronegative groups at the N1-position and electropositive and moderate-sized groups at ring E; (2) electrogroups featured at R2; (3) carbon atoms at the X-position or ring C replaced by a benzene ring; and (4) an electrogroup as R4. Conclusion: Previous studies, to our knowledge, only utilized a single approach of 3D-QSAR and did not integrate this method with other sophisticated techniques such as molecular dynamics simulations to discover new potential inhibitors of CDK2, CDK4, or CDK6. So we applied the intergenerational technology, such as 3D-QSAR technology, molecular docking simulation techniques, molecular dynamics simulations and MMPBSA19/MMGBSA20-binding free energy calculations to statistically explore the correlations between the structure with biological activities. The constructed 3D-QSAR models of the three receptors were reasonable and confirmed by the excellent statistical data. We hope the results obtained from this work will provide some useful references for the development of novel CDK2/4/6 inhibitors. [ABSTRACT FROM AUTHOR]

Milling is the primary machining method for manufacturing thin-walled workpieces. Due to the low rigidity, these workpieces are easy to deform during the milling process, which significantly affects machining accuracy. This paper proposes a fusion model to predict the milling deformation based on the U-NET neural network and the physical model. Firstly, a deformation measurement experimental platform is designed to capture the deformation distribution on the surface of the thin-walled workpiece. Secondly, an approximate solution for the theoretical deformation caused by axial cutting force is obtained based on the elastic deformation behavior of the thin-walled workpiece. At last, the captured original deformation and the theoretical deformation are then used as inputs for the fusion model to predict the relative deformation distribution of the machined thin-walled workpiece. The end milling experiment of the thin wall cavity is conducted to validate the accuracy of the prediction results and the effectiveness of the fusion model, the deformation in the milling process is predicted by the U-NET model and fusion model, and then compared with the measured deformation. The result shows that the proposed fusion model achieved an average root mean square error of less than 2.65% on the normalized dataset, providing accurate predictions close to measurements and with the speed of the physical model. Furthermore, compared to the data-driven U-NET model, the fusion model exhibited significant improvement in prediction performance on the test set, demonstrating good physical interpretability and generalization ability. The fusion model is used to realize the high-precision and high-speed milling deformation prediction, to guide the milling process planning of thin-walled parts, provide a basis for realizing the online machining compensation of thin-walled parts, and help to improve the machining quality and processing efficiency of thin-walled parts. [ABSTRACT FROM AUTHOR]

Background: Tamoxifen is a first-line endocrine agent and is often used to treat estrogen receptor-positive (ER+) breast cancer. Unfortunately, approximately 30-40% of patients who received tamoxifen therapy experience recurrence or progression to a fatal advanced stage due to tamoxifen resistance. However, the mechanisms of tamoxifen resistance remain unclear. Methods: The expression of lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) was detected by qPCR. The effect of DLGAP1-AS2 on tamoxifen resistance was evaluated by MTT, colony formation, TUNEL and flow cytometric assays. The mechanisms by which DLGAP1-AS2 regulates tamoxifen resistance were investigated through qPCR, RNA pull-down assays and RNA immunoprecipitation (RIP) assays. Results: Our results showed that DLGAP1-AS2 is significantly upregulated in breast cancer and that tamoxifen can induce DLGAP1-AS2 expression. Further investigation suggested that upregulation of DLGAP1-AS2 can increase cell viability and inhibit apoptosis, while downregulation of DLGAP1-AS2 results in the opposite effects. Mechanistically, DLGAP1-AS2 can bind to the AFF3 protein to inhibit its degradation, which further promotes ER signalling. Conclusions: Our research clarified that DLGAP1-AS2 promotes ER signalling to induce tamoxifen resistance and that targeting DLGAP1-AS2 might be a promising strategy to overcome tamoxifen resistance in breast cancer. [ABSTRACT FROM AUTHOR]

Numerous procedures have been described for the operative management of acromioclavicular (AC) joint injuries. Some of these techniques, including hardware fixation and non-anatomical reconstructions, are associated with serious complications and high failure rates. Recently, AC joint reconstruction techniques have focused on anatomical restoration of the coracoclavicular ligaments to achieve optimal clinical outcomes. We used a triple endobutton technique to separately reconstruct the trapezoid and the coronoid portions of the coracoclavicular ligament. We evaluated the preliminary clinical and radiological results of this technique in patients with acute complete dislocation of the AC joint. All patients achieved a significant improvement in the pain and function of shoulder at a mean follow-up interval of 12 months (range, 8-14 months). Excellent reduction of the AC joint was maintained. The triple endobutton technique may be safe and effective for the treatment of acute complete AC joint dislocations. [ABSTRACT FROM AUTHOR]

Anterior decompression and fusion is an established procedure in surgical treatment for multilevel cervical spondylotic myelopathy (MCSM). However, contiguous corpectomies and fusion (CCF) often induce postoperative complications such as nonunion, graft subsidence, and loss of lordotic alignment. As an alternative, noncontiguous corpectomies or one-level corpectomy plus adjacent-level discectomy with retention of an intervening body has been developed recently. In this study, we prospectively compared noncontiguous anterior decompression and fusion (NADF) and CCF for MCSM in terms of surgical invasiveness, clinical and radiographic outcomes, and complications. From January 2005 to June 2007, 105 patients with MCSM were randomized to NADF group ( n = 55) and CCF group ( n = 50), and followed up for average 31.5 months (range 24–48 months). Average operative time and blood loss decreased significantly in the NADF group as compared with those in the CCF group ( p < 0.05 and <0.001, respectively). For VAS, within 3 months postoperatively, there was no significant difference between the two groups. But at 6 months after surgery and final follow-up, VAS improved significantly in NADF group than that in CCF group ( p < 0.05). No significant difference of JOA score was observed between the two groups at every collection time. In NADF group, all 55 cases obtained fusion at 1 year after operation (average 5.1 months). In CCF group, 48 cases achieved fusion 1 year postoperatively, but the other 2 cases were performed posterior stabilization and achieved fusion 6 months later. The differences of cervical lordosis between two groups were insignificant at the same follow-up time. But the loss of lordosis and height of fusion segments in 6 months postoperatively and final follow-up were significantly more in CFF group than in NADF group ( p < 0.001). Complications were similar in both groups. But in CCF group three cases needed reoperation, one case with extradural hematoma was immediately re-operated after anterior decompression and two cases mentioned above were performed posterior stabilization at 1 year postoperatively. In conclusion, in the patients with MCSM, without developmental stenosis and continuous or combined ossification of posterior longitudinal ligaments, NADF and CCF showed an identical effect of decompression. In terms of surgical time, blood loss, VAS, fusion rate and cervical alignment, NADF was superior compared with CCF. [ABSTRACT FROM AUTHOR]

In recent years, there have been numerous papers emphasizing the relationship between Glutathione S-transferases polymorphisms and bladder cancer risk, but the findings have not reached a consensus. The relationship between glutathione S-transferase T 1 null genotype and bladder cancer susceptibility is now even more disputable. Therefore, we present a meta-analysis of (nested) case–controlled, genotype-based studies (including 37 studies, 6,986 cases and 9,166 controls) examining this association. Using a fixed-effect model, statistically significant increase was observed between glutathione S-transferase T 1 deletion and bladder cancer risk for the overall studies (OR = 1.12; 95% confidence interval (CI): 1.04–1.21; P = 0.004 for Z test; I2 = 47.43 for heterogeneity). After adjusting the result using trim-and-fill method, the outcome still had significant difference with little downgrade (OR = 1.10, 95% CI = 1.02–1.18). Three potential sources of heterogeneity including ethnicity, source of control and smoking status were also assessed. Minor increased correlation was found only in population-based studies (OR = 1.16; 95% CI = 1.03–1.30; I2 = 47.16). Our analysis suggests that glutathione S-transferase T 1 null status is associated with a modest increase in the risk of bladder cancer and the difference exiting in source of control has been confirmed. Due to limited sample size, various confounding variables as well as discrepancy in study design, a valid conclusion still cannot be confirmed. [ABSTRACT FROM AUTHOR]

A cDNA encoding a bifunctional acetylxylan esterase/xylanase, XynS20E, was cloned from the ruminal fungus Neocallimastix patriciarum. A putative conserved domain of carbohydrate esterase family 1 was observed at the N-terminus and a putative conserved domain of glycosyl hydrolase family 11 was detected at the C-terminus of XynS20E. To examine the enzyme activities, XynS20E was expressed in Escherichia coli as a recombinant His6 fusion protein and purified by immobilized metal ion-affinity chromatography. Response surface modeling combined with central composite design and regression analysis was then applied to determine the optimal temperature and pH conditions of the recombinant XynS20E. The optimal conditions for the highest xylanase activity of the recombinant XynS20E were observed at a temperature of 49°C and a pH of 5.8, while those for the highest carbohydrate esterase activity were observed at a temperature of 58°C and a pH of 8.2. Under the optimal conditions for the enzyme activity, the xylanase and acetylxylan esterase specific activities of the recombinant XynS20E toward birchwood xylan were 128.7 and 873.1 U mg−1, respectively. To our knowledge, this is the first report of a bifunctional xylanolytic enzyme with acetylxylan esterase and xylanase activities from rumen fungus. [ABSTRACT FROM AUTHOR]

Abstract  This retrospective study compared the results after anterior cruciate ligament (ACL) reconstruction using a four-strand hamstring tendon graft (4SHG) versus Ligament Advanced Reinforcement System (LARS) artificial ligament in 60 patients between January 2003 and July 2004 with a minimum four-year follow-up. The KT-1000 examination, the International Knee Documentation Committee (IKDC) scoring systems and Lysholm knee scoring scale were used to evaluate the clinical results. The mean side-to-side difference was 2.4 ± 0.5 mm and 1.2 ± 0.3 mm in the 4SHG group and LARS group, respectively (P = 0.013). Although other results of ACL reconstruction, measured by IKDC evaluation, Lysholm scores and Tegner scores, showed using a LARS graft clinically tended to be superior to using a 4SHG, there were no significant differences calculated. Our results suggest that four years after ACL reconstruction using a LARS ligament or 4SHG dramatically improves the function outcome, while the patients in the LARS group displayed a higher knee stability than those in the 4SHG group. [ABSTRACT FROM AUTHOR]

Abstract It has been suggested that zinc' may have a protective role against heart defects during fetal development. We investigated the effects of zinc on the development of fetal cardiac malformations induced by homocysteine. Pregnant Sprague-Dawley rats were randomized into one of five groups: control (C), homocysteine (H), homocysteine + zinc (Z), homocysteine + folic acid (F), or homocysteme + zinc + folic acid (ZF) (each n = 8). Homocysteine (8 nmol/day) was administered intraperitoneally in the H, Z, F, and ZF groups on gestation days (GD) 8, 9, and 10. Zinc (30 mg/kg day), folic acid (30 mg/kg day), or both (30 mg/ kg day each) were administered intragastrically daily in the Z, F, and ZF groups, respectively, throughout the pregnancy. In each group, two fetuses were removed on GD 13, 15, 17, and 19 and examined for cardiac malformations; maternal copper/zinc-containing-superoxide dismutase (Cu/Zn-SOD) activity and metallothionein type I (MT-1) mRNA expression were measured simultaneously. The prevalence of cardiac malformations was significantly higher in group H than in group C, and significantly lower in group Z than in group H at the studied time points. Cu/Zn-SOD activity and MT-1 mRNA levels were significantly lower in group H than in group C, and significantly higher in group Z than in group H. Our data suggest that zinc antagonizes homocysteine-induced teratogenic effects on the fetal heart, possibly via the inhibition of excessive peroxidation. [ABSTRACT FROM AUTHOR]

Summary  Photochromic nanoparticles with spiropyran moieties were prepared by a facile one-step miniemulsion polymerization. The nanoparticle dispersion was obtained by mixing the monomers, spiropyran-containing molecules and hydrophobe, dispersing them into an aqueous solution with surfactant, subjecting the dispersion to ultrasonification and polymerizing the monomers by using a water soluble initiator. The shape and size of the nanoparticles was determined with the atomic force microscope (AFM) and dynamic light scattering (DLS), and the determined average diameter of the nanoparticles ranges from 30 nm to 60 nm. The absorption and fluorescence spectra for the nanoparticles dispersions reveal that the spiropyran molecules were successfully incorporated in the polymer nanoparticles. Moreover, the nanoparticle dispersions were found to exhibit enhanced photo-reversibility, photo-stability and relatively fast photo-responsive property compare to the same species in aqueous solution. [ABSTRACT FROM AUTHOR]

Extracorporeal shock wave treatment appears to be effective in patients with avascular necrosis of the femoral head. However, the pathway of biological events whereby this is accomplished has not been fully elucidated. The purpose of this study was to investigate the effect of extracorporeal shock waves on vascular endothelial growth factor (VEGF) expression in necrotic femoral heads of rabbits. VEGF expression was assessed by immunohistochemistry, quantitative real-time PCR, and Western blot analysis. The degree of angiogenesis was also assessed, as determined by the microvessel density (MVD), the assessment of which was based on CD31-expressing vessels. Bilateral avascular necrosis of femoral heads was induced with methylprednisolone and lipopolysaccharide in 30 New Zealand rabbits. The left limb (the study side) received shock wave therapy to the femoral head. The right limb (the control side) received no shock wave therapy. Biopsies of the femoral heads were performed at 1, 2, 4, 8, and 12 weeks. Western blot analysis and real-time PCR showed that shock wave therapy significantly increased VEGF protein and mRNA expression, respectively, in the subchondral bone of the treated necrotic femoral heads. Compared with the contralateral control without shock wave treatment, the VEGF mRNA expression levels increased to a peak at 2 weeks after the shock wave treatment and remained high for 8 weeks, then declined at 12 weeks, whereas the VEGF protein expression levels increased to a peak at 4 weeks after the shock wave treatment and remained high for 12 weeks. The immunostaining of VEGF was weak in the control group, and the immunoreactivity level in the shock-wave-treated group increased at 4 weeks and persisted for 12 weeks. The most intensive VEGF immunoreactivity was observed in the proliferative zone above the necrotic zone. At 4, 8, and 12 weeks after the shock wave treatment, MVD in subchondral bone from treated femoral heads was significantly higher than that in subchondral bone from untreated femoral heads. These data clearly show that extracorporeal shock waves can significantly upregulate the expression of VEGF. The upregulation of VEGF may play a role in inducing the ingrowth of neovascularization and in improving the blood supply to the femoral head. [ABSTRACT FROM AUTHOR]

The surface of aramid fibers was modified with a polymer coating — a surface treatment reagent containing epoxy resin. The resulting fibers were examined by using NOL tests, hydroburst tests, and the scanning electron microscopy. The modified fibers had a rougher surface than the untreated ones. The interlaminar shear strength of an aramid-fiber-reinforced epoxy composite was highest when the concentration of polymer coating system was 5%. The translation of fiber strength in an aramid/epoxy composite vessel was improved by 8%. The mechanism of the surface treatment of fibers in improving the mechanical properties of aramid/epoxy composites is discussed. [ABSTRACT FROM AUTHOR]

An alternative approach was adopted to prepare colloidal crystal with polyhedral building blocks. First, monodisperse polystyrene particles that contained about 30% wt of monomer were obtained by emulsifier-free emulsion polymerization at 38 °C. These monomer-containing particles were used to prepare colloidal crystal on the surface of dispersion, before the spherical particles in the colloidal crystals underwent deformation between two quartz plates at 75 °C for 40 min by interfacial tensions, and finally the deformed particles were ?frozen? through post-polymerization. [ABSTRACT FROM AUTHOR]

The binding of mixed surfactants of cationic cetyltrimethylammonium bromide (CTAB) and nonionic octaethylene glycol monododecyl ether (C 12E 8) on anionic polyelectrolyte poly[2-acrylamido-2-methylpropanesulfonic acid (PAMPS)] and fluorophore-labeled copolymers containing about 40 mol% of AMPS was investigated at different mole fractions, Y , of CTAB in the surfactant mixture. The excimer emission of the cationic probe 1-pyrenemethylamine hydrochloride (PyMeA·HCl), nonradiative energy transfer (NRET) between pyrene and naphthalene labels and I 1/ I 3 of the pyrene label were determined by varying the total surfactant concentration, c Surf. The I E/ I M value of PyMeA·HCl firstly increases and then decreases to 0 with c Surf, showing a maximum on every curve. The critical aggregation concentration of the mixed surfactants determined from the I E/ I M maximum decreased from 5Ö10 -5 to 1Ö10 -5 mol/l as Y increased from 0.1 to 0.50, and then leveled off as Y increased up to unity. And at least 5Ö10 -6 mol/l CTAB was required for the mixed surfactants to bind on the PAMPS cooperatively. Equimolar binding of CTAB on AMPS was formed at I E/ I M=0 when Y =0.25, while at Y =0.1 some CTAB molecules in the mixed micelle were directed to the water phase without binding with AMPS. Both the intramolecular and the intermolecular NRET increased and then decreased with c Surf, having a maximum on each curve corresponding to the equimolar binding of CTAB and AMPS so long as Y >0, indicating the coiling of the chain and interchain aggregation upon bound surfactants. The I Py/ I Np value at the maximum decreased with decreasing Y because more nonionic surfactant C 12E 8 participated into the polyelectrolyte-mixed surfactant complexes together with bound CTAB. [ABSTRACT FROM AUTHOR]