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Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the Kmfor ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 μM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down’s syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivoand demonstrated drug-like properties. The inhibition of DYRK1A in vivotranslated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

We use elementary iterated function techniques to show there is a function in C[0, 1] whose iterated derivatives are dense in C[0, 1] and provide several related results.

Unstable intertrochanteric fractures are commonly treated with a cephalomedullary nail due to high failure rates with a sliding hip screw. The Omega3 Trochanteric Stabilizing Plate is a relatively new device that functions like a modified sliding hip screw with a proximal extension; however, its mechanical properties have not been evaluated. This study biomechanically compared a cephalomedullary nail, that is, Gamma3 Nail against the Omega3 plate. Unstable intertrochanteric fractures were created in 24 artificial femurs. Experimental groups were as follows: Nail (i.e. Gamma3 Nail) (n = 8), Plate A (i.e. Omega3 plate with four distal non-locking screws and no proximal locking screws) (n = 8), Plate B (i.e. Plate A plus five proximal locking screws) (n = 8), Plate C (i.e. Omega3 plate with three distal locking screws and no proximal locking screws) (n = 8), and Plate D (i.e. Plate C plus five proximal locking screws) (n = 8). All specimens were stiffness tested, while the Nail and Plate D groups were also strength tested. For lateral bending, Plate B was less stiff than the Nail (p = 0.001) and Plate A (p = 0.009). For torsion, Plate A was less stiff than Plate D (p = 0.020). For axial compression, the Nail was less stiff than Plate A (p = 0.036) and Plate B (p = 0.008). Axial strength for the Nail (5014 ± 308 N) was 66% higher than the Plate D construct (2940 ± 411 N) (p < 0.001). All Nails failed by partial or complete cutout through the femoral head and neck, but Plate D failed by varus collapse and deformation of the lag screw. When the cephalomedullary nail is clinically contra-indicated, this study supports the use of the Omega3 plate, since it had similar stiffness in three test modes to the Gamma3 Nail, but had lower strength. Stability of Omega3 plate constructs was not improved with locked fixation proximally or distally.

Transient synovitis is a benign, self-limiting condition that is diagnosed after the exclusion of more serious causes of acute hip pain in children. Although its etiology remains unclear, it is largely believed to be viral in nature. Transient synovitis typically presents as an acute onset of thigh pain with a limp or an unwillingness to bear weight. It can be distinguished from similar conditions by the absence of fever, as well as unremarkable bloodwork (WBC, CRP, ESR), radiographs, and hip aspiration. Conservative treatment and observation are the mainstay of management. Resolution of symptoms generally occurs by 1 week and may be accelerated by NSAIDs. Although numerous papers have emerged over the years with an effort to advance our understanding, many questions remain about its pathomechanics, etiology, and how to exclude other more serious conditions that present similarly.

The article explores how growing geopolitical and economic unity is being felt in the sports sector in the Association of South-East Asian Nations (ASEAN) region. It discusses the significance of ASEAN sporting competitions and the extension of the idea of regional competition from national team to club level. It also cites region's commercial potential and the lack of understanding by local agencies and brands about sports events, media, marketing opportunities and sponsorships.

The article discusses the developments in the domestic sports marketing sector in the Gulf states of Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates (UAE). A report by the Pan Arab Research Center showed that advertising investment in the UAE alone stood at 1.44 billion dollars in 2011 but sports sponsorship accounted only for a relatively small share. The opinion of the Abu Dhabi-based agency Professional Sports Group's Jamie Cunningham on the developments is cited. INSET: NATIONAL SPORTS DAY: SPONSORSHIP POTENTIAL.

The article explores how the Nordic region is bringing joint-bidding back into fashion to remain competitive in the sports bidding market. One driver for a new round of join-hosted bids is the issue of the region's venue capacity. Another driver is the escalating competition established hosts like the Nordic countries confront from the developing economies. Finland and Sweden will share the 2013 International Ice Hockey Federation event.

The article looks at the latest sports venues that are installing or offering W-Fi access and other wireless mobile technology. The increased competition with other leisure activities, as well as the rising trend of mobility and video are factors driving new business models and change in wireless connectivity. New propositions addressing stadium cost and revenue issues are being worked on by technology providers and sports marketers. Branded applications also enhance visitors' enjoyment.

The article looks at how the high-class facilities and training camps built for the 2012 London Olympic Games in England can maximize their return on investment after the event. Olympic training hosts, the University of East London, University of Surrey's Sports Park, Essex County Council, and the Welsh government share the view that these facilities would increase the levels of grassroots sports participation. Other destinations use the facilities to create a niche market for themselves.

In the article, the author discusses the bidding process in the selection of cities and countries to host major sporting events, like the Olympic Games. It cites the high standards that were set by the International Olympic Committee (IOC) in the selection of host to such event. According to professor Simon Shibli of Sheffield Hallam University's Sport Industry Research Centre (SIRC), social legacy has been included as a criteria in the selection process.

The article discusses the different factors and requirements that make a port an appealing stop-over for a major ocean race. A main consideration of venues is the economic benefits, and objectives vary. Promoting tourism is another aim and this eventually leads to hosting given the right natural environment, infrastructure and amenities. Presented are the entry-level requirements to host such as space, accessibility and good routes among others. As stated, venues can land on a race either by paying for it or going through the bidding process.

The article examines the free-to-air coverage and off-course betting appeal of horseracing and how it will impact media rights and distribution strategies. In Australia, racing revenue comes mainly from betting, as shown by joint venture between Racing Victoria and Tabcorp. In Great Britain, sponsors and bookmakers take advantage of wall-to-wall terrestrial coverage. Organizers are encouraged to ensure that sport remains to be a fixture in mainstream media platforms.

The article presents an interview with disc jockey (DJ) and sound designer Theo Parrish about his personal life and work. Topics covered include Parrish's views about the electronic repetition of rhythm, the exploitation he experienced while working at a packing plant in Detroit, Michigan, and his thoughts on the difference between sound and noise.

The article discusses the naming rights included in the business plan for every new sports facility. JPMorgan Chase has invested 300 million U.S. dollars in a 10-year naming rights deal with Madison Square Garden. Gillette has renewed its sponsorship of the New England Patriots' National Football League stadium also at 300 million U.S. dollars but over 15 years. One expert claims the range of rights delivered to the advertiser is become more essential, not just the rights linked to the venue but likewise those connected to the teams that play there.

The article discusses the status of sports tourism in South Africa amidst the financial crisis. The sports travel sector has reportedly lost more than 10 percent of its value in 2009. South Africa has been able to stage big sporting events and draw tourists to watch them because of the appeal of the place as a tourist destination and having a sales cycle that is able to avoid the recession. The advantage of offering game information early enough for fans to plan ahead and prepare for the games is also explained.

The article focuses on the sports marketing business in Turkey, citing the growth of local and international brand sponsorships with football and basketball as dominant investments as well as women's volleyball. It also discusses the opportunities for Turkey as host of the 2020 Olympic Games. Comment from Murat Gunenc, joint managing director of CIS Sports Global agency, is presented. INSET: GROWTH PARTNERS.

The article discusses how sports marketing in Russia is transforming into a genuine marketing platform, as the country prepares to host the 2014 Sochi Winter Olympic Games. The 2014 Sochi Winter Olympic Games organizing committee has already raised more than 1.3 billion U.S. dollars from 43 sponsors. Some of sports with the largest sponsorships are football, ice hockey and figure skating.

The article focuses on the Union of European Football Associations (UEFA) Euro 2016 to be hosted by France. It alleges that the event will usher in a new era in sports. It discusses consolidation through sponsorships, the theme of development and the potential of the Qatari investment in media rights in France and in the television and broadcasting business. Comments from Pierre-Emmanuel Davin of SPORT+ MARKT and Cédric Girard at SPORTFIVE agency are presented.

The article focuses on the evolution of the sports sponsorship sector in Japan and whether a history of domestic backing has restricted the growth of Japanese sport. It was said that one distinction between Japan and Western markets is the ties between the sports and corporate sectors. Corporate connections reportedly extend beyond the title sponsorship privileges that ownership offers. Tom Smith of World Sport Group said owner-sponsors should not be seen as enjoying a free ride.

The article examines changes in title sponsorship and naming rights for sports. Sponsorship in the 1970s focused on exposure. Naming rights, which sought exposure on a more localised level, emerged in the 1980s. Naming rights and title sponsorships have evolved to be a large, more integrated version of a partnership deal. The challenges of executing a naming rights or title sponsorship strategy are discussed.

The article discusses the issues surrounding the bid programs for sporting events. According to Lars Haue-Pedersen of TSE Consulting, bids have deadlines to meet and are run by communities who have not done it before, requiring the appointment of external advisors. The scandal about the accusation of corrupt voting within the Salt Lake City who was awarded the right to host the 2002 Winter Olympic Games in 1995 is recounted. Moreover, Pedersen noted the growing use of technology like digital channels among the second-tier hosts with whom TSE works.

The article describes the potential of small cities to host sports events. EventScotland states that they want to be known as a hosting destination and boost its tourism and media coverage, while Graeme Osborne of Tourism Auckland noted that they look for economic impact and destination profile. Community engagement and natural assets are the advantages of small cities against large ones. Alex Byars of Deloitte's Sport Business Group notes that new options for a sport may not be possible in a large city because it may impact on the infrastructure.

The article discusses the role of government funding to support hosting major sports events. It cites that public sector involvement in staging events focused on issues including the scope and sophistication of the hosting policy of the government and the extent of government involvement in staging sports events. It explains the alternatives to direct involvement which enable a partnership approach to have significant value to sports such as hands-on approach.

The article discusses how South Africa and New Zealand are preparing to host various international sporting events. The former will take on the Fédération Internationale de Football Association (FIFA), and the latter the 2010 World Rowing Championships and the 2015 Cricket World Cup. South Africa reportedly cannot follow the models used by country's like Germany, as it is not yet a developed nation, but hopes the event will allow them to boost tourism to their country. New Zealand, an old pro at hosting such events, hopes to attract more.

The article discusses sports tourism strategies and the requirements for their successful delivery. It explains the importance of understanding the way in which the market is segmented as a cornerstone for any successful sports tourism strategy. It also explores the need to isolate sports tourism spending. It notes that measuring sports tourism spending involves clearly defining where expenditure begins and ends.

The article focuses on the growing number of prospective hosts of major international sports events that are viewing their bids as a means of positioning their city, region or country as a place to visit, do business with, or invest in, as an act of what is known as place branding. The Middle East is said to be one region that has taken the pioneering role in place branding. According to Lars Haue-Pedersen of TSE Consulting Lausanne, they see place branding as the main reason for hosting sports events.

The article focuses on the belief of Beach Soccer Worldwide (BSWW) chief executive officer (CEO) Joan Cusco on the impact the 2013 Beach Soccer World in Tahiti from September 18-28, 2013 in the sports commercial development. Cusco says that the packages sold for the first time has an impact on the commercial brand of BSWW. He adds that the attraction of brands on a worldwide basis is challenging because it needs to prove its capacity.

The article discusses the developments in the global sports sector. Based on the intelligence report titled "The Bid Book" by the SportBusiness Group, Europe has remained as the top host of sporting events, but Asia is fast-catching up. It cites that from 2003 to 2007, 86 Asian cities hosted major sports event from Astana, Kazakhstan to Zhangjiagang, China.

The article discusses the pros and cons of potential naming rights for several event venues in London, England that will be used during and after the 2012 Olympic Games. It addresses the Olympic Park Legacy Co.'s (OPLC) tendering of the naming rights to the main Olympic Stadium, Aquatics Centre, and Multi-Use Arena. The Lee Valley Regional Park Authority's hiring of consultants Grant Thornton to market similar rights to venues it will own and operate after the Olympics is mentioned.

The article discusses the extension of the Isle of Man TT motorcycle race brand into affiliated international series. It mentions the commissioning of a feasibility study by the government to The Sports Consultancy toward the formation of the Isle of Man World Series. Comment from Angus Buchanan, a director at The Sports Consultancy, is presented.

The article discusses the role of government in helping cities host international sporting events. It states that sporting events are no longer mere games, they have become multi-billion dollar businesses which can boost a venue's economy through tourism and promotion. Various developing nations like China and the Gulf States recognize this, as well. The German government spends 3 billion dollars annually for sports facilities, while Denmark, Sweden and Norway have opted to host only medium sized events because of the staggering costs involved.

The article focuses on the report "Sports Tourism: Strategies for Successful Development," published by SportBusiness Group. It cites the factors considered by organizers in assessing a particular event opportunity. It details the reason of the ski resort of Aspen/Snowmass in Colorado for hosting the ESPN Winter X Games. It mentions the increasing popularity of the tourism strategy of meshing spectator events and sports participation for the mutual benefit of both.

The article discusses the marketing initiative by the Finnish city of Lahti to win the hosting rights to the 2017 International Ski Federation (FIS) Nordic Ski World Championships in June 2012 with its 'Join the Celebration' narrative as part of the 100th year of the independence of Finland. Comment from Vili Nurmi at the Sports Business School of HAAGA-HELIA University is presented.

The article reports on the increase in polo events in China, which are used by wealthy businessmen for networking.

Two cases of this disease are reported in The Journal February 9 and March 30. I wish to add a third case: PATIENT. —On July 22, 1906, Mr. W., aged 40, married, one child, healthy up to the present, consulted me for the first time. HISTORY. —The case dates back to injury to the right testicle by a baseball during high-school days. Pain and swelling followed the injury, and atrophy followed the subsidence of the local symptoms. The left testicle was normal. The man became reconciled to his injury, and being fully developed in every respect, paid no further attention to the deformity until the beginning of July, 1906, when his attention was drawn to it by a feeling of fulness and slight uneasiness of the atrophied organ. His family history is good. I advised close watching of the parts. On September 20 I again examined the patient, finding the