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Qianmao Liang, Yongfei Chen, Kailin Yu, Cheng Chen, Shouxiang Zhang, Aoli Wang, Wei Wang, Hong Wu, Xiaochuan Liu, Beilei Wang, Li Wang, Zhenquan Hu, Wenchao Wang, Tao Ren, Shanchun Zhang, Qingsong Liu, Cai-Hong Yun, Jing Liu
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...
March 2, 2017: European Journal of Medicinal Chemistry
Xiaofei Liang, Fengchao Lv, Beilei Wang, Kailin Yu, Hong Wu, Ziping Qi, Zongru Jiang, Cheng Chen, Aoli Wang, Weili Miao, Wenchao Wang, Zhenquan Hu, Juan Liu, Xiaochuan Liu, Zheng Zhao, Li Wang, Shanchuan Zhang, Zi Ye, Chu Wang, Tao Ren, Yinsheng Wang, Qingsong Liu, Jing Liu
BMX is a member of TEC family nonreceptor tyrosine kinase and is involved in a variety of critical physiological and pathological processes. Through combination of irreversible inhibitor design and type II inhibitor design approaches, we have discovered a highly selective and potent type II irreversible BMX kinase inhibitor compound 41 (CHMFL-BMX-078), which exhibited an IC50 of 11 nM by formation of a covalent bond with cysteine 496 residue in the DFG-out inactive conformation of BMX. It displayed a high selectivity profile (S score(1) = 0...
February 14, 2017: Journal of Medicinal Chemistry
Zrinka Rajic, Artak Tovmasyan, Otávio L de Santana, Isabelle N Peixoto, Ivan Spasojevic, Silmar A do Monte, Elizete Ventura, Júlio S Rebouças, Ines Batinic-Haberle
We disclose here the studies that preceded and guided the preparation of the metal-based, redox-active therapeutic Mn(III) meso-tetrakis(N-n-butoxyethylpyridyl)porphyrin, MnTnBuOE-2-PyP(5+) (BMX-001), which is currently in Phase I/II Clinical Trials at Duke University (USA) as a radioprotector of normal tissues in cancer patients. N-substituted pyridylporphyrins are ligands for Mn(III) complexes that are among the most potent superoxide dismutase mimics thus far synthesized. To advance their design, thereby improving their physical and chemical properties and bioavailability/toxicity profiles, we undertook a systematic study on placing oxygen atoms into N-alkylpyridyl chains via alkoxyalkylation reaction...
April 2017: Journal of Inorganic Biochemistry
Lee P Rylands, Howard T Hurst, Simon J Roberts, Robert W Graydon
Rylands, LP, Hurst, HT, Roberts, SJ, and Graydon, RW. The effect of "pumping" and "nonpumping" techniques on velocity production and muscle activity during field-based BMX cycling. J Strength Cond Res 31(2): 445-450, 2017-The aim of the current study was to determine if a technique called "pumping" had a significant effect on velocity production in Bicycle Motocross (BMX) cycling. Ten National standard male BMX riders fitted with surface electromyography (sEMG) sensors completed a timed lap of an indoor BMX track using the technique of pumping, and a lap without pumping...
February 2017: Journal of Strength and Conditioning Research
S Kothari, A Arunachalam, C Chen
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
Yu Shi, Wenchao Zhou, Lin Cheng, Cong Chen, Zhi Huang, Xiaoguang Fang, Qiulian Wu, Zhicheng He, Senlin Xu, Justin D Lathia, Yifang Ping, Jeremy N Rich, Xiu-Wu Bian, Shideng Bao
Glioblastoma (GBM) is the most malignant and lethal brain tumor harboring glioma stem cells (GSCs) that promote tumor propagation and therapeutic resistance. GSCs preferentially express several critical cell surface molecules that regulate the pro-survival signaling for maintaining the stem cell-like phenotype. Tetraspanin CD9 has recently been reported as a GSC biomarker that is relevant to the GSC maintenance. However, the underlying molecular mechanisms of CD9 in maintaining GSC property remain elusive. Herein, we report that CD9 stabilizes the IL-6 receptor glycoprotein 130 (gp130) by preventing its ubiquitin-dependent lysosomal degradation to facilitate the STAT3 activation in GSCs...
January 2017: Cell Death and Differentiation
Kelsey Stover, Tomoki Fukuyama, Ashlyn T Young, Michael A Daniele, Rebecca Oberley, James D Crapo, Wolfgang Bäumer
In this study, we topically administered two antioxidant compounds, the manganese-porphyrin-derivatives BMX-001 and BMX-010, in a mouse model of allergic dermatitis and compared the efficacy for reduction of itch and inflammation. In vitro effects of BMX-001 and BMX-010 on keratinocytes, bone marrow derived dendritic cells (BMDCs) and T-cells were initially analysed. For assessment of scratching behaviour, BMX-001 and BMX-010 (0.01 and 0.1 %) were topically applied 16 h and/or 1 h before compound 48/80 or toluene-2,4,-diisocyanate (TDI) challenge in a TDI induced mouse dermatitis model...
December 2016: Archives of Dermatological Research
Mohamed A Eldeeb, Richard P Fahlman
Cellular signaling leading to the initiation of apoptosis typically results in the activation of caspases, which in turn leads to the proteolytic generation of protein fragments with new or altered cellular functions. Increasing numbers of reports are demonstrating that the activity of many of these proteolytically activated protein fragments can be attenuated by their selective degradation by the N-end rule pathway. Here we report the first evidence that selective degradation of a caspase product by the N-end rule pathway can be modulated by phosphorylation...
October 21, 2016: Journal of Biological Chemistry
Ben Beck, Mark Stevenson, Stuart Newstead, Peter Cameron, Rodney Judson, Elton R Edwards, Andrew Bucknill, Marilyn Johnson, Belinda Gabbe
The aim of this study was to describe the crash characteristics and patient outcomes of a sample of patients admitted to hospital following bicycle crashes. Injured cyclists were recruited from the two major trauma services for the state of Victoria, Australia. Enrolled cyclists completed a structured interview, and injury details and patient outcomes were extracted from the Victorian State Trauma Registry (VSTR) and the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR). 186 cyclists consented to participate in the study...
November 2016: Accident; Analysis and Prevention
Lee P Rylands, Simon J Roberts, Howard T Hurst
The aim of this study was to ascertain if gear ratio selection would have an effect on peak power and time to peak power production in elite Bicycle Motocross (BMX) cyclists. Eight male elite BMX riders volunteered for the study. Each rider performed three, 10-s maximal sprints on an Olympic standard indoor BMX track. The riders' bicycles were fitted with a portable SRM power meter. Each rider performed the three sprints using gear ratios of 41/16, 43/16 and 45/16 tooth. The results from the 41/16 and 45/16 gear ratios were compared to the current standard 43/16 gear ratio...
March 2017: European Journal of Sport Science
Lee P Rylands, Simon J Roberts, Howard T Hurst, Ian Bentley
The aims of this study were to analyse the optimal cadence for peak power production and time to peak power in bicycle motocross (BMX) riders. Six male elite BMX riders volunteered for the study. Each rider completed 3 maximal sprints at a cadence of 80, 100, 120 and 140 revs · min(-1) on a laboratory Schoberer Rad Messtechnik (SRM) cycle ergometer in isokinetic mode. The riders' mean values for peak power and time of power production in all 3 tests were recorded. The BMX riders produced peak power (1105 ± 139 W) at 100 revs · min(-1) with lower peak power produced at 80 revs · min(-1) (1060 ± 69 W, (F(2,15) = 3...
August 1, 2016: Journal of Sports Sciences
Jenny Veitch, Jo Salmon, Kate Parker, Shaun Bangay, Benedicte Deforche, Anna Timperio
BACKGROUND: The neighbourhood environment such as the availability of parks are a key, but under-researched, influence on adolescents' physical activity. In addition to overall physical activity levels, park-based physical activity and park visitation is low in this age group. Thus, it is critical to identify park features that may encourage or discourage adolescents from visiting parks. This study used a novel methodology to identify key physical characteristics of parks that are perceived to be important for park visitation and park-based physical activity among adolescents...
July 4, 2016: International Journal of Behavioral Nutrition and Physical Activity
Monica E Burgett, Justin D Lathia, Patrick Roth, Amy S Nowacki, Deni S Galileo, Elena Pugacheva, Ping Huang, Amit Vasanji, Meizhang Li, Tatiana Byzova, Tom Mikkelsen, Shideng Bao, Jeremy N Rich, Michael Weller, Candece L Gladson
The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM). Here, we show that angiogenesis also can be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and endothelial cells (ECs). As shown in vitro, this direct interaction is mediated by binding of integrin αvβ3 expressed on ECs to the RGD-peptide in L1CAM expressed on CSCs...
July 12, 2016: Oncotarget
Hyoung-Joo Lee, Hye-Jung Kim, Daniel C Liebler
Analysis of small biological samples would benefit from an efficient microscale fractionation strategy that minimizes sample handling, transfer steps, and accompanying losses. Here we describe a microscale basic reverse phase liquid chromatographic (bRPLC) fractionation method that offers high reproducibility and efficiency for peptide mixtures from small (5-20 μg) samples. We applied our platform to detect differentially expressed proteins from lung tumor cell lines that are sensitive (11-18) and resistant (11-18R) to the tyrosine kinase inhibitor erlotinib...
July 1, 2016: Journal of Proteome Research
Lee P Rylands, Howard T Hurst, Simon J Roberts, Robert Graydon
The aim of the current study was to determine if a technique called 'pumping' had a significant effect on velocity production in BMX cycling. Ten National standard male BMX riders fitted with sEMG sensors completed a timed lap of an indoor BMX track using the technique of pumping, and a lap without pumping. The lap times were recorded for both trials and their surface sEMG recorded to ascertain any variation in muscle activation of the biceps brachii, triceps brachii, vastus lateralis and medial gastrocnemius...
May 28, 2016: Journal of Strength and Conditioning Research
Antonio Bruni, Andrew R Pepper, Boris Gala-Lopez, Rena Pawlick, Nasser Abualhassan, James D Crapo, Jon D Piganelli, A M James Shapiro
Islet transplantation is a highly effective treatment for stabilizing glycemic control for select patients with type-1 diabetes. Despite improvements to clinical transplantation, single-donor transplant success has been hard to achieve routinely, necessitating increasing demands on viable organ availability. Donation after circulatory death (DCD) may be an alternative option to increase organ availability however, these organs tend to be more compromised. The use of metalloporphyrin anti-inflammatory and antioxidant (MnP) compounds previously demonstrated improved in vivo islet function in preclinical islet transplantation...
July 3, 2016: Islets
Danielle S Potter, Melanie Galvin, Stewart Brown, Alice Lallo, Cassandra L Hodgkinson, Fiona Blackhall, Christopher J Morrow, Caroline Dive
Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737...
June 2016: Molecular Cancer Therapeutics
Joshua C Anderson, Robert B Taylor, John B Fiveash, Rik de Wijn, G Yancey Gillespie, Christopher D Willey
BACKGROUND: We sought to profile Atypical Meningioma in a high-throughput manner to better understand the altered signaling within these tumors and specifically the kinases altered in recurrent atypical meningioma. Kinomic Profiles could be used to identify prognostic biomarkers for responders/non-responders to classify future patients that are unlikely to benefit from current therapies. Directly these results could be used to identify drug-actionable kinase targets as well. METHODS: Peptide-substrate microarray kinase activity analysis was conducted with a PamStation(®)12 analyzing the tyrosine kinome in each tumor kinetically against ~144 target peptides...
July 2015: Medical Research Archives
Akito Nakagawa, Atsuhiko T Naito, Tomokazu Sumida, Seitaro Nomura, Masato Shibamoto, Tomoaki Higo, Katsuki Okada, Taku Sakai, Akihito Hashimoto, Yuki Kuramoto, Toru Oka, Jong-Kook Lee, Mutsuo Harada, Kazutaka Ueda, Ichiro Shiojima, Florian P Limbourg, Ralf H Adams, Tetsuo Noda, Yasushi Sakata, Hiroshi Akazawa, Issei Komuro
Activation of β-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/β-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of β-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of β-catenin, which activates Wnt/β-catenin signaling in Bmx-positive arterial endothelial cells (Bmx/CA mice) led to progressive cardiac dysfunction and 100% mortality at 40 weeks after tamoxifen treatment...
2016: Scientific Reports
Juan Peng, Qiongyao Wang, Huanxin Liu, Minting Ye, Xiaoxia Wu, Linlang Guo
Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). EPHA3 has been revealed to be the most frequently mutated Eph receptor gene in lung cancer with abnormal expression. Growing evidence indicates that the signaling proteins of EPHA3 downstream, including PI3K, BMX and STAT3, play crucial roles in tumorigenesis and cancer progression. To explore the possible role of EPHA3 in MDR, we assessed the influence of EPHA3 on chemoresistance, cell cycle, apoptosis, and tumor growth, as well as the relationship between EPHA3 and the expression of PI3K, BMX, and STAT3 in SCLC...
September 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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