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Objective To be able to treat irreducible unilateral vertically displaced pelvic ring disruption (UVDPRD) using closed reduction, we introduced a technique named Unlocking Closed Reduction Technique (UCRT) and evaluated its effectiveness with improved pelvic closed reduction system (PCRS). Methods A retrospective study was performed in our department. Between January 2014 and December 2017, 43 patients whose UVDPRD were not successfully reduced using transcondylar traction. Subsequently, they were treated with UCRT using improved PCRS. The study included 19 male and 24 female patients, with a mean age at the time of the operation of 46.2 years. During surgery, operation time and blood loss were recorded. Post‐surgical reduction quality was evaluated using Matta scoring criteria and patient lower‐extremity functional outcome was evaluated using Majeed functional scoring criteria. Results When used with improved PCRS, UCRT achieved pelvic reduction in all 43 cases of irreducible UVDPRD with postoperative pelvic reduction quality rated excellent and good for 42/43 (97.6%) patients according to the Matta scoring criteria (Matta Score, Unlocking Closed Reduction Technique (UCRT) first unlocks the dislocated iliosacral joint or overlapping edges of the sacral fracture through a force generated by framed‐based unlocking reduction device (FBURD) that pulls the posterior ilium laterally and then corrects the cranial and posterior displacement of posterior ring through transcondylar traction force.

Lateral locking plate (LLP) fixation has gained popularity for the treatment of proximal humeral fractures (PHFs); however, complications can occur due to loss of the medial cortical buttress from fracture comminution.We designed a novel intramedullary anatomical medial strut with allograft bone (IAMSAB) using MIMICS software to specifically fill the intramedullary canal of the proximal humeral bone. We used finite element analysis to evaluate the biomechanical characteristics of a LLP, LLP-intramedullary fixation system (IFS), LLP-anatomical medial locking plate (AMLP), or the combined application of a LLP and IAMSAB (LLP-IAMSAB) fixation construct in patients with a PHF and an unstable medial column.For axial or rotational loads, under (normal) Nor or osteoporotic (Ost) bone conditions, the LLP-IAMSAB fixation construct was significantly stiffer than the LLP-IFS fixation construct, and displacement at the fracture site after LLP-IAMSAB fixation was significantly less than after LLP or LLP-IFS fixation (P 0.05). Stiffness of the LLP-IAMSAB and LLP-AMLP fixation constructs and displacement at the fracture site after LLP-IAMSAB and LLP-AMLP fixation were not significantly different. The IFS, AMLP, and IAMSAB shared the load in the LLP and decreased the risk of implant failure. There were no significant differences in von Mises stress and stress distribution after fixation with the LLP-IFS, LLP-AMLP, and LLP-IAMSAB constructs.These data suggest that the IAMSAB can provide direct medial support or resistance to rotation and augment the biomechanics of the LLP. The combined application of the IAMSAB and LLP may achieve functional outcomes that are similar to the LLP-AMLP fixation construct.

All along, all kinds of courses mainly impart knowledge to students, and ideological and political education is mainly carried out through ideological and political theory courses. Starting from the connotation of "curriculum ideological and political education", this paper introduces the necessity of promoting the construction of "curriculum ideological and political education", and puts forward some ideas for the construction of the ideological and political education of computer basic courses in universities.

H3B-6545, a novel selective estrogen receptor (ER)α covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα, is in clinical development for the treatment of metastatic breast cancer. Preclinical studies were conducted to characterize the pharmacokinetics and metabolism of H3B-6545 in rat and monkeys. The clearance and metabolic profiles of H3B-6545 were studied using rat, monkey and human hepatocytes, and reaction phenotyping was done using recombinant human cytochrome P450 enzymes. Blood stability, protein binding, and permeability were also determined in vitro. Pharmacokinetics of H3B-6545 was assessed after both intravenous and oral dosing. A nonclinical PBPK model was developed to assess in vitro–in vivo correlation of clearance. H3B-6545 had a terminal elimination half-life of 2.4 h in rats and 4.0 h in monkeys and showed low to moderate bioavailability, in line with the in vitro permeability assessment. Plasma protein binding was similar across species, at 99.5–99.8%. Nine metabolites of H3B-6545 were identified in hepatocyte incubations, none of which were unique to humans. Formation of glutathione-related conjugate of H3B-6545 was minimal in vitro. H3B-6545, a CYP3A substrate, is expected to be mostly cleared via hepatic phase 1 metabolism. Hepatocyte clearance values were used to adequately model the time-concentration profiles in rat and monkey. We report on the absorption and metabolic fate and disposition of H3B-6545 in rats and dogs and illustrate that in vitro–in vivo correlation of clearance is possible for targeted covalent inhibitors, provided reactivity is not a predominant mechanism of clearance.

Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs. Significance: Nearly 30% of endocrine therapy–resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176–93. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1047

Objective To compare the clinical effectiveness between the channel-assisted mini-invasion and open Achilles shortening for treatment of the elongated Achilles tendon following previous rupture. Methods The clinical data of 19 patients admitted from Dec. 2013 to Dec. 2015 and met the inclusion criteria were analyzed retrospectively. Eight patients were treated with shortening operation by channel-assisted minimally invasive repair system, while 11 patients received dissection of Krackow Achilles tendon shortening. There was no significant difference between the two groups in gender, age, injury to operation time, preoperative calf circumference and preoperative AOFAS (American Orthopaedic Foot & Ankle Society) score (P>0.05). Results The operation time, incision length and postoperative hospital days were significantly less in min-invasion group than in incision group (P0.05). Conclusion Channel-assisted minimally invasive Achilles tendon shortening operation has not only similar effectiveness to the incision shorting operation for the treatment of elongated Achilles tendon following previous rupture, but also has the advantages of shortening operation time and stay in hospital and avoidance of sural nerve injury. DOI: 10.11855/j.issn.0577-7402.2017.07.12

Mutations in the estrogen receptor (ER) are detected in up to 30% of patients that initially respond but subsequently relaps to anti-endocrine therapies. ERα mutations, likely through constitutively activating ERα, can functionally confer resistance to existing classes of endocrine therapies. Current endocrine therapies are only partially effective in the ERα mutant setting and a significant proportion of endocrine-therapy resistant breast cancer metastases continue to remain dependent on ERα signaling for growth/survival indicating a critical need to develop the next generation of ERα antagonists that can overcome ERα wild-type and mutant activity. Here we describe a novel series of compounds with a unique mode of inhibition that potently target both wild-type and mutant ERα. These compounds are Selective Estrogen Receptor Covalent Antagonists (SERCAs) that inactivate the estrogen receptor by targeting a cysteine that is not present in other nuclear hormone receptors, leading to a unique biological and activity profile differentiated from Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs). Using structure-based drug design approaches we have identified a first-in-class clinical candidate, H3B-6545. H3B-6545 is a highly selective small molecule that potently antagonizes wild-type and mutant ERα in biochemical and cell based assays. In vitro comparisons with standard of care and other experimental agents confirm increased cell potency of H3B-6545 under continuous as well as washout treatment conditions. In vivo, once daily oral dosing of H3B-6545 shows potent activity and superior efficacy to fulvestrant in the MCF-7 xenograft model with maximal antitumor activity at doses >10x below the maximum tolerated dose in mice. In addition, H3B-6545 shows superior antitumor activity to tamoxifen and fulvestrant in patient derived xenograft models of estrogen receptor positive breast cancer including models carrying ERα mutations In non-clinical safety studies in rat and monkeys, H3B-6545 is well tolerated across a broad dose range and at exposures that significantly exceed those required for efficacy in mouse xenograft models. In summary, H3B-6545 is a first-in-class, orally available and potent selective estrogen receptor covalent antagonist with a compelling preclinical efficacy and safety profile that is being developed for the treatment of breast cancer. Citation Format: Peter G. Smith, Xiaoling Puyang, Craig Furman, Guo Zhu Zheng, Deepti Banka, Michael Thomas, Vanitha Subramanian, Sean Irwin, Nicholas Larsen, Benjamin Caleb, Craig Karr, Jeremy Wu, Morgan O’Shea, Joyce Yang, Allison Davis, Amy Kim, Nathalie Rioux, Victoria Rimkunas, Huilan Yao, Crystal MacKenzie, Pavan Kumar, Sherri Smith, Sean Eckley, Andrew Hart, George Lai, Christopher Rowbottom, Peter Fekkes, Silvia Buonamici, Dominic Reynolds, Lihua Yu, Tarek Sahmoud, Markus Warmuth, Lorna Mitchell, Ping Zhu, Manav Korpal. Discovery and development of H3B-6545: A novel, oral, selective estrogen receptor covalent antagonist (SERCA) for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-04. doi:10.1158/1538-7445.AM2017-DDT01-04

Computational thinking is the important content and research direction of university curriculum construction and teaching reform at home and abroad. Taking the C language course for non-computer majors as an example, this paper analyzes the importance of Computational Thinking in the cultivation of innovative talents, discusses how to cultivate Computational Thinking Ability in the teaching process, and puts forward the teaching reform of C language course based on the cultivation of Computational Thinking ability.

With the wide range of computer applications and more rapid development of applied technology, the society needs college students with more computer technology knowledge and stronger ability of computer technology applications. So the teaching contents, methods and measures of university computer class foundation teaching need to be improved and make a great break through. This article brings out some suggestions for university computer foundation teaching ,on the base of discussing the shortcomings of the foundation teaching of computer at the moment.

Dynamic Voltage Compensator (DVR) is able to handle the dynamic power quality problems in distribution network, such as voltage sags and voltage unbalance, and the parameters of the output filter will have important affect on the compensation results. In this paper, the parameter design method of the output filter of a cascaded H-bridge based DVR applied in medium-voltage distribution grid is studied. Through the analysis of the case when filter inductor current has the maximum value, the theoretical expression of the relationship between the low limit of the value of filter inductor and the capability of voltage compensation and power factor is derived. Meanwhile, the method of selecting the filter capacitor value is ​​obtained. The realization of the proposed method are given by taking an engineering project as an example, the correctness and validity of the design method of filter parameters proposed in this paper are verified by simulation.

The design of a Dynamic Voltage Restorer that is suitable for compensating regional voltage sags in 10kV distribution system is introduced in this paper. The design of the main circuit based on cascaded H-bridge, the device for energize DVR and the transformer-less coupled circuit are presented. For the voltage sags in neutral point non-grounded system, a reference voltage calculation method with the aim is to restore the line voltages on the load side is put forward. The simulation model of a substation including the designed DVR device has been built in PSCAD, and the compensation results under different fault types are simulated and analyzed, the influence of the energize device on the distribution system is studied. The simulation results verify the correctness and effectiveness of the design of DVR hardware and the reference voltage calculation method.

This paper proposes the designing of regional compensation type Dynamic Voltage Restorer (DVR), and the topology of main circuit, the detection algorithm for voltage sag, the calculation method of reference voltage and pulse modulation method. Based on the different load types of the target substation and the sensitivity to voltage sags, the selection principle of the location of compensation line for regional compensation DVR is proposed, and the realization of substation feeder selection method is illustrated by taking a substation as an example. The compensation effect of the DVR under different fault types are simulated, and the validity and rationality of the designing are verified.

In accordance with characteristics of super-small-distance tunnels in Nanjing metro, the peak value distribution of vibration velocity for existing tunnel was investigated when cut-hole blasted under the conditions of different surrounding rock Grades, followed by dynamic response rule of super-small-distance tunnels blasting. In addition, monitoring emphasis should be placed on upper bench for right tunnel blasting. Therefore, controlled measures of the small-distance tunnels were obtained during construction. Not only is the result fit for the metro tunnel, but it can be as reference for similar engineering.

In the nearly 150 years of the US history, following big historical events or business ethical dilemmas, the business ethical laws have evolved gradually, which can be divided into 11 stages in 4 levels. In each stage, the emphases or governance purposes of the business ethical laws differ greatly, but tend to bear the sign of the times. Through the systematic review and analysis, the paper concludes that in a specific era of the history, when facing a specific ethical dilemma, the government or regulatory authority will develop and perfect the related regulations or norms of business ethical behaviors in line with the feature of the period so as to effectively prevent or solve the ethical problems in the business environment. The practice of the US institutional construction may be of some enlightenment for developing countries like China.

Hotspot mutations in several components of the spliceosome have been reported in various hematological (CLL, MDS, etc.) and solid tumor (melanoma, pancreatic, etc.) malignancies. SF3B1 is a component of the U2 snRNP complex of the spliceosome and is involved in the recognition of 3′-splice sites during early spliceosomal assembly. We and others have demonstrated that mutations in SF3B1 result in neomorphic activity and trigger the production of aberrantly spliced transcripts. Thus, the discovery of small molecule modulators of SF3B1 splicing activity may have therapeutic potential in cancers harboring SF3B1 mutations. Members of the pladienolide family of natural products have been shown to affect RNA splicing through interaction with SF3B1. We have found that one particular natural product in this family, 6-deoxypladienolide D, demonstrates potent growth inhibition and cellular lethality in Panc 05.04 cells (a hotspot mutant SF3B1 cancer cell line). Due to the limited natural supply of 6-deoxypladienolide D and our interest in identifying chemical matter able to modulate splicing in these newly-identified mutant SF3B1 cancers, a total synthesis of 6-deoxypladienolide D using versatile and modular fragments was initiated. We will describe the first total synthesis of the natural product 6-deoxypladienolide D. Two noteworthy synthetic attributes are: 1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and 2) the use of cost-effective starting materials and reagents to enable access to 6-deoxypladienolide D and its analogs for biological evaluation. We will show that 6-deoxypladienolide D demonstrates: 1) high binding affinity to the SF3b complex, 2) ability to modulate canonical pre-mRNA splicing, and 3) modulation of aberrant splicing induced by mutant SF3B1. Citation Format: Kenzo Arai, Silvia Buonamici, Betty Chan, Laura Corson, Atsushi Endo, Baudouin Gerard, Ming-Hong Hao, Craig Karr, Kazunobu Kira, Linda Lee, Xiang Liu, Jason T. Lowe, Tuoping Luo, Lisa A. Marcaurelle, Yoshiharu Mizui, Marta Nevalainen, Morgan Welzel O'Shea, Eun Sun Park, Samantha A. Perino, Sudeep Prajapati, Mingde Shan, Peter G. Smith, Parcharee Tivitmahaisoon, John Yuan Wang, Markus Warmuth, Kuo-Ming Wu, Lihua Yu, Huiming Zhang, Guo Zhu Zheng, Gregg F. Keaney. Total synthesis of 6-deoxypladienolide D and assessment of splicing inhibitory activity in a mutant SF3B1 cancer cell line. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5564. doi:10.1158/1538-7445.AM2015-5564