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15 Years Ago
1996 – Bob Bowen, chief deputy of the Fayette County Sheriff's Office since 1991, submitted his resignation. He had taken a job with Bowen Cabinet & Appliances.
The Greater Brownstown Park District and Brownstown Village Board began pursuing the idea of building a nine-hole, par-3 golf course in the community.
Arthur and Irene Dial were making plans to celebrate their 50th wedding anniversary. Also planning to celebrate a golden anniversary were the Rev. Dale and Valeria Diveley.
By David Porter
Let's face it. The government really doesn't want you, the taxpayer, knowing what it's doing with your money. It really doesn't.
Regarding the efforts of a number of downstate legislators to restore the death penalty in Illinois, a number of arguments in favor of doing so rest upon the Biblical injunction of an eye-for-an-eye, or its natural extension of a life-for-a-life. Justice is done. Were it so.
Nearly a century ago, U.S. Supreme Court Justice Louis Brandeis stated that "sunlight is said to be the best of disinfectants."
Though he was referring to the need for scrutiny into the corruption that was prevalent in the large business monopolies of that time, his sunlight reference has been adopted in recent years by the media and others concerned about the need for the sun to shine into the workings of our government.
Nearly 20 years ago, I was in one of the local antique shops on Gallatin Street when two large portraits caught my eye. The portraits, created in charcoal and pencil, obviously by the same hand, were framed and in very good condition.
This week's Mystery Banks Photo: These five girls, pictured in April 1963, were all from the Bingham area. Though they now live in Ramsey, Herrick, Pana, Springfield and Willow Hill, they remain very close friends.
1996 – The Vandalia City Council voted to seek candidates for the vacant position of director of community development.
The Vandalia Volunteer Fire Department purchased a new set of hydraulic cutters and a new power unit. Half of the $7,500 for the equipment came from city funds, and the fire department paid the other half of the bill.
Landreth Lumber & Home Center in Vandalia was sold to R.P. Lumber, the owner of lumber yards in a number of Central Illinois towns.
Copyright © 2017
The Leader Union is your source for local news, sports, events and information in Vandalia, Il, and the surrounding area.


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This is your resource to discuss support topics with your peers, and learn from each other.
I own two BB playbooks, a 16Gb and a 64Gb. Had on the 16, blackberry News installed, not so on the 64. Upgraded the 16, and lo and behold my BB news could not be found anywhere. Tried to download it again but RIM tells me that my current profile is not the correct one for the apps. Tried downloading through my computer and the same thing. Can anybody help me out, so that I may have BB news again and in both tablets? Thanks for any help. Can I change my profile? How do I do that? Step by step?
03-29-2013 02:47 PM - edited 03-29-2013 02:47 PM
Hey alvinape,
To better assist you, what is the full error message you receive when attempting to download the BlackBerry News App for BlackBerry PlayBook?
Thank you.
Come follow your BlackBerry Technical Team on twitter! @BlackBerryHelpBe sure to click Kudos! for those who have helped you.
Click Solution? for posts that have solved your issue(s)!

subset: commoncrawl


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Play MASH just like you did when you were younger - find out where you are going to live, how many children you are going to have, who you will marry, and even what your profession would be.
Nostalgia is something that keeps this game going to the extreme - you will play it just because of the memories brings. The visuals are very cutesy and resemble what you would have done. The controls are fun and respond well to your touch. The best thing is that it is highly addictive and you will want to keep playing.
The text and email results are weird. The paid version is superior to the Lite edition, but it won't be worth it for everyone.
Tags: mash lite , play mash , mansion apartment shack house , how to play mash , solo lite , paper games like mash , mash mansion, apartment, shack, house , how to play mash the game , lite mash
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Make Your LinkedIn Profile Work for You | chrisbrogan.com
Buzz Marketing for Technology
Make Your LinkedIn Profile Work for You. May 19, 2008. Make Your Job Descriptions Work Two Ways. want people who read my profile to see that I'm happily employed, that I work for a "real company, and that my company has capabilities in certain areas. If you work for yourself, be clear about that, too. Further, make sure that when people read your job description, they are thinking about how to put you to work on their issues. Comment by Hjörtur Smárason on May 19, 2008 @ 7:13 am. Comment by Julius on May 19, 2008 @ 7:16 am.
YouTube - Education Today and Tomorrow
Buzz Marketing for Technology
Tom used the work of Karl Fisch from Colorado who created a PPT using various quotes and statistics from "flat world" thinking. Developer APIs. © 2008 YouTube, LLC Sign Up. QuickList ( 0 ). Sign In. Worldwide. English. Close. Set Your Country Content Preference. Close. Set Your Language Preference. Videos. Channels. Community. Upload. Videos. Channels. advanced. Loading. Education Today and Tomorrow. Rate: 182 ratings Sign in to rate. Views: 171,510. Share. Favorite. Playlists. MySpace. Facebook. more share options. fewer share options. Loading. Loading.
YouTube - Informal Learning in 10 minutes
Buzz Marketing for Technology
Ive been following your work for a year, and this summary of your theses generated numerous quotables. Developer APIs. © 2008 YouTube, LLC Close. Sign Up. QuickList ( 0 ). Sign In. Site: Home. Videos. Channels. Community. Upload. Videos. Channels. advanced. Loading. Informal Learning in 10 minutes. Rate: 23 ratings Sign in to rate. Views: 14,848. Share. Favorite. Playlists. MySpace. Facebook. more share options ). fewer share options ). This video will appear on your blog shortly. Loading. Loading. Loading. Loading. Thank you for sharing this video! Saving. close ).
Social Media U: Take a Class in Social Media - ReadWriteWeb
Buzz Marketing for Technology
Written by Sarah Perez / May 21, 2008 7:00 AM. / 25 Comments. Soon-to-be sophomore and official Yale blogger, Sam Jackson , puts this concept to work on his own site, where he blogs about higher education marketing trends. Whats Next on the Web: a ReadWriteWeb Toolkit for 2008. Posted by: Marshall Kirkpatrick | May 21, 2008 8:03 AM. David Zotter | May 21, 2008 6:02 PM.
What Do We Need to Teach About Knowledge Work? | Computer Writing and Research Lab
Buzz Marketing for Technology
What Do We Need to Teach About Knowledge Work? Series Number : 060925-1--> Keywords : knowledge work, teaching, pedagogy. Abstract : Knowledge work is work in which the primary product is information that is continually interpreted and circulated across organizationally boundaries. This paper examines the teaching practices necessary in a climate of knowledge work.
YouTube - What is LinkedIn? Part 2
Buzz Marketing for Technology
Added: June 30, 2008. Added: June 30, 2008. practical example of how LinkedIn works. Added: June 30, 2008. practical example of how LinkedIn works. LinkedIn Company Profiles | March 20, 2008. SAP Groups on Linkedin June 2008. Developer APIs. © 2008 YouTube, LLC Close. Sign Up. QuickList ( 0 ). Sign In. Site: Home. Videos. Channels. Community. Upload. Videos. Channels. advanced. Loading. What is LinkedIn? Part 2. Rate: 1 ratings Sign in to rate. Views: 288. watch in standard quality. watch in high quality. Share. Favorite.
6 Ways to Filter Your RSS Feeds - ReadWriteWeb
Buzz Marketing for Technology
Written by Josh Catone / March 4, 2008 8:06 PM. / 26 Comments. Whats Next on the Web: a ReadWriteWeb Toolkit for 2008. Posted by: Four20 | March 4, 2008 8:41 PM. Posted by: rss123 | March 4, 2008 9:45 PM. Posted by: Aaron Mentele | March 4, 2008 10:32 PM. Posted by: benkepes | March 4, 2008 10:46 PM. It always works for me, you can both splice and filter, it has OPML, and it also has re-syndicating delivery in HTML (even customise the code), java, PDF, etc.other features are timezone, language, ordering. Posted by: Tony | March 5, 2008 12:57 AM.
Web2.0@work: In Pursuit Of Passion
Buzz Marketing for Technology
work: In Pursuit Of Passion. work: In Pursuit Of Passion view presentation (tags: web2.0@work work web2.0 work: In Pursuit Of Passion. The Gen Y Guide to Web 2.0 at Work. Developers & API. © 2008 SlideShare Inc. Slideshare.net (beta). My Slidespace. Upload. Community. Widgets. Latest. |. Most Viewed. |. Most Embedded. |. Featured. |. Most Favorited. |. Most Downloaded. |. Slidecasts. Uploading. Post: Download file. From: sachac , 2 months ago. 2.0 ). SlideShare Link. close. All Comments (13). Comments on Slide 1. Favorites (46) -->. web2.0.
New Communication Tech and Work Literacy Presentation
Buzz Marketing for Technology
Post: New Communication Tech and Work Literacy Presentation. New Communication Tech and Work Literacy Presentation View SlideShare presentation or Upload your own. New Communication Tech and Work Literacy Presentation. Slide 1: New Communication Technologies and Work Literacy for the 21st Century Knowledge Worker Slide 2: Purpose of Presentation ï?® Recruit researchers and educators into Work Literacy Group ï?® Discuss some ideas I have been working with lately Slide 3: 4 Categories Dependent on Use of New Communication Technologies used in Workplace ï?®
Buzz Marketing for Technology
How does it work? If you and Jane have shared your third party identities on these services on your MyBlogLog profile, well do the work to figure out if youre connected or not. Posted by Tilly McLain on June 23, 2008 at 11:19 AM in New Features | Permalink. |. Posted by Tilly McLain on June 11, 2008 at 09:47 PM in Service Updates | Permalink. |. June 2008. No way!
eLearning & Deliberative Moments: The present and future of Personal Learning Environments (PLE)
Buzz Marketing for Technology
For example, the priorities for a PLE are different for a tertiary student, a university administrator, an instructor, a working professional, or an adult who persues an eclectic path of lifelong learning. These allow custom extensions, which may pave the way for the development of open APIs for connection by PLEs. APIs ) available. Posted by Deborah | 21 May, 2008 06:11.
5 Excellent Productivity Tips For Google Reader
Buzz Marketing for Technology
Written by: Abhijeet Mukherjee on Wednesday, June 18th, 2008 Posted to: Reader 6 comments, add yours! Jake on 18 Jun 2008 at 10:55 pm. like the idea of List View, but it just doesn't work with me. å·§ on 19 Jun 2008 at 1:03 am. […] å??æ??é?¾æ?¥: Erica DeWolf on 19 Jun 2008 at 2:13 pm. Edwin Hl Metzler on 19 Jun 2008 at 8:23 pm. on 20 Jun 2008 at 2:14 pm. That would be awesome. # jez on 22 Jun 2008 at 5:40 am. but more importantly sort them into : * Work. Google Tutor. Excellent Productivity Tips For Google Reader. Tools.
Your Guide to the Crowdsourced Workforce - ReadWriteWeb
Buzz Marketing for Technology
Written by Josh Catone / May 12, 2008 5:00 AM. / 22 Comments. Generally, these sites exist in the form of graphic design contest web sites where clients put up a call for submissions for a piece of graphic design work, and designers compete for a cash prize by submitting designs. In essence, that means people can give the crowd an incentive to work on a software development project. The idea behind Kluster is that a group of passionate people working together can come up with better solutions for any decision-making problem than a single person. It worked perfectly.
Social Search at LinkedIn Beats Google - ReadWriteWeb
Buzz Marketing for Technology
Written by Bernard Lunn / May 21, 2008 11:15 AM. / 12 Comments. Sort of.) It only works for a defined use case, but, in a search market that is 85% going on 90% Google-dominated, this can still be significant. have been in business for 30 years and have worked across many markets, in many countries and I have worked the LinkedIn system to get those contacts usable. have re-connected with people that I worked with over 20 years ago who are now senior people in specialist areas and I have found those connections valuable in my work. 2008 Web Predictions.
4 Easy Ways of Subscribing to Feeds in Google Reader
Buzz Marketing for Technology
Phil on Thursday, June 26th, 2008 Posted to: RSS/Atom , Reader One comment, add yours! Discover is a little tool that works in two ways: Recommendations Tab: Google Reader analyzes your existing feeds and makes suggestions for feeds you might like, based on a number of parameters. Caleb Elston on 27 Jun 2008 at 11:37 am. Google Tutor. Your how-to guide for Google with Google tutorials, tips for using Google and advice. Easy Ways of Subscribing to Feeds in Google Reader. Written by: J. Google Reader is a very popular online tool for reading RSS feeds. bundlesâ?? box above.
Pardot Offers Refined Demand Generation at a Small Business Price
Customer Experience Matrix
Conversely, although SMB vendors stress their products' ease of use, simple things are not necessarily harder to do in the Enterprise products. I'm still trying to work out a systematic approach to measuring usability, but my current feeling is that there are large variations among products with both the SMB and Enterprise groups. My little tour of demand generation vendors landed at Pardot just before Thanksgiving. As you'll recall from my post on Web activity statistics , Pardot is one of the higher-ranked vendors not already in the Raab Guide to Demand Generation Systems.
Ple - LTCWiki
Buzz Marketing for Technology
Numerous other factors play a role: content creation tools, content storage, tools for communication, protocols/APIs, and identity management. A few definitions: "A Personal Learning Environment (PLE) is a collection of free, distributed, web-based tools, usually centred around a blog, linked together and aggregating content using RSS feeds and simple HTML scripts." simple blog or podcast works well for instructors new to technology.and more experienced instructors may end up using a wide array of tools to achieve intended learning aims. APIs and Protocols. From LTCWiki.
Market2Lead Offers Enterprise-Strength Demand Generation System
Customer Experience Matrix
That difference is that Market2Lead is designed to work with other company systems, rather than assuming it will provide almost all of the marketing department's customer-facing functions. Let's talk first about working with other company systems, because that strikes me as the most distinctive aspect of Market2Lead. Instead, it provides an API that lets users set up their emails with Market2Lead and then have them sent by external email specialists like Responsys and Exact Target. Working in yet another dimension, the system extends to channels beyond Web and email.
Sailthru Offers End-to-End Omnichannel Personalization for B2C Marketers
Customer Experience Matrix
This distinguishes it from systems that rely primarily on feeds from external systems via API connectors or batch files. Technical users can still set up a feed using API calls or JSON posts when necessary. This is one reason I haven't classified Sailthru as a customer data platform: although Sailthru does a great job of building a unified customer database, most CDPs are specifically designed to work with other systems when sending messages. Sailthru was founded in 2008. Sailthru is a good example. Perhaps I shouldn''t complain. customer profiles. data store.
Open Research: A Framework for Social Analytics
delicious b2bmarketing
After interviewing nearly 40 experts and working with Charlene Li and a bit of help from myself, she's found six distinct use cases (see compass below) on how companies are measuring using these new toolsets. Why are social analytics so important? This is a new medium, and proof over re allocation of investment is key. The more you share it, the easier it is for us to produce more.
Kred tries to one-up Klout by taking influence to the masses
grow - Practical Marketing Solutions
Andrew Grill: When we gained access to the Twitter firehose back in 2008, we developed our architecture to be able to handle the masses of data that come from sources like Twitter, Facebook, and the ever-growing social networks. Andrew Grill: Having an amazing technical team who work around the world in multiple time zones means that we're ready for anything. Tweet.
8 Interesting Things You Probably Didn't Know About Google's Algorithm
mean, they get us our search results, after all.But how does Google's algorithm work? Where and how your pages rank in Google can make or break your organic search traffic, so it's important to understand how the algorithm works and how to ethically optimize for it. Google enlists the work of human beings to evaluate the quality of search results. Okay, fine. Trillions."
WMC Interviews: Tim Young of Socialcast
The Socialcast application is a customizable internal corporate social network designed to allow the employees within a company to share information, ask questions, get answers, and engage more deeply in their daily work. We are currently in process of working with a number of enterprise search providers to connect our Socialcast API into their search products. Last week I had the opportunity to interview Tim Young, CEO of Socialcast , an on-demand social networking platform that brings collaboration and knowledge-sharing capabilities to intranets. platform.
Klout Founder says Lithium deal will propel new development
grow - Practical Marketing Solutions
The genesis of Klout circa 2008. Klout Founder Joe Fernandez spoke to me shortly after the public announcement and discussed his emotional journey in founding a company, fighting for funding and legitimacy, building an enterprise, and finally positioning his life's work for a new era of growth. When I got un-wired, I did some consulting but I was always working on this idea.
Optify Lets Agencies Provide Small Business with Marketing Automation, Distributed Marketing, and Sales Enablement
Customer Experience Matrix
Optify was founded in 2008 and launched its original product, a search engine optimization (SEO) tool, about a year later. You can also think of Optify as having worked its way down from the top of the funnel (SEO) to the middle (marketing automation) and towards the bottom (CRM). proper API for bi-directional integration with any CRM system is under development.
Analytics CEO makes a passionate case against marketing attribution
Cross-channel attribution (or "multi-touch attribution") became a popular concept at the time when web analytics had just completed its journey from IT to the marketing department (circa 2008). This means cross-device and cross-media integration at a user level are imperative if attribution is to work. Has anybody actually got this thing to work? BLACK HOLE. What was it about?
Get More Email Opens and Clicks Using Behavioral Targeting
Modern B2B Marketing
When David Daniels, founder of the Relevancy Group, was an analyst at Jupiter Research (acquired by Forrester Research in 2008), he reported that targeting emails based on Web click-stream data increased open rates by more than 50%, and increased conversion rates by more than 350%. . These ESPs work primarily from imported lists and spreadsheets. Examples of Behavioral Targeting .
The Ultimate Glossary: 120 Social Media Marketing Terms Explained
Application Programing Interface (API) - An API is a documented interface that allows one software application to interact with another application. An example of this is the Twitter API. Creative Commons - Creative Commons is a nonprofit corporation dedicated to making it easier for people to share and build upon the work of others, consistent with the rules of copyright.
Integrate Social Networks with your Corporate Website with 'Social Sign On'
delicious b2bmarketing
Managing these multiple login systems from all these social networks is cumbersome due to changing APIs, protocols. Primary Vendors Most social networks offer integration features such as Facebook, LinkedIn, Google Myspace, and Twitter, see my complete matrix list (I worked with these vendors to create this list). Registration pages go away …much to the approval of consumers.
Do You Know the History of Your Favorite Social Media Websites?
WindMill Networking
After working for Apple and PayPal and getting a generous payout from the latter's sale to eBay, Reid Hoffman was now ready to start his own company. He started collaborated with Naveen Selvadurai in 2008 and soon launched a new location-based app in the popular South by Southwest (SXSW) festival the next year. It was the culmination of a round of drinks in 2008 in Montreal.
The Ultimate Glossary: 101 Social Media Marketing Terms Explained
Application Programing Interface (API) - An API is a documented interface that allows one software application to to interact with another application. An example of this is the Twitter API. Creative Commons - Creative Commons is a nonprofit corporation dedicated to making it easier for people to share and build upon the work of others, consistent with the rules of copyright.
5 Proven Strategies for B2B Social Media Marketing
delicious b2bmarketing
Furthermore, there was a 33% percent conversion rate on leads generated through the New York landing page , compared to a 12% conversion rate on 2008. From 2008 to 2009, Kinaxis saw a 270% increase in web traffic to Kinaxis.com and a 320% increase in conversions (customer leads), as a direct result of introducing the community. We're a small B2B software startup and we focus on testing out new campaigns/tools and are constantly reviewing the metrics to determine what's working. Captivating Works of Crowdsourced Art 7 A/B Testing Resources for Startups. link].
5 Proven Strategies for B2B Social Media Marketing
delicious b2bmarketing
Furthermore, there was a 33% percent conversion rate on leads generated through the New York landing page , compared to a 12% conversion rate on 2008. From 2008 to 2009, Kinaxis saw a 270% increase in web traffic to Kinaxis.com and a 320% increase in conversions (customer leads), as a direct result of introducing the community. We're a small B2B software startup and we focus on testing out new campaigns/tools and are constantly reviewing the metrics to determine what's working. The B2B Social Media Marketing Series is supported by IDG Enterprise. Learn more.
50 (of the) Best Twitter Guides, Stats, Tips and Tools of 2010 (So Far)
Awareness of Twitter has exploded; 87% of Americans said they were "familiar with" Twitter in a poll taken earlier this year, versus just 5% in 2008 and 26% in 2009. Among the findings: during the work week, people are happiest in the early morning and late evening. And only status updates and my favorite: "You share would-be Zen gems through a f*cking API.. Crabs.
Will Your Social Media Service Tell You When It Hits The Iceberg?
WindMill Networking
The FeedBurner API is set to be decommissioned this month. Phil reminds me of a CEO I once worked for who grew a small computer components company into a global Fortune 500 personal computer juggernaut. Joel has worked for several PR and marketing agencies, and previously served as a public information officer at UCLA and UC Irvine. Benjamin Franklin. Global reach.
5 Alternative Ways to Search Twitter for People by Location
WindMill Networking
In fact, Twitter didn't even have an integrated search engine until it bought one from Summize in July, 2008, 2 years after they had launched their service. That's where Twitter's APIs come in. Here's a simple task to prove my point: I work for a company and am targeting Twitter users who live in a certain area. How do I find them? Not Usable. WRONG!
ClickSquared System Combines Marketing Database, Campaign Management and Multi-Channel Message Delivery
Customer Experience Matrix
In fact, Click 3G was officially launched last week, although the company has been migrating clients to the platform since Fall 2008. Customer data can be loaded via API posts or self-service file uploads. These can be executed in batch or triggered by events posted to the system API in real time. Campaign outputs can include dynamically-customized content for direct mail, email, and mobile (SMS) messages, as well as messages sent to CRM systems via an API. The main advantage is tight integration of database build, campaign management and message delivery. options.


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The Best of ASCO Meetings condense the most cutting-edge science and education from the world's premier oncology event, the ASCO Annual Meeting, into a two-day program. The abstracts chosen for presentation and discussion reflect the foremost research and strategies in oncology that will directly impact patient care. The program features in-depth discussion and analysis on the latest scientific findings in primary disease sites and practice-changing advances in cancer treatment. Expert faculty will place abstract findings into clinical context and discuss how the results may change the current standard of care. The Meetings' smaller size allows for ample time for audience participation and attendee interaction.
Join us in Washington, DC, to learn from leaders in the field, network with peers, and experience two days of in-depth analysis and discussion that you can bring back to your colleagues and your clinic.
State Society Collaborators
Thank you to the following State Societies for their support of the Best of ASCO Meetings
Maryland/DC Society of Clinical Oncology (MDCSCO)
Virginia Association of Hematologists & Oncologists (VAHO)
North Carolina Oncology Association (NCOA)
Pennsylvania Society of Oncology & Hematology (PSOH)
South Carolina Oncology Society (SCOS)
West Virginia Oncology Society (WVOS)


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- 1 having the job or duty of doing something or taking care of somebody/something, so that you may be blamed if something goes wrong responsible (for doing something) Mike is responsible for designing the entire project. responsible (for somebody/something) Even where parents no longer live together, they each continue to be responsible for their children. causing something
- 2 responsible (for something) being able to be blamed for something Who's responsible for this mess? Everything will be done to bring those responsible to justice. He is mentally ill and cannot be held responsible for his actions.
- 3 responsible (for something) being the cause of something Cigarette smoking is responsible for about 90% of deaths from lung cancer. to somebody in authority
- 4 responsible to somebody/something having to report to somebody/something with authority or in a higher position and explain to them what you have done The Council of Ministers is responsible to the Assembly. reliable
- 5 (of people or their actions or behaviour) that you can trust and rely on synonym conscientious Clare has a mature and responsible attitude to work. opposite irresponsible See related entries: Job skills and personal qualities job
- 6 [usually before noun] needing somebody who can be trusted and relied on; involving important duties a responsible job/position Word Origin late 16th cent. (in the sense 'answering to, corresponding'): from obsolete French responsible, from Latin respons-
having job/duty
adjectivejump to other results
BrE BrE//rɪˈspɒnsəbl//; NAmE NAmE//rɪˈspɑːnsəbl//Job skills and personal qualities
Check pronunciation: responsible


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Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis
DOI: 10.1186/ar2706
© Hueber et al.; licensee BioMed Central Ltd. 2009
Received: 7 December 2008
Accepted: 21 May 2009
Published: 21 May 2009
Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis (RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers.
Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept.
We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts (positive predictive values 58 to 72%; negative predictive values 63 to 78%).
We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients.
Rheumatoid arthritis (RA) is a prototypical systemic autoimmune disease that affects 1% of the world population. TNF antagonists have become the most widely used biological therapies for patients with RA [1]. Based on criteria to quantify response to therapy with disease-modifying anti-rheumatic drugs [2], 30 to 50% of patients achieved an ACR50 or greater response to anti-TNF therapies in sentinel clinical trials [3–5]. American College of Rheumatology (ACR) response criteria are a composite index of measures indicative of the percentage improvement over baseline that was achieved by an individual patient while on treatment for at least 12 weeks, with ACR20 the primary measure of efficacy [6]. Clinical trials, however, generally focus on homogeneous populations that frequently include more severely ill patients who are more likely to show statistically significant improvement over placebo [7, 8]. In contrast, large observational studies of the mixed populations of RA patients typical of clinical practice indicate that longer term response rates to anti-TNF therapies may be considerably lower than those reported in these landmark clinical trials [7–10].
Great need exists for molecular biomarkers for the prediction of response to anti-TNF therapies, and a number of candidate markers are currently under investigation, including genetic and protein markers [11]. RA is associated with the production of multiple autoantibody specificities and the dysregulation of multiple cytokines, which are both present in the serum proteome in RA patients [12]. Since cytokines and potentially autoantibodies contribute to the pathogenesis of RA, we reasoned that characterization of spectra of serum autoantibodies and cytokines, rather than characterizing the entire serum proteome, might yield tractable biomarkers for guiding anti-TNF therapy in RA.
We previously reported the development of antigen microarrays and application of these arrays to characterize autoantibody phenotypes associated with a variety of autoimmune diseases [13]. We further developed RA antigen microarrays, and applied these arrays to identify autoantibody profiles that molecularly stratify RA patients into clinical subgroups [14]. We have also demonstrated the utility of blood cytokine profiling to subclassify patients with early RA, and demonstrated an association of elevated blood levels of the proinflammatory cytokines TNF, IL-1β, IL-6, IL-13, IL-15 and granulocyte- macrophage colony-stimulating factor with autoantibody targeting of citrullulinated antigens [12].
Materials and methods
Patient sera
Pretreatment sera from three cohorts of patients with the diagnosis of RA based on the ACR classification criteria [15], who were initiated on therapy with the anti-TNF therapy etanercept (Enbrel®, Amgen, Thousand Oaks, CA, USA), were analyzed using synovial antigen microarrays (except for the third cohort), ELISAs, and a multiplex 12-cytokine bead assay. The cytokines assayed were selected based on previous screening studies using a 22-cytokine assay [12].
Demographic, clinical and serologic characteristics of the three cohorts
US-based (ABCoN)
Age (years)
50 (35 to 78)
Female sex
23 (79)
56.6 (1.2 to 500)
CRP (mg/l)
60 (2 to 79)
ACR response < 20
15 (51.7)
ACR response > 50
14 (48.3)
Shared epitope present
16/24 (66)
Disease duration (months)
96 (12 to 396)
Age (years)
54 (32 to 77)
Female sex
34 (79)
CRP (mg/l)
37.5 (10 to 166)
ACR response < 20
19 (44.2)
ACR response > 50
24 (55.8)
Shared epitope present
Disease duration (months)
108 (1 to 464)
Age (years)
56 (24 to 76)
Female sex
20 (95%)
Rheumatoid factor (units)
66.9 (14.9 to 1,675)
CRP (mg/l)
55 (33 to 75)
ACR response < 20
9/21 (29.0)
ACR response > 70
12/21 (38.7)
Shared epitope present
Disease duration (months)
151 (11 to 444)
Blood samples were obtained at baseline (pretreatment sample) and at least 3 months after initiation of therapy with etanercept. Analysis of the pretreatment samples was performed for the present study. Response to therapy with etanercept was assessed at least 3 months after etanercept was started, based on the ACR criteria for improvement [2]. All samples were immediately aliquoted upon receipt at the Stanford research laboratory, and separate aliquots were used for each assay to minimize the effects of additional freeze- thaw cycles.
Cytokine assay
All cytokine measurements were performed using the Luminex ×200 platform, following a previously described optimized assay protocol [12]. Briefly, to minimize potential false-positive elevations of cytokine measurements due to rheumatoid factor and other heterophilic antibodies that can cross-link the capture and detection antibodies, HeteroBlock® was added to achieve a final concentration of 3 μg/ml, as previously described in detail [12]. For the studies performed herein, we utilized a custom 12-plex human cytokine FLEX® kit (Upstate, Millipore, Billerica, MA, USA) that included beads specific for TNFα, IL-1α, IL-1β, IL-6, IL12p40, IL-12p70, IL-15, granulocyte- macrophage colony-stimulating factor, fibroblast growth factor-2 (FGF-2), monocyte chemoattractant protein-1 (MCP-1), eotaxin, and IFNγ-inducible protein 10.
RA antigen microarrays
The production of RA antigen microarrays was previously described in detail [13, 14]. Briefly, more than 500 peptides and proteins representing candidate autoantigens in RA were printed at 0.2 μg/μl onto derivatized Epoxy ArrayIt® microscope slides (ArrayIt®; TeleChem International Inc., Sunnyvale, CA, USA) using a robotic arrayer. The arrays were blocked and probed with sera at 1:200 dilutions, and bound serum autoantibodies detected using Cy3-conjugated goat anti-human IgG secondary antibodies (Jackson ImmunoResearch Laboratories, Inc. West Grove, PA, USA). Probed arrays were scanned with a GenePix 4000B scanner (MDS Analytical Technologies, Sunnyvale, CA, USA), and antibody reactivities quantified using GenePix Pro 5.0 software.
Candidate biomarkers identified in array screening experiments, subsequently used for training and cross-validation in PAM
Peptide sequence
SwissProt ID
Ace-DPMSSTYIEELGKREVTIPP- [NH]2
Apolipoprotein E(277–296)cit
A [cit]LKSWFEPLVEDMQ [cit]QWAG
TIHAHPGS [cit]RGG [cit]HGYHH
AE [cit]LT [cit]KYNELLKSYQWKML
Fibrinogen A(616–635)cit3
THSTK [cit]GHAKS [cit]PV [cit]GIHTS
Serine protease 11(433–452)
Cartilage oligomeric matrix protein(453–472)
Fibrinogen cit
Cytokines and chemokines
Fibroblast growth factor-2
Granulocyte- macrophage colony-stimulating factor
IFNγ-inducible protein 10
Monocyte chemoattractant protein-1
Enzyme-linked immunsorbent assay
Peptides and fibrinogen protein from human plasma (Calbiochem, Gibbstown, NJ, USA) were coated onto medium-binding 96-well flat-bottom polystyrene plates (Costar, Corning Inc, Corning, NY, USA) at 1 μg peptide/ml at 4°C overnight. Plates were then washed and blocked for 1 hour at room temperature using 5% dry milk in PBS, and incubated for 90 minutes using serum at 1:200 dilution in PBS. Horseradish peroxidase-conjugated anti-human IgG secondary antibodies (horseradish peroxidase-conjugated goat anti-human IgG, Fcγ-fragment specific; Jackson Immuno Research Laboratories Inc., West Grove, PA, USA) were used at 1:20,000 dilutions, and bound autoantibodies were detected by chemoluminescence (Onestep® TMB ELISA; Pierce, Rockford, IL, USA).
Data analysis
The data analysis was performed using significance analysis of microarrays (SAM) (version 1.21) and prediction analysis of microarrays (PAM) (version 1.23), and the hierarchical clustering software Cluster® and TreeView® [16], as described previously [14, 17]. PAM uses internal cross-validation by which 90% of the training samples are randomly selected 10 times, followed by one-by-one class prediction of the remaining 10% of samples, thus identifying classification errors and overfitting [18]. PAM was used in the training, cross-validation and prediction analyses described. The general-purpose statistical package R has also been used for the analysis [19].
Non-normalized datasets were used for all analyses in the article. Although this approach limits the ability to detect differences in the low signal intensity range, the rationale for this approach is based on the observation that high-level reactivities became significantly distorted when z-normalization procedures were applied.
Expansion of RA antigen microarrays for profiling autoantibodies in RA sera
To further develop previously-described RA autoantigen microarrays [14], we expanded the number of peptide and protein autoantigens on the arrays. The arrays used in the experiments described herein were 2,180-feature arrays that include > 540 proteins and peptides, representing the following candidate RA antigens: biglycan; decorin; fibromodulin; clusterin; osteoglycin; fibrinogen; type I, type II, and type V collagens; vimentin; filaggrin; serine protease 11; apolipoprotein E; calpastatin; glucose-6-phosphate isomerase; heat shock proteins HSP60, HSP70, HSP90, and BiP; hnRNP-A2/B1; histones H2A and H2B; and cartilage oligomeric matrix protein (COMP), vitronectin and fibronectin. Candidate antigens were selected based on literature searches and screening experiments. Briefly, for the antigen screening experiments, immune complexes were isolated from RA cartilage and synovial tissues, and the protein antigens contained in the synovial immune complexes were identified by mass spectrometry (PM, manuscript in preparation). Identified proteins were, when available, purchased from commercial sources and peptides representing the candidate antigens synthesized for printing on arrays. Overlapping 20-amino acid peptides, both native and containing citrulline substitutions, were synthesized on a commercial custom peptide synthesis platform using Fmoc chemistry (PepScreen®; Sigma Genosys, St Louis, MO, USA).
To determine the correlation of antigen array and ELISA results from a subset of peptide antigens, several native and citrulline-substituted peptides were tested in ELISA experiments. We observed moderate to strong correlations for these peptide antigens, with correlation coefficients R2 ranging from 0.49 for clusterin(386–405)cit to > 0.92 for hFibA(211–230)cit (see Additional data file 2).
Exploratory profiling using samples from the ABCoN cohort
Pretreatment autoantibody profiles differentiate anti-TNF therapy responders from nonresponders
Cytokine profiling using a bead-array system
We performed multiplex cytokine profiling using the Luminex bead array system and methods previously optimized to minimize the impact of rheumatoid factor [12]. Our analysis of 12 cytokines in the initial 29 ABCoN samples characterized did not reveal significant differences between responders and nonresponders based on both linear regression as well as SAM and PAM analysis, probably due to a substantial number of patients with very low or undetectable levels of many of the cytokines (data not shown). When 64 further samples from etanercept-treated patients from two additional cohorts became available, and cytokine profiling results from this larger set of samples were analyzed by regression analysis, however, significant differences in baseline cytokine levels were identified in responders (response ≥ ACR50) as compared with nonresponders (response ≤ ACR20). These results are presented in detail below.
Combinations of autoantibody and cytokines improve differentiation of etanercept responders from nonresponders
To determine whether combinations of cytokines and autoantibodies might provide superior differentiation of pretreatment samples derived from etanercept responders and nonresponders, we next performed SAM analysis on integrated antigen array and cytokine datasets obtained for the 29 ABCoN samples. This analysis demonstrated that a panel of antigens and cytokines more effectively differentiated baseline samples derived from responders and nonresponders (q < 3; data not shown). Based on these preliminary observations, combined autoantibody and cytokine analyses were used in the subsequent experiments outlined below with the objective to develop a multi-parameter biomarker for predicting response to etanercept therapy.
Autoantibody and cytokine profiling of pretreatment samples derived from three cohorts
In the next series of experiments, we utilized pretreatment samples from three independent cohorts of etanercept new-start RA patients. These cohorts included the US-based ABCoN cohort, a Swedish cohort, and a Japanese cohort.
Analysis of cytokines
In a first step, concentrations of 12 cytokines were measured and analyzed by logistic regression in all 93 pretreatment samples derived from the three independent cohorts. When cytokine results from baseline samples derived from responders and nonresponders were compared, TNF and IL-15 were elevated in responders as compared with nonresponders (P < 0.05), while MCP-1 and IL-6 exhibited a trend towards being elevated in responders as compared with nonresponders (P < 0.1).
The classification error rates, however, were determined to be 39.8% to 48.4%; thus, taken alone, pretreatment blood cytokine levels appear to be of no practical utility in classifying the likelihood for response to etanercept therapy. We concluded that only in combination with other biomarkers do pretreatment blood cytokine concentrations contribute to a predictive biomarker signature for response to etanercept.
Analysis of autoantibodies only
Based on the initial RA antigen array experiments in the ABCoN cohort described above, to further test candidate antibody biomarkers with the greatest predictive utility we developed peptide ELISAs for the most promising peptide antigens. All 93 pretreatment samples from etanercept new-start patients were analyzed with these ELISAs, and the relative autoantibody measurements optical density (OD) values were used for further analyses. Since relative expression levels were the primary measure of interest for these assays, no standard curves for calculation of antibody concentrations were developed. All measurements from the single-antigen ELISAs were combined with the measurements from the bead-array cytokine assay for integrated analysis of cytokine and autoantibody profiles in baseline samples derived from all three cohorts of etanercept new-start RA patients.
Combined autoantibody and cytokine profiles are most predictive for response to etanercept in three independent cohorts
We describe the proteomic screening and discovery of a 24-biomarker signature in pretreatment samples derived from RA patients for class prediction of response to therapy with the anti-TNF therapy etanercept. We developed and tested the signature using three independent population-based cohorts from the USA, Sweden and Japan. Our results indicate that the 24-variable biomarker has utility to predict good to excellent response to etanercept therapy (equivalent to response ≥ ACR50 for the ABCoN and Swedish cohorts, and to response ≥ ACR70 for the Japanese cohort), and to predict lack of response to etanercept therapy (response < ACR20). This biomarker signature enabled superior pretreatment classification of response in three ethnically diverse cohorts, in comparison with a theoretical benchmark based on clinical observation and previous experience in population-based cohorts (one-third of patients no response, one-third of patients partial response, and one-third of patients good response).
Identification of clinical predictors and development of molecular biomarkers have been hampered by many factors, including the molecular complexity and clinical heterogeneity of RA, the inherent difficulty in classifying response to therapy that appears random and does not follow a Gaussian distribution [20], and the lack of enabling technologies to broadly screen for potential biomarkers. Several single-cohort studies reported associations of acute phase parameters [21], genetic factors [22], Fcγ receptor type IIIA polymorphisms [23], – 308 TNFα gene polymorphisms [24], and rheumatoid factor or anti-citrulline autoantibody titers [25] with response to anti-TNF therapies. Nevertheless, studies investigating multiple cohorts using proteomic-scale biomarker signatures have not yet been reported. Although providing great potential, genomic and proteomic profiles identified in single cohorts of patients have frequently failed to replicate when subsequently applied to independent cohorts [26].
To address this unmet clinical need and some of the above-mentioned limitations, we applied proteomics technologies to characterize pretreatment samples from three independent cohorts, whereby all patients were treated with a single anti-TNF therapy (etanercept).
Using data from all three cohorts, we identified a panel of proteins, characterized by elevations of both serum antibody and cytokine concentrations, which were associated with patients who exhibited clinically good response (≥ ACR50) and excellent response (≥ ACR70) to etanercept therapy (positive predictive value = 58 to 71%). In contrast, patients who exhibited minimal or no significant response to etanercept therapy after 3 months or more were found to predominantly lack this biomarker signature (response < ACR20; negative predictive value = 63 to 78%).
The RADIUS program – the Rheumatoid Arthritis DMARD Intervention and Utilization Study [8], which follows two multicenter observational registries of thousands of RA patients from rheumatology practices – demonstrated that ACR response rates were notably lower as compared with the sentinel clinical trials. This observation might suggest that the benchmark for novel biomarkers to predict response in general rheumatology practice could be different from the benchmark for clinical trials. It is possible that, with further refinement and use of Good Laboratory Practice assays, autoantibody and cytokine profiling could provide significantly higher predictive values for predicting response to anti-TNF therapies. A biomarker that increases the precision of pretreatment prediction of the ACR50 response (that is, from 50 to 70%) provides the potential to have a significant impact on clinical decision-making and potentially trial design [27].
Our study investigated samples from three population-based cohorts. Within the US-based ABCoN cohort, for which the multi-parameter biomarker demonstrated the best response prediction, analysis of the responders exhibiting an ACR50 response or greater provided a positive predictive value of 71% (Figure 6c). In the Japanese cohort, the level of positive prediction observed was lower (positive predictive value = 58%), while the biomarker identified Japanese nonresponders with a negative predictive value of almost 80%, which was the highest of any predictive value seen in this study.
Some of the markers in the 24-variable biomarker signature were previously proposed to have some value for prediction, such as MCP-1 [28] and titers of autoantibodies targeting certain citrullinated antigens or mixtures thereof, as measured in the cyclic citrullinated peptide ELISAs [29, 30]. Our data corroborate these earlier notions since several citrullinated peptides emerged as useful variables, as well as MCP-1 demonstrating a near-significant trend of being elevated in responders. Newly described markers include several native and nonfilaggrin-derived citrullinated antigen epitopes as presented in Table 2. Our data also demonstrate that cytokines alone are probably insufficient to accurately predict treatment responses in a general population, and combinations of autoantibodies and cytokines provide increased predictive utility across ethnically diverse and clinically heterogeneous RA populations. Additional markers (imaging, genetic, clinical) may eventually have to be incorporated into a definitive panel of biomarkers [31], for the future development of a prediction score that could be applied for reliable patient stratification.
Although the present study utilizes samples from three cohorts of patients, important limitations remain: the number of samples per cohorts is relatively small; a number of samples demonstrated undetectable serum levels of cytokines; the quantification of response to therapy in RA is intrinsically inaccurate since response classification is based on short term follow-up; and our data may underestimate the predictive value of these biomarkers for predicting response to anti-TNF therapy since concomitant disease-modifying anti-rheumatic drug medication in the three cohorts was not uniform. Moreover, a full validation in independent cohorts of the identified markers is not presented in this paper. Because of the small sample numbers in the individual cohorts and the fact that the experiments were performed over a 3-year period, the present article represents a discovery and testing study. The training was performed on the full dataset, and the resulting panel of markers was tested in the three individual cohorts. These limitations indicate the need for larger validation studies and prospective serum proteome studies in cohorts where longer-term response outcomes are available.
We identified a 24-parameter autoantibody and cytokine biomarker that enables pretreatment classification and prediction of etanercept responders in three cohorts of patients with RA. Although further validation in prospective and larger cohorts is needed, it is proposed that the multi-parameter protein biomarker presented in this study will facilitate the development of molecular biomarkers with even higher predictive utilities for guiding use of anti-TNF therapy and other disease-modifying therapies in RA patients.
American College of Rheumatology
cartilage oligomeric matrix protein
enzyme-linked immunosorbent assay
monocyte chemoattractant protein-1
prediction analysis of microarrays
phosphate-buffered saline
rheumatoid arthritis
significance analysis of microarrays
tumor necrosis factor.
The authors are grateful to Maya BenBarak for technical help with data analysis, to Markus Britschgi for critically reading the manuscript, and to the members of the Robinson laboratory for scientific input. The present work was funded by an Arthritis Foundation Investigator Award, NIH NHLBI contract N01 HV 28183, NIH NIAMS AI069160, and Veterans Affairs Health Care System funding to WHR.
Authors' Affiliations
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- Weaver AL, Lautzenheiser RL, Schiff MH, Gibofsky A, Perruquet JL, Luetkemeyer J, Paulus HE, Xia HA, Leff JA, Investigators TR: Real-world effectiveness of select biologic and DMARD monotherapy and combination therapy in the treatment of rheumatoid arthritis: results from the RADIUS observational registry. Curr Med Res Opin. 2006, 22: 185-198. 10.1185/030079905X65510.View ArticlePubMedGoogle Scholar
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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Editorial Review
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3 reviews of roy's restaurant, first by kathrasher.
September 28, 2008
When can I go back again!
Wow, ordered the Lakanilau Roll
(Seared Kobe Beef wrapped around Snow Crab, Tempura Asparagus and Avocado) and I still cannot stop thinking about it. Great service, wonderful food.
Dishes Tried:
Lakanilau Roll
The combination of the texture and flavors were amazing. I cannot stop thinking about this dish. All I want is one more bite.
July 17, 2009
Hawaii in Orange County
love dining here - the atmosphere is nice and the service is excellent
August 1, 2008
The best food around. We have dines in about 6 of these restaurants and everyone has been excellent. Pricey but worth it. This is an excellent location and you can go shopping before hand. recommend reservations.
Best Dishes at roy's restaurant
These dishes from the roy's restaurant menu are contributed by Menuism users directly, as part of a restaurant review, or as part of an image upload.
Lakanilau Roll ()
½ Dozen Oysters On The Half Shell
Arare Crisped Temura Shrimp Roll
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text:
The knight rode his horse through the dense forest, the small bundle cradled in his arms. The horse's breath was labored, as if it had been galloping for hours. The knight kept spurring it on, desperate to complete his mission. It was a matter of life or death…for both him and the baby he was holding.
He kept looking behind him, making sure he wasn't being followed by anyone, friend or enemy. No one else can know about what he's doing. It was the queen's dying wish for the baby to survive.
The forest had opened its arms out to him, concealing him from evil hands. He knew, however, he'd be dead soon. He decided that the next habitation he encounter. The trees began to thin out and soon enough, he was riding along the edge of a field. From the top of the hill, he saw a small wooden cottage, quaint and simple, but isolated from anything else. It would work. Quietly, he rode his horse, a beautiful chestnut gelding, to the edge of the accompanying barn. He tied it up by its halter. Walking up to the front of the cottage, he placed the baby on the front step, leaving the Queen's signet ring tied to the cradling cloth.
"Farewell, my princess," his voice rasped. The poison was taking effect.
Bowing to the infant, he backed off. The sun was just beginning to rise. Smiling, with pain in his eyes, he left the cottage and its surrounding fields. He had barely made it into the forest by the time the poison took full effect.
Back at the cottage, the baby opened her eyes, the piercing green associated with royalty and magic.
© Copyright 2017 ClassyClarinet. All rights reserved.
Status: Finished
Genre: Young Adult
Sad but mysterious ,i would love to read it all.
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text: Great, great Frankish food. Huge portions. The pork shoulder was excellent, but enough for three. The usual enormous potato dumplings and the server brought extra sauce without us asking. An excellent value as well. Small doorway a few blocks from the tram, check the street numbers or you could miss it. Make reservations. We went on a Tuesday and they... More


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/play Nickelback instrumental here
Did You Know? WWE has over 5,000,000 Facebook Fans, more than the NFL, ESPN, Major League Baseball, NASCAR, hamburgers, the sneezing panda, the What What In the Butt guy, Stove Top Stuffing, handlebar mustaches and the word "sports" COMBINED. [citation needed]
Did You Know? WWE's next pay-per-view event, Over The Limit, takes place in two weeks!
Did You Know? "Over The Limit" is a WWE pay-per-view? I think it's the one where Raw faces Smackdown in a car race and the winner gets the prestigious "Over The Limit" trophy. I also think it's the PPV where The Big Show is always turning on people. They should at least call it "In Your House: Over The Limit."
Worst: Are We Sure This Wasn't Taped Four Months Ago
Maybe I shouldn't have tried to soldier through Raw immediately after the gym and only a few hours of sleep the previous night, but what happened, did I fall asleep in the afternoon and travel time? This Raw looked like a "WWE BEST OF 2010-2011" DVD, with Cena beating up Alex Riley to antagonize the Miz, Michael Cole making Jerry Lawler mad by insulting his dead mother, and a spotlight on the Mysterio/Del Rio, Swagger/Kingston and Punk/Big Show feuds. All we needed was for the That's What I Am commercials to be The Chaperone (tagline: "I'm the chaperone!") and we'd have been set.
Speaking of living in the past…
Worst: Either Have Michael Cole Skullf**k Jerry Lawler's Mother on TV or Move On
I championed the Cole/Lawler angle for a few months, then spent about four years wishing it would stop. They had a match at Wrestlemania that was supposed to end in blood and piledrivers, but it couldn't, and didn't. So they had another match with less heat at the artist formerly known as Backlash, complete with straps for the lashing of backs, that should've ended with Cole being held down and beaten with a belt until he apologized. It didn't end that way, so now we have to have a rushed little two week Lawler vs. Cole re-rematch for stipulations nobody outside of Lawler and Cole care about, and guess what? It isn't going to end like it's supposed to. It's going to end with Cole winning Lawler's Hall of Fame ring, getting inducted into the WWE Hall of Fame (by Lawler? Can Lawler do that?) and spending the NEXT pay-per-view cycle calling himself WWE Hall of Famer Sir Michael Cole.
Then, at Fatal 4-way we have to watch Michael Cole vs. Jerry Lawler vs. Jim Ross vs. Jack Swagger, with maybe Lawler's crown and JR's hat on the line, and Cole wins that with a roll-up after getting punched maybe once, and he can call himself WWE Hall of Famer Good Ol' Sir Michael Cole. After that, Cole wins Money in the Bank (Mr. Money in the Bank, WWE Hall of Famer Good Ol' Sir Michael Cole) and cashes in, somehow winning the WWE Championship with a roll-up on Jerry Lawler, and then we build to the big blow-off at Night of Champions where Lawler gets his "one last shot" at the WWE Championship, and nobody watches it.
And also Michael Cole wins that.
Best: Ricardo Rodriguez and Alberto Del Rio's Reaction To Him
Raw's opening segment (once again reinforcing the kayfabe idea that the Raw general manager doesn't make any matches before the show and just waits for a bunch of guys to walk out when it starts and throw out some challenges … there's like a huge single-file line of guys waiting to start off the show, but Ryder and Kaitlyn always show up late and never get on the show … also, if nobody starts off the show with a challenge, the Raw GM sends Michael Cole an e-mail that says RAW ROULETTE or BATTLE ROYAL FOR NOTHING) was fun. Alberto Del Rio and his personal ring announcer Ricardo Rodriguez continue to be a wonderful part of my wrestling program, especially now that their dynamic is evolving past "rich guy and his employee employed for arrogant purposes."
Del Rio is easily the best addition to WWE programming in the last few years, and he'd win that if he never wrestled and just stood in the ring winking and making faces at people. Watching him get surprised, then turn and start clapping his hands with a big smile on his face when Ricardo interrupted the Miz with ALBERTOOOO DEEEEEEL RRRRRRIOOOO was tops. I love that Del Rio really seems to like Ricardo, and claps for him like he's a disaffected parent with a talented child. It's sort of like Lisa Simpson telling Snowball to "be the baby" for Nelson Muntz. And then he did this!
Ricardo Rodriguez is money, and until Archibald Peck ends up WWE Champion (and it will happen) he's my favorite CHIKARA-alumni success story.
Best: John Morrison is Dead, So Let's Forget About Him Forever
The best wrestling news of the week is that John Morrison was parkouring across the street and got murdered by an oncoming bus, simultaneously ending his life and disproving his parkour "overcome any obstacle in front of you" philosophy. Then I checked my facts (thanks a lot, Bleacher Report) and found out he was having neck surgery and would be out for a long time, which is also okay. I'm not happy that a human being is going through so much pain, but I am extremely happy that fictional character John Morrison assumedly broke his own neck a la the Joker in The Dark Knight Returns by flipping his hair out of the way after the attack on last week's Raw. Maybe Morrison can learn to squirm around through some handrails while he's in a wheelchair.
I'm hoping the rehabilitation process involves Morrison telling Melina that it's okay if she wants to have sex with Mason Ryan, he understands, because he can't really move. And then she looks up from Mason Ryan's lap and is all "I'm sorry honey did you say something."


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Push It!
By Kristopher Bunker
April 20, 2015
These Entry Level Class A Diesel Pushers Pack In the Amenities Without Breaking the Bank Mention "diesel pusher" to a fellow RVer and you're likely to get a predictable, old-fashioned response: He/she will laud the diesel's muscle, long-term durability, relatively quiet ride and improved... Read more »
Realm of One
By Chris Hemer
March 31, 2015
Foretravel and Motor Home Specialist Team Up to Create a Unique Luxury Motor Coach Significant achievements are rarely the work of just one mind. The seed that becomes a tree of inspiration is usually sown by a dedicated team, motivated by a singular vision. In the world of luxury motor... Read more »
A is for Affordable
By Kristopher Bunker
March 30, 2015
This baker's dozen of Class A motorhomes offer top-notch amenities without busting the budget In the art of sales, few words are as open-ended as "affordable." From vacuums to appliances on up to RVs, the A-word is thrown around with seemingly reckless abandon, and is often used as a sales... Read more »
Axis Vegas
by Chris Hemer
February 23, 2015
Thor Motor Coach's "Recreational Utility Vehicle," referred to as the RUV, continues to grow with the addition of the 25.2, available in Axis and Vegas brands. The RUV is sized like a large SUV, and drives like one, but offers all the conveniences and amenities of a motorhome. The 25.2 is the first... Read more »
Tantalizing (RV) Tech
by Chris Hemer and Rick Kessler
February 23, 2015
The annual Recreation Vehicle Industry Association Show highlighted motorhomes both big and small, plus a host of exciting technologies Elkhart, Indiana, and its surrounding suburbs are to RVs what Detroit is to automobiles, with more than 80 percent of the market coming from this essentially... Read more »
Retro 'Bago: The Brow is Back … Again
by Chris Hemer
December 23, 2014
Winnebago has just introduced its new Brave 31C floorplan sporting the legendary "eyebrow" design. Offered in three floorplans in both the Winnebago Brave and Itasca Tribute lines, this retro coach is loaded with all of the modern conveniences you'd expect in a contemporary motorhome. The... Read more »
A Glimpse Into 2015
By Bruce Hampson
December 18, 2014
Creative floorplans and continuing advances in technology lead the charge for new motorhomes introduced to dealers; Class B's are the fastest-growing segment There's a good reason why toy haulers number among the most popular RVs going into 2015 — and it doesn't necessarily have anything... Read more »
Adventurous Launch
by Chris Hemer
November 22, 2014
The new Touring Series (TS) Adventurous recently made its way into Roadtrek's lineup of luxury Class B motorhomes. Though the Sprinter-based motorhome is sleek and modern on the outside, it's the interior that the company is most proud of. Take a look around and you'll find true granite countertops,... Read more »
Ford Increases Chassis Output to Meet Demand
October 23, 2014
Ford Motor Co. has boosted production of its Class A motorhome chassis in response to growing consumer confidence and demand for motorhomes. According to data from Statistical Surveys Inc., a market analysis company specializing in the RV industry, total motorhome sales are up 13 percent year... Read more »
Class C's On the Rise
by Rick Kessler
September 24, 2014
A look at what's new from Coachmen, Fleetwood RV, Holiday Rambler, Jayco, Thor Motor Coach and Winnebago A recent morning at the Coachmen RV manufacturing facility in Middlebury, Indiana — specifically in the building where the company's Concords, Freelanders, Leprechauns and Prisms... Read more »


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The risks addressed when some terrorism-insurance pools around the world were created were different from present-day risks, according to a technical guide issued by Airmic and Willis Group Holdings. "Globally speaking, the terrorism threat is complex, nuanced and constantly evolving," Willis' James Borrie said in a statement. Some terrorism-insurance plans were established following the Sept. 11, 2001, terrorist attacks but vary in their coverage, which Borrie said "makes the design of a truly comprehensive global terrorism insurance policy very complex."
Full Story:Business Insurance (tiered subscription model)


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|[jira] Closed: (GERONIMO-390) Transaction timeout can leak memory
|Sun, 24 Oct 2004 05:41:26 GMT
Message: The following issue has been closed. Resolver: David Jencks Date: Sat, 23 Oct 2004 10:40 PM I've modified the timeout implementation so transaction completion cancels the timertask. I wasn't experiencing the unit test failure that demonstrated this problem, so I don't know for sure it is fixed. --------------------------------------------------------------------- View the issue: http://issues.apache.org/jira/browse/GERONIMO-390 Here is an overview of the issue: --------------------------------------------------------------------- Key: GERONIMO-390 Summary: Transaction timeout can leak memory Type: Bug Status: Closed Priority: Major Resolution: FIXED Project: Apache Geronimo Fix Fors: 1.0-M3 Assignee: David Jencks Reporter: Jeremy Boynes Created: Sat, 23 Oct 2004 3:46 PM Updated: Sat, 23 Oct 2004 10:40 PM Description: When a tx is created a new timer task is created so that it can be cancelled; this task is never cancelled so it remains referenced until it is fired. Under high load, a lot of pending tasks can build up leading to an OutOfMemoryError. Solution is to cancel the timer on tx commit/rollback --------------------------------------------------------------------- JIRA INFORMATION: This message is automatically generated by JIRA. If you think it was sent incorrectly contact one of the administrators: http://issues.apache.org/jira/secure/Administrators.jspa If you want more information on JIRA, or have a bug to report see: http://www.atlassian.com/software/jira
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Located in Downtown Cleveland, this hotel is within a 15-minute walk of Cleveland Mall, Quicken Loans Arena, and Rock and Roll Hall of Fame. FirstEnergy Stadium ...
love this hotel its great nice and quiet and very clean. The people that work there are wonderful and very helpful . I will be back!
Situated in Strongsville, this hotel is 3 mi (4.8 km) from Southpark Mall and 3.1 mi (4.9 km) from Baldwin Wallace College. Lazer X Treme and Mill Stream Run ...
This hotel on Cleveland's Public Square is linked to Tower City Center, Quicken Loans Arena, and Progressive Field via indoor walkways. Rock and Roll Hall of ...
Centrally located and quick pick ups w Uber to take you anywhere. Great coffee shop across street Rebol. Go to Town Hall for great food. Bartender in the lobby knows where to go for nightlife
Located in Downtown Cleveland, this hotel is within a 10-minute walk of The Corner Alley and Quicken Loans Arena. Progressive Field and Rock and Roll Hall of ...
Walking distance to great dining, Quicken Arena, bowling alley, movies, and arcade.
Located in Cleveland's Entertainment District, adjacent to East 4th Street and within walking distance of the Horseshoe Casino, the Theater District, the Rock ...
It is a beautiful hotel in an amazing building. Centrally located in downtown close to lots of great shops and restaurants.
Situated in Strongsville, this hotel is 1 mi (1.6 km) from Southpark Mall and within 3 mi (5 km) of Mill Stream Run Reservation and Gardenview Horticultural ...
Hotel was clean, and comfortable. Vending machines were out of everything but all in all was a good value.
Adjacent to the theater district and four blocks from Lake Erie, this 13-story hotel overlooks PlayhouseSquare.
Stayed during the world series. The service was great. The staff was wonderful. Everyone went above and beyond to make are stay as pleasant as possible. Would definitely stay again!
Situated in Strongsville, this hotel is 1 mi (1.5 km) from Southpark Mall and within 3 mi (5 km) of Mill Stream Run Reservation and Gardenview Horticultural ...
Room heater didn't work properly. Otherwise, no problems.
This Cleveland hotel is across the street from Quicken Loans Arena, one block from Progressive Field, four blocks from Tower City Center, and a half-mile from ...
Good experience. Rooms were comfortable. Staff was very courteous.
Hampton Inn Cleveland Downtown is a 10-minute walk from the Rock and Roll Hall of Fame and the streets of the Playhouse Square Theater District. The hip Historic ...
The staff was very helpful and nice. The rooms were clean, updated and the Hampton bed makes me feel so much better about staying in the hotels, they totally change out all the bedding for each stay.., including the comforter!
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* Prices reflect the lowest "base rate" found over the next 30 days. Rates are subject to change and may not include taxes and fees, hotel service charges, extra person charges, or incidentals, such as room service. All rates are displayed in USD unless otherwise noted. Converted rates are provided for your convenience. They are based on today's exchange rate, but the hotel will charge you in the local currency.


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Cosmetics articles for website (250 words)
- Status Completed
- Budget $10 - $30 USD
- Total Bids 11
Project Description
I'm looking for someone who can write 18 fashion related articles, these will be 250 words each and for use on our website which sells Korean cosmetics exclusively.
This job calls for someone who has a fun writing style and knows something about cosmetics, its more desirable if you know something about Korean cosmetics. For each article you'll need to do a little research and come up with a few ideas, but the information should be freely available on the internet somewhere.
I can pay $1 per 250 word article, I've written this size article myself in the past and I know that it will not take much time to do.
You don't need to be a native speaker of English to apply, but you will need US English level 1 qualification, all articles must be in US English, with correct spelling. I'm looking for good grammar and good grasp of the article ideas.
Plagiarized or copied articles will not be accepted, everything will be checked through Copyscape, so be sure that your articles will pass this.Get free quotes for a project like this
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Remembering Joe Green
In Memorium
Professor Emeritus Joe Green, a charter member of the Faculty of Fine Arts (now AMPD) and the founding Chair of York University's Department of Theatre, passed away on Feb. 3, 2017.
Professor Green joined York in 1968 and the following year directed Theatre @ York's first production: a double bill of one-act plays by Tennessee Williams. In the course of his distinguished academic career, he served as Dean of the Faculty of Fine Arts (1973-1980) and director of the Graduate Program in Arts and Media Administration (1982-1994). In recognition of his outstanding contributions as a teacher, administrator, cultural consultant and advocate, he was named University Professor in 1993. The Joseph. G. Green Studio Theatre in the Centre for Film and Theatre is named in his honour.
Alongside his academic career, Joe Green was an acclaimed director and producer for the stage and screen. With Gemstone Productions, he produced the Canadian tour and Toronto run of The Dining Room, a revival of The Sunshine Boys, and Sullivan and Gilbert, a co-production with the National Arts Centre, Ottawa and the Kennedy Center, Washington, DC. He served as executive producer for the award-winning television mini-series, Glory Enough For All, seen on CBC, Thames Television/UK and Masterpiece Theatre/PBS. As a principal of Fundamentally Film Inc. he co-produced Syncopation for Mirvish Productions at Toronto's Winter Garden Theatre in 2002.
Through his formidable professional achievements and the generous heart and spirit he brought to everything he did and everyone he encountered, Joe Green has left an indelible mark on our program, our School, and the Canadian arts scene. For more information, including links to media and an online memorial book, go to the YFile story.


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I feel like my face is too long for my features, giving me an awkwardly masculine/stretched out look. I feel like my face would look much better if my eyes and nose were seated a bit farther down on my face. I think part of this is because my filtrum is too long, but in general my features don't look balanced. Is there anything I can do to achieve greater femininity and balance in my features?
Face Too Long/features Too Small? (photo)
Doctor Answers 2
Facial symmetry issues
You may be too critical of your appearance. From the front view I really do not notice any of your mentioned problems. Your nasal tip may be a bit large but other than that it is hard to give you suggestions without an examination.
Facial issues
I think that you should be seen in person to review your main concerns. Give more specifics of what you do not like. Sometimes simple things like facial injectables can give improvement.
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.


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Live updates
Tsunami warning for Sumatra lifted
A tsunami warning for Sumatra that was issued following a major earthquake off the western part of the island has been lifted, a meterological agency official told Indonesian channel TVRI.
Australia cancels tsunami watch after earthquake
The tsunami watch for Western Australia after an earthquake struck Indonesia has been cancelled.
There are still active marine warnings for Christmas Island and Cocos Island.
Tsunami watch issued for Western Australia
A tsunami watch has been issued for parts of Western Australia, said the Australian Tsunami Warning Centre.
Indonesia issues tsunami warning after earthquake
Indonesia has issued a tsunami warning after a powerful earthquake struck of the coast of Sumatra.
The warning is for West Sumatra, North Sumatra and Aceh after a powerful and shallow earthquake of magnitude 7.9 struck off the west coast of the Indonesian island of Sumatra on Wednesday, the National Meteorolgical Agency said.
USGS originally put the magnitude at 8.2, and then 8.1, before lowering it to 7.9.
Indonesia, especially Aceh, was badly hit by the Indian Ocean tsunami in 2004.
The country straddles the so-called "Pacific Ring of Fire", a highly seismically active zone, where different plates on the earth's crust meet and create a large number of earthquakes and volcanoes.
Powerful earthquake strikes off coast of Indonesia
A powerful and shallow earthquake of magnitude 8.1 struck off the west coast of the Indonesian island of Sumatra on Wednesday, the U.S. Geological Survey said.
The epicentre was 502 miles southwest of Padang and it was six miles deep, USGS said.
There were no immediate reports of damage or casualties but the shallower a quake, the more likely it is to cause damage.
Britons warned to 'maintain vigilance' in Indonesia
Britons in Indonesia have been warned to "maintain vigilance" after terror attacks in the capital Jakarta.
Foreign Secretary Philip Hammond condemned the "utterly senseless acts of terror".
"My thoughts are with the victims and their families," said Mr Hammond.
"We advise British nationals in Jakarta and elsewhere in Indonesia to maintain vigilance and monitor FCO travel advice, local media and to follow the advice of local security authorities."
Islamic State claims responsibility for Jakarta attacks
So-called Islamic State has claimed responsibility for the Jakarta attacks, which were "targeting foreign nationals and security forces".
The announcement was made on an IS-allied news agency.
The police chief in the Indonesian capital has also said the group is "definitely" behind the attack.
Lawyer tells ITV News of panic after Jakarta explosion
An eyewitness to the Jakarta attacks has described panic in the streets following the first explosions.
Australian Andrew Gadd, who works in the Indonesia capital, told ITV News he heard a loud bang while in his office and then someone began shouting "bomb, bomb, bomb".
He said when he looked out of a window he saw another explosion and people running in the street.
"You could see people running away and ducking and hiding behind cars," said Mr Gadd.
Indonesian authorities 'expected attack'
ITV News Security Editor Rohit Kachroo tweets:
Indonesian authorities had expected an attack: 150,000 security personnel deployed, arrests made, talk of 'credible threat' over recent wks
Authorities say Jakarta attackers imitated the Paris terrorists. Assumption perhaps. But they can't yet say for sure whether IS responsible
Before Xmas, Australians Attorney-General said IS wanted a 'distant caliphate' in Indonesia.... Great deal of skepticism about comments
Few hundred Indonesians have gone to Syria to join IS/other groups - perhaps 500. Many more Brits are thought to have gone
Figures suggest Indonesian authorities have been relatively successful in combatting draw of extremism - relative to UK for one
Jakarta militants 'imitated Paris attacks', say police
Militants who attacked a busy shopping area in downtown Jakarta were copying the Paris attacks, authorities have said.
Indonesia's national police spokesman also said they probably had connections to so-called Islamic State.
General Anton Charliyan said: "They imitated the terror actions in Paris...they are likely from the (Islamic State) group."


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By Mark Belko Pittsburgh Post-Gazette
It will be Majestic Star no more. In Pittsburgh, it will be the Rivers casino.
That's what the group led by Chicago billionaire Neil Bluhm has decided to name the Pittsburgh casino.
The new name was included in the briefing material on casino signs and site amenities presented to the city planning commission today.
Mr. Bluhm and his group decided to rename the casino after taking control of it from Detroit businessman Don Barden, who was unable to complete financing for the $800 million project. Mr. Barden had dubbed the slots parlor Majestic Star, the same name given to his casino chain.
The new group, however, has chosen a name more compatible with Pittsburgh's identity.
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