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Falling Jewels Chewing Gum Tins make a delicious favor!
These Falling Jewels Chewing Gum Tins are printed with the look of trailing diamonds along with the word Prom. You will select your wording and font to personalize the tins. Include one of the Falling Jewels Chewing Gum Tins in each of your Prom gift bags.
Gum Tin features:
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Outcome studies show endodontic treatment is more successful when PERFORMED BY A SPECIALIST!*
Welcome to Temecula Valley Endodontics, a leading dental practice dedicated to the specialty of endodontics (root canals) for over 15 years! Located in Murrieta, our team realizes the importance of your dental health and strives to provide all your endodontic needs in a clean, comfortable and stress-free environment. All of our treatment is supported by evidence-based dentistry.
Using the most advanced techniques available today, including high-power endodontic microscopes and 3-D digital imaging, we can perform root canal treatment with ultimate precision and comfort. We utilize only in-house, state-of-the-art technology to ensure you are receiving the specialized care you deserve.
We are a traditional, independent practice which collaborates with the many excellent dentists and dental specialists in our area to optimize your dental experience. We are immune to the conflicts of interest and interruptions of care that may arise in practices and clinics that employ "contract" or "traveling" endodontists.
Thank you for placing your trust in Temecula Valley Endodontics to address your endodontic needs. We look forward to seeing you soon!
*Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004.Jul;98(1):115-8

subset: commoncrawl


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Great BluCor Heron
After seeing how good the EPP Eagle looks, I thought I'd build my own big bird from FFF BluCor. Not wanting to directly rip off the Eagle, I thought I'd go with a different big bird. The Great Blue Heron comes to mind: it's an equally impressive, graceful glider that'll look "real" at 100 meters +. And, it's blue, so I can leave a majority of it the natural BluCor color.
It will be a winter project... so for now I'm just collecting ideas.Here are a few things I thought about doing:
The heron cruises with it's neck coiled up into and "S"... so the shoulders are prominent- often higher than the head. The prop "could" be mounted on the shoulders, behind the head. Otherwise I'd put the prop at the tip of it's long beak with a small 1" yellow spinner and folding prop so it blends in when gliding.
The heron's keel-bone is also prominent in flight - so I can embed a single wheel in the center of the keel for grass landings - much like a full-scale glider.
Gullwing, top-KF airfoil, with the step defined by the boundary between primary and secondary feathers. I might do spoilerons on top of the KF step instead of regular ailerons.
The heron has really long legs that trail the tail feathers. Rather than a V-tail like the EPP Eagle, I think I'll stick with conventional elevator on the tailfeathers, and make the feet bend left-right at the ankles as rudders.
Here are a few "inspiration" pictures:
ImagesView all Images in thread
Cool birds.
I have one that hangs out on my dock.
They like to fly in ground effect just above the water and head to roost at sundown.
The only noise I have heard them make is a loud GAAACK.
We call them BAB's.
Big (donkey) Birds
We call em' S**T pumpers up here. Ya' know ya' get close to em', they take off and then they pump it out........hehehe.
haha that's a good idea, maybe you can make "dull white liquid" coming out of it's tail when some one gets close to it
Warhead, why don't you make your bird a flying wing with elevons and then you don't have to worry about elevators or rudders. You got tons of wing area and the KFm1 lends itself well to flying wings. Then you can steer it the same way as the real bird!
Put a small drag wedge on the feet (as part of the foot) and you won't need any fins.
Just a thought...
That's a cool idea warhead !
A similar thing has been done by Martin Mueller from Germany he built a flying dragon, have a look at the video here: http://www.rc-fliegerfilme.de/flash/wallhalla2.htm
It has quite a unique concept of propulsion and control that makes it even more "scale"
The dragon is very cool... (as is the "fish" at the end of that clip - definitely an indoor flier). I hadn't thought of making it a thrust vectoring model.. but I'm sure it could be done. I'd probably opt for more traditional controls simply because I am more familiar with the controls that way.
The more I look at the dragon clip and think about thrust vectoring, and looking at the shape of the Heron, I think I could also do a Pterodactyl the same way... now that would be a head-turner, circling over the schoolyard. I think that has been done before though... so maybe I should do a search.
Found one:
i guess i would at least make the rudder a head turner, the heron head has a lot more side area with the long beak than the legs, it would look more "scale" too The rest doing it with elevons and a S-twist wing for scale reasons sounds pretty good
Great idea. That third pic makes it look like an organic Klingon Bird of Prey
We have them here too. Wiped out a buddy's Koi pond in a weekend.... $1000 worth of Koi He now has a nylon mesh just above the surface so they cant get the fish.
Should be a very cool flyer.
Joined Nov 2005
580 Posts
While not exactly what you are looking for, I think this adaption of a Blue Funder is pretty cool (I stumbled on this looking for something else). Might provide some inspiration.
Here's what I was wanting to try for the airfoil. It's a top KF airfoil with the ailerons on the TE of the top step instead of the TE of the full chord: a.k.a. - "spoilerons".
The beauty of spoilerons is that they don't create adverse yaw, which would be a big problem with such a wide wingspan/chord ratio. The obvious advantage is that you don't need rudder input to coordinate smooth turns. In fact, spoilerons create yaw in the correct direction, by only inducing drag on the wing with the raised control surface - slowing the wing in the direction of the turn. Building it into the KF top step keeps it clean and neat... from the ground you won't see servos or control surfaces.
I'll still have to create upswept wingtips with some added washout to reduce tip-stalling at low speed.
|Thread Tools


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Aerin's Song 'O The Day: "Fuge E Moll" by the Eccentric Opera
Are you seriously kidding me right now.
Now I've heard it all. Axe has come up with a chocolate scented cologne for men. What a way to attract the ladies. All I can say is that if any man I went out with smelled like chocolate WASN'T a pastry chef, I'd wonder about him. REALLY wonder. Obviously new product creation isn't a mark of genius anymore.
Seriously, cologne-slash-perfume should be subtle, with lots of notes. The complexity is why I spend so damn much on the stuff.
It's all rigged.
So I was talking about America's Best Dance Crew at work, and my co-worker summed it up best: "That's the only show that proves that Asians can dance better than you." My other co-worker, who's a dance major, said: "Asians and tiny Latinas are the best street dancers." I LOL'd, especially considering the past two seasons. I liked the Box Cuttahz, and the Beat Freaks, but my money's on Quest Crew. They're Asian, they're B-boys, AND they're from Southern Cali, and that's what's won the past two seasons. Oddly, this is why I stopped watching Project Runway-- because more often than not the most obnoxious flaming guy would win. Because in reality TV shows, it's all about perpetuating stereotypes. Discuss in the comments, please.
MY third place
The Third Place is a socio-economic term suggesting the place where you spend your time that is not home (your first place) or work (your second place). There are layers to this, there's a whole book about it, and my place of work has exploited it as part of its propaganda sweep, but one can easily argue that my third place is Disneyland. I'll go there on Wednesday, and I'm thinking, making a food blog about it. Hm. Depends on how much I want to overeat.
In any case this is what I've been doing with my time (besides getting my alt to Fighmaster in PSU)-- taking peektures of the random dolls hiding in my closet. I need a new camera, the one I have is getting old, and can't take any non-daylight peektures, but I think I captured the light pretty well.
I admit there's a certain enjoyment to being a crazy, mindless tank, beating everything up in MMORPG(lite)s. When I was a Red Mage in FFXI I had to think every moment I was in a party, calculate the best time to cast certain things, and above all don't get anybody killed (because more often than not I was the only healer in the party). My main is (currently) the equivalent of a white mage, so the focus is less on killing everything. But while everyone I know has 4 or 5 alternate characters I've just been focused on getting my main... perfect. I don't know how successful I am. But over the course of that I've been on the receiving end of some uber drops, packing away things that I was clueless about. Took stock of the inventory the other day and I've discovered that my puny level 71 tank is now... pretty uber. (15 star armor? I was like, when did I find THAT???) Who knew. There's an event on PSU now, one where it's easier to run through and get XP for your class. I've been getting her to one of those master classes pretty quickly, and it's real nice after a long day at work, to sit in front of the TV with a bottle of Newcastle and... kill everything. Mindlessly.
Oh. Did I say that already?


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Museum of Wisconsin Art opens new building
After researching and refining the history of Wisconsin art for decades, the Museum of Wisconsin Art will be able to tell more of its story starting this weekend. It will reopen in a dramatic new building nestled on the Milwaukee River at 205 Veterans Ave., West Bend - a gleaming, white wedge with twice the space for art inside.
The museum also is altering its narrative, opening up what it means to focus on "Wisconsin art" and creating a greater focus on contemporary art. »Read Full Article
St. Paul & the Broken Bones brings soul and star power to sold-out Shank Hall
Paul Janeway would have made one hell of a preacher man.
We'll just have to settle for one hell of a soul star. »Read Full Article
Advice columnist Mrs. Griggs subject of new biography
Her Milwaukee Journal column started as advice for the lovelorn, but Ione Quinby Griggs and her legion of letter writers soon ventured into other topics and dilemmas of 20th century life in the Midwest, especially among women.
A new book, "Dear Mrs. Griggs: Women Readers Pour Out Their Hearts from the Heartland," traces Griggs' career from brash "girl reporter" in Chicago, through personal tragedy, and then an astounding 51 years of answering readers' personal questions on the back page of the Journal's Green Sheet. »Read Full Article(10)
'Jesus Christ Superstar' tour, Milwaukee show canceled
A U.S. arena tour of "Jesus Christ Superstar" — headlined by music stars such as former Destiny's Child Michelle Williams as Mary Magdalene and ex-Sex Pistol John "Johnny Rotten" Lydon as King Herod — has been scrapped. That includes the Aug. 1 show scheduled for the BMO Harris Bradley Center.
The tour of the famed Andrew Lloyd Webber-Tim Rice musical — which also featured Incubus frontman Brandon Boyd as Judas and 'N Sync alum JC Chasez as Pontius Pilate — was set to hit 54 cities, beginning in New Orleans June 9. A statement was posted on the show's website Friday; no explanation was given. »Read Full Article(7)
Another Refuge Smoothie Cafe will open, in Wild Flour Bakery in Bay View
Refuge Smoothie Cafe, which has locations downtown and on the east side, will open its third cafe June 7, in the Wild Flour Bakery at 422 E. Lincoln Ave. in Bay View.
From 9 a.m. to 7 p.m. June 7, customers will be able to sample smoothies and baked goods at the Lincoln Ave. store. »Read Full Blog Post


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Big game will snare me New Zealand Test spot, says Alex Glenn
- From: mX
- April 12, 2013
BRISBANE'S Kiwi Test backrower Alex Glenn admits he needs one more blockbuster showing tonight to lock in a spot for next week's trans-Tasman Test.
The 24-year-old appears a near certain selection for New Zealand in the Canberra showdown next Friday after another consistent start to the season in the Broncos pack.
Writing in his column in today's mX, Glenn says tonight's Suncorp Stadium derby with the Cowboys offers a golden chance to impress Kiwi coach and Brisbane assistant Stephen Kearney.
Match centre: Broncos v Cowboys
"Personally I'm not getting ahead of myself in terms of Test selection," he wrote.
"I've been happy with my form but I know I need another strong showing tonight.
"Having Stephen Kearney as assistant at the Broncs may seem like a benefit to Test goals, but he gives little away."
Glenn admitted he has extra motivation for a call-up after previous running battles with Broncos teammate and Aussie certainty Justin Hodges.
"I'd absolutely love to be there, if for no other reason than to have another friendly crack at Hodgo," he wrote.
"He still claims when we faced off last year he sent me rocking with a hit, although I recall that I powered past him.
"I've already warned him to watch out for my left shoulder if we're both lucky enough to win a Test start."


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These Are Our Most Popular Smartphone Activities
Almost 8 in 10 Americans who own cell phones own a smartphone, per recent data from comScore, and smartphones' rapid growth in recent years has led to the devices now accounting for half of all time spent online. So what are the most popular activities on smartphones? A recent report from Forrester Research offers some […]Read more »


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4 posts tagged with citizenship and america.
Displaying 1 through 4 of 4. Subscribe:
Questions about an American couple moving to Canada.
American here, with spouse. Thinking of moving to Canada within 5 years, but retaining US citizenship (both of us). One of us has quite marketable skills, the other is on disability. Will one of us being on disability hurt our chances?? Where do we start looking to learn about this process? How long does it usually take? What can we do to increase our chances of making this change? Anonymous so that work and a few other people don't find out before we let them know.
dual citizenship, should I?
Eligible for a dual citizenship, should I? [more inside]
Move this Aussie from down under to up yonder.
Immigration Law! Help me get my bagged Aussie into the U.S. and A. [more inside]
What happens (legally) when an American and a Japanese person marry?
International Marriage filter: When a US Citizen marries a foreigner, what process is involved in bringing the new spouse to the US and getting permanent resident status? [more inside]
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Office of Development & Alumni Relations Hosts 32nd Annual John Sherman Myers Society Celebration
Dean Nelson Named to New Governing Council for ABA Center for Innovation
Fall Class to Be First to Start 1L Year at New Tenley Campus – View Updated Campus Photos
Students Begin Orientation Week with "In My Back Yard" Day of Service
Two AUWCL Alumnae Selected as Immigrant Justice Corps Fellows
AUWCL's Stephen S. Weinstein Trial Advocacy Program hosted an Advanced Advocacy Training Program from Sept.19-23 for twenty-four U.S. Marine Corps Judge Advocates. Military attorneys traveled from all over the world to attend the week long training that focused on trial skills in the context of sexual assault cases in the military justice system. MORE
Professors Andy Popper and Robert Vaughn are among the many high profile speakers to present this week at the four-day "Breaking through Power" conference held in Washington, D.C. The Conference is a celebration of the civil justice system featuring speakers such as Ralph Nader and Rep. John Conyers. Professor Vaughn is addressing whistleblowing and Professor Popper is talking about tort law. See the full schedule.
The Center for Human Rights & Humanitarian Law is pleased welcome the 2016-17 Herman Schwartz Israel Human Rights Law Fellows. The Herman Schwartz Israel Human Rights Law Fellowship was founded by Professor Herman Schwartz in 1984 as a joint initiative between AUWCL and the New Israel Fund. This year's fellows are Yasmin Mansour and Shimri Segal. MORE
Experiential Learning


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Acme contract talks continue; decision was expected late FridayBy ERIK ORTIZ Staff Writer | Posted: Friday, November 20, 2009 | 0 commentsContract talks were set to end late Friday between Acme supermarkets and the union representing cashiers and clerks at more than a dozen locations in southern New Jersey, including Cumberland County.But it was unclear before The Press' deadline whether a contract agreement had been reached, or if members of the United Food and Commercial Workers Local 1360 would walk off the job as soon as today. Members voted overwhelmingly Nov. 10 to strike should talks break down this week.The supermarket chain and the union have been unable to agree on a new contract since April, when the current five-year one expired. The two sides resumed talks Thursday.But as of Friday afternoon, there were no further negotiation dates on deck, Acme spokeswoman Gail Street said.Local 1360, based in Berlin Township, Camden County, has about 2,400 members working as cashiers and clerks at Acmes in Cumberland, Burlington, Salem, Camden, Gloucester and Mercer counties. Also included in the negotiations are workers from lower Bucks County, Pa.In Cumberland County, the union represents the cashiers and clerks at the Acme in Bridgeton, Local 1360 President Sam Ferraino said.He was unavailable for further comment Friday but has said the union wants secure health care benefits and salaries. He would like members to be able to join a new health care plan that he believes will save Acme money, but the supermarket will not agree to it, he said.Minneapolis-based Supervalu Inc., Acme's parent company, has said it wants to work out "a mutually beneficial contract without a labor dispute" and that "nobody wins in a strike."Acme resolved contract talks this year with other unions, including UFCW Local 152 in Hammonton, which represents meat cutters, produce workers and other back-end employees at Acmes throughout southern New Jersey.In September, Local 152 members ratified a new four-year contract that included wage increases, an increase in pension contributions by Acme totaling 36 percent over four years and a protection of workers' health benefits.But the union must sit down with Acme early next year, when its five-year contract for cashiers and clerks expires. That would involve workers at 17 stores, including locations in Atlantic, Cape May and Cumberland counties, Local 152 officials said.Depending on what happens with Acme and Local 1360, however, the start of those negotiations next year could be delayed.http://www.pressofatlanticcity.com/news/breaking/article_ed868e68-d651-11de-a452-001cc4c03286.html
Contracts Talk Continue Between Acme and the Union Contract talks between Acme and the union representing clerks at 28 area supermarkets continued on Saturday. The 2,500 members of U-F-C-W Local 1360 had threatened to go on strike before Thanksgiving without a contract agreement -- but as the talks continue, there appear to be no immediate plans for a walkout.The local represents clerks at Acme markets in South Jersey and Lower Bucks County. http://www.kyw1060.com/Contracts-Talk-Continue-Between-Acme-and-the-Union/5728357


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The top two schools that receive the most votes in each category will receive $150K grants of security products and services from STANLEY Security. Western is in category two (8,000-19,999 students). The first place school will receive a $150,000 safety grant, with the second place school receiving a $50,000 grant. More info. available at http://bit.ly/1yzgkfb
Established in 1899, Western Illinois Normal and Training School opened its doors Sept. 23, 1902 to 229 students. Throughout the years, Western Illinois grew and its name changed from Western Illinois State College to Western Illinois University on July 5, 1957.
Today, Western Illinois University offers a variety of bachelor's and master's degree programs, pre-professional programs, a doctorate degree in education, and certificate programs to more than 12,200 students.
Some of the larger goals behind Western Illinois University's mission, and what you'll experience as a student, are available at www.wiu.edu/core_values/
Recognition & Awards
Best Midwestern College — Princeton Review
Top tier "Best Regional University" — U.S. News & World Report
One of three Illinois public universities that best support students from disadvantaged socioeconomic backgrounds — College Access &Opportunity Guide
"Best Practice": 1 of 13 institutions named nationally for the retention of first-generation and low-income students — The Pell Institute for the Study of Opportunity
"Military Friendly School" — GI Jobs Magazine
"Best Practice" model institution among 15 colleges and universities in the U.S. for retention and graduation rates — Southern Regional Educational Board


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------Sue (Toowoomba Qld)
Love to sew....
------Brother Innovis 1250D
Babylock Enlighten
Singer Curvy 8763
Brother 1034D
Janome 385.19606
Brother 2340CV
------ http://beccabeckstuff.blogspot.com/
Damn the muslin, full speed ahead!
Stash can be very good. After promising to make a red Lil Orphan Annie dress for a friend's child, I got the urge late on a Friday evening a week agao. The whole thing was stash! I got the dress started that evening and finished it the next afternoon. No fussing around... Yes, stash can be a very good thing.
------"We don't see things as they are, we see them as we are." Anais Nin
"Attitude is the difference between an adventure and an ordeal." unknown
------I have no idea what Apple thought I was saying so be a Peach and credit anything bizarre to auto correct.
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London – January 14 , 2014 – Global Supply Chain Commerce Solutions provider, Manhattan Associates (NASDAQ: MANH), has released its predictions for the retail industry in 2014.
As the next generation of shopper becomes ever more demanding, going into 2014, retailers must place the customer experience at the forefront of their retail strategy. And, whilst striving for a high quality experience, they mustn't lose sight of profitability.
"We're still seeing some high profile casualties on the high street, including most recently Blockbuster and Barratts. Retailers are in an all-out battle for sales but this should not blind them from ensuring that they are offering their customers the highest level of customer service, whilst ensuring they do so profitably," said Craig Sears-Black, UK managing director at Manhattan Associates. "To survive and thrive in 2014, retailers need to make their existing assets work harder whilst continually innovating on their service offering. Those that don't will lose out through poor loyalty and lower sales," he continued
Manhattan Associates has identified seven trends that are likely to influence the UK retail scene in 2014:
1. Personal and Profitable
One of the first steps retailers can take and one Manhattan Associates expects to see more of in 2014, is gaining enterprise-wide visibility of inventory and customer transactions via the deployment of centralised order management systems. Embracing such technology will allow retailers to know exactly where their inventory is, to whom they can make it available and when it will get there, regardless of which channel is calling for it. This in turn will allow retailers to offer the best level of service to their customers.
2. Faster and More Flexible Fulfilment
Customers want their purchases – and they want them now. Too few retailers are currently offering customers next day delivery, two-hour click-and-collect or ship-from-store services. Recent research found that only 13 per cent of UK retailers offer their customers next day delivery, and only 11 per cent currently ship from store[1].
And what can retailers do when next day delivery and click-and-collect are no longer fast enough for their customers? Ebay's acquisition of Shutl comes as it looks to offer UK customers one-hour delivery – and the fulfilment battle won't stop there. Shutl's current delivery record is 14 minutes and 58 seconds – indicating that it believes shoppers will demand this level of speed in the near future.
For this to be possible, retailers need to have a 360-view of their channels, know exactly where their stock is and be able to see where the demand is coming from. This will allow them to manage inventory as a single, centralised pool and get stock to where it is needed quickly and efficiently. It will also mean they can offer a seamless shopping experience and increase the likelihood of them earning customers' loyalty. At present, 37 per cent of UK retailers still treat their individual retail channels separately[2], often making it time-consuming and costly to locate inventory and fulfil orders. Omni-channel retailers with this 360-degree insight into their inventory and customers will seamlessly be able to view product availability across channels, and dispatch and fulfil orders both quickly and profitably. Shoppers do not want to wait whilst calls are made to neighbouring stores in a bid to source the item. This approach loses sales and customers in today's fast-paced retail world.
3. Greater Supply Chain Control
The global horse meat scandal in early 2013 highlighted one of the biggest issues within the food industry - sourcing and traceability. In February 2013, a number of UK retailers were found to be selling products that included unexplained horse DNA.
As a result of globalisation, products are now crossing more international boundaries than ever before as retailers seek to cut costs even further. This means supply chains are getting longer and more difficult to manage. To avoid a repetition of the horse meat scandal, retailers need to have accurate and actionable data across the entire supply chain. This is in addition to ensuring that sufficient testing has been done of products before they are shipped, especially in the food industry. Following the intensity of this year's scandal and the resulting fall-out, this is something retailers will be taking a lot more seriously going forward.
4. Social Shopping
Social media has been having an impact on the retail sector for some time. A key example is the 'Kate effect'. When the Duchess of Cambridge wears an outfit, it is posted over social media networks and instantly sells out online. Retailers who effectively monitor their online channels can give themselves a big head start and maximise their sales.
But the next development of this is likely to be retailers using social channels to take customer orders. Few larger retailers have capitalised on the opportunity of selling directly to their social channel audiences. Engagement has so far been driven by photos or discount vouchers rather than direct orders – something we are likely to see change this year as retailers become keener than ever to differentiate themselves from competitors. Those retailers that will succeed in this difficult market are those that see social media as another retail channel.
5. Incentives and Rewards to Shape Fulfilment
Continuing on the theme of profitable selling, incentives and rewards will continue to be deployed by retailers to boost sales in 2014. Omni-channel retailers will also be using incentives and rewards to influence how consumers take delivery of their goods.
Consumers who are charged for home delivery of their purchases are now considering collecting the purchased item(s) from a nearby collection point or store. Thereby both saving money, and most probably, receiving the goods in a shorter timeframe. This helps the consumer by offering a greater choice of fulfilment options, but also makes the fulfilment of that specific order more profitable for the retailer.
6. Hyper Targeting to Change Buyer Behaviour
Data analytics in the retail sector is now so advanced that customer transactions, online conversations and shopping habits can now all be absorbed by retailers in real-time, so brands can understand better how to service their customers.
Shoppers crave a personal service, and the digital world makes it much easier for retailers to track shoppers' buying patterns and preferences. Frequency of online visits, transactional spend amount, time period spent in store and preferred delivery method can all be tracked. Retailers need to use this information to their advantage to provide customers with a personalised service and to be able to reward them for their loyalty.
7. New Consumer Technologies Go Mainstream
Google Glass is likely to launch in early 2014 and its impact on the retail sector could be huge, particularly when it comes to mobile shopping. This new technology has the opportunity to improve the customer experience throughout the shopper's journey – whether it be information on product availability, special offers or offering alternative or supplementary products.
So what impact is it likely to have? A recent survey by Venda found that 28 per cent of customers would use wearable technology like Google Glass to access in-store promotions. In addition to that, the research found that 45 per cent of 18-24 year olds would use the technology to search for available stock and products to purchase while in-store.
To facilitate this, retailers' supply chains must be able to comprehend a seamless flow of data in real-time. The opportunities for retailers of implementing Google Glass are huge – however, they must have the back-office systems in place to fully capitalise on the opportunity. With more data from customers flowing through their channels than ever before, retailers' supply chains need to be at the height of fitness and flexibility to maximise these opportunities.
Receive up-to-date product, customer and partner news directly from Manhattan Associates on Twitter and Facebook.
About Manhattan Associates
Manhattan Associates, Inc. brings companies closer to their customers. We design, build and deliver market-leading Supply Chain Commerce Solutions that drive top-line growth by converging front-end sales with back-end supply chain execution and efficiency. Our software, platform technology and unmatched experience help our customers around the world adapt to the challenges of the omni-channel marketplace. For more information, please visit www.manh.co.uk.
[1] Manhattan Associates research conducted at Manhattan Associates UK Exchange event, October 2013
[2] Manhattan Associates research conducted at Retail Week Ecommerce Summit, October 2013


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ATLANTA -- Back-to-school basics will be the focus of buying for 1998, said nonfood grocery buyers planning to hit the School & Home Office Products Association's annual trade show here this week, Nov. 19 to 22. Although executives said they are open to new items and emerging categories, most buying will be based on the performance of the past season, which many said was generally good. Some buyers said they will proceed cautiously with licensed-themed goods, however. These often prove ...
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text: Israeli commandos killed two Palestinians who allegedly were planting a bomb. The commandos also shot and killed three other Palestinians who later approached the bodies. The incident occurred when the commandos spotted three Palestinians who they said were trying to plant a bomb in the area of Shavei Shomron, an Israeli settlement near the West Bank city of Nablus.


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Protect your eyes on sun-filled days with these uniquely personalized red sunglasses!
Our Red Personalized Sunglasses are fantastic favors for each of your party guests because you choose the text and imprint color! Each pair of Red Personalized Sunglasses is made of plastic measuring 1 3/4 inches high x 6 inches wide. Your guests will love wearing these red shades that are customized to match their special event.
Please allow ample time for delivery. Our ship date for this product is noted in your shopping cart. Many items are shipped separately, so please allow extra time for these items to arrive. Shipping charges are based on the value of the merchandise and not the number of shipments. For additional shipping information, please contact our Customer Service Department at (email@example.com or 1-800-314-8794).


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Latest News
Latest news
New SOLON Remix of VAANI track "The Jewel"
The future sound of yoga mix III - out now
New track for Savansana - just released
Matt (aka SOLON) has just released a remix of a track by Jo Mall-Kahn (aka VAANI), who tragically passed away last year from cancer. All proceeds from the track go to the charity (A Sound Life) which she set up with her husband, Edo Kahn.
To find out more go here.
The Future Sound of Yoga Mix III is the third Yoga Mix created by SOLON: a gentle intensity of cutting edge electronica seamlessly mixed to fit the flow of a 60 min yoga practice.
"Phlebas" is the third electronic meditation track to be released by Matt Singmin (aka SOLON). Designed specifically to induce a state of yoga nidra (yogic sleep), the ambient composition is inspired by a sequence in T.S.Eliot's poem the Wasteland.


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The Grandma Hypothesis: Couldn't have done it without her!
In honor of Grandparents' Day, that we celebrated this past Sunday, September 13, here are some fond memories.
Those of us fortunate enough to grow up with grandparents understand how important they were (and are) in our lives. I grew up knowing my mother's parents and maternal great-grandmother; my paternal grandparents had died when I was quite young, although I do remember some holiday celebrations
My great-grandmother took care of my mother when she was little, so her parents (my grandparents) could work without worry. Today, this model is still common in many cultures around the world. Both parents are often working and grandmothers (and grandfathers) are helping to raise their grandchildren.
I remember my grandmother's visits very well, and saw my great-grandmother, quite elderly by that time, during the summer vacations. Grandma would arrive for visits laden with boxes and jars of wonderful delicacies that our mother didn't have time to prepare. When we were little, she kept us busy and happy with painting, making pasta necklaces and pasta artwork, trying to teach us how to sew dresses for our dolls. Her legendary attempts to teach me to crochet, unfortunately, fell on hands that just didn't catch on. Continue reading "The Grandma Hypothesis: Couldn't have done it without her!" »
Genealogy: What's your motivation?
In this Huffington Post article, the author describes her motivations for conducting family history research.
Both her father and grandfather keep quiet when it comes to discussing their family history and even try to lure her away from digging up the past through short references to "dark secrets and family feuds."
But like most people with curious minds and a sense of investigation, preventing her from making inquiries only makes her even more interested.
What are my motivations for investigating my own family?
For me, it's a strong desire to know who my ancestors were and where I come from, to understand my ancestors and how they lived, to use that information and apply it to the present.
What about you?
What are your motivations for researching your unique family history? Are you trying to unlock anything in particular?
Share your stories in the comments below.


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A lot has been written about the health care public option over the past few days. While some commentaries discuss the honest concerns many Americans have, others claim the would-be government-run plan is dead in the water.
The public option is going nowhere, nor will it cut costs, they argue.
For example, Washington Post columnist Steven Pearlstein writes, 'There is nothing about having a government-owned health insurance company that is likely to change the competitive dynamic and bring costs under control.'
Quite pessimistically, he adds, 'If there is anything that's been made clear over the last two weeks, it is that the public option is a political non-starter that threatens the entire reform effort.'
What does Pearlstein mean? What evidence does he use to back up his claims?
First, according to our esteemed columnist, costs won't come down because hospital chains 'dictate rates to private insurers' and 'drug companies have monopoly pricing power ... Ditto for medical-equipment makers.' Additionally, 'there's no particular evidence that a government-run insurance plan will be any more successful than what we currently get from big private insurers.'
Second, Pearlstein argues that 'liberals have played right into the hands of Republicans who aim to defeat any reform by mischaracterizing it as a government takeover.'
According to this theory, since Republicans will inevitably mischaracterize the public option, liberals, progressives and average Americans shouldn't fight for it — or else we play into their hands and threaten other, more realistic reforms.
So just to be clear, here is what Pearlstein's logic boils down to: The health care reform movement should give up on the public option because hospitals dictate rates and drug companies price fix. Additionally, we should give up on the public option because Republicans will lie about it.
Wow, that is quite the logical summersault! I wonder if Pearlstein actually read what he wrote. Because it sure as hell didn't make any sense to me!
To the average American, I'm sure it sounds like a lot of baloney. To them, it sounds like the insurance companies, the drug companies, and the hospitals all have too much power. And as for the Republicans, average Americans are tired of their outright lies. In addition, the professional town-hall disrupters from the fringe, with all their yelling, heckling and assaulting, only illustrate the right wing's desperation.
In fact, the only thing the past two weeks has proven is the desperate depths to which the Republicans and their health care industry lobbyists will go.
If anything, to honest, sincere people — to the majority of Americans — the health care public option is a complex — maybe even scary — plan that they are unsure about. But, that's OK. After eight years of government mismanagement a little skepticism is only natural.
However, most Americans want to have a sincere, open, honest discussion, free from lies and mischaracterizations. If open, honest discussions take place, most Americans will continue to support a health care public option — as they currently do.
Far from threatening the entire reform movement, the public option emboldens the reform movement. It provides cohesion and a unified voice. It provides a benchmark. As Gov. Howard Dean recently remarked: 'You can't have reform without a public option.' In addition, it would give the Obama administration another victory, reinforcing its progressive trajectory, while giving millions of Americans access to health care.
tonypec @ cpusa.org


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Most Cited Journal of Dermatological Science Articles
The most cited articles published since 2011, extracted from Scopus.
The circulating microRNA-221 level in patients with malignant melanoma as a new tumor markerHisashi Kanemaru | Satoshi Fukushima | Junji Yamashita | Noritoshi Honda | Rie Oyama | Asako Kakimoto | Shinichi Masuguchi | Tsuyoshi Ishihara | Yuji Inoue | Masatoshi Jinnin | Hironobu Ihn
Volume 61, Issue 3, March 2011, Pages 187-193
Background: MicroRNA-221 (miR-221) is known to be abnormally expressed in malignant melanoma (MM) cells, and it favors the induction of the malignant phenotype through down-modulation of p27Kip1/CDKN1B and the c-KIT receptor. This suggests that the serum level of miR-221 might increase in patients with MM and thus could be used as a new tumor marker. Objective: To evaluate the possibility that the serum miR-221 level can be a marker of MM. Methods: Serum samples were obtained from 94 MM patients and 20 healthy controls. MicroRNAs were purified from serum, and miR-221 levels were measured by quantitative real-time polymerase chain reaction. Results: Circulating miR-221 was detectable and could be quantified in serum samples. MM patients had significantly higher miR-221 levels than healthy controls. Among the MM patients, the miR-221 levels were significantly increased in patients with stage I-IV MM compared to those with MM in situ, and the levels were correlated with tumor thickness. Moreover, a longitudinal study revealed a tendency for the miR-221 levels to decrease after surgical removal of the primary tumor, and to increase again at recurrence. Conclusions: Serum levels of miR-221 were significantly increased in MM patients and may be useful not only for the diagnosis of MM, but also for the differentiating MM in situ from stage I-IV MM, and for evaluating tumor progression and monitoring patients during the follow-up period. In addition, considering that the serum levels of miR-221 were correlated with tumor thickness, miR-221 might also be useful as a prognostic marker for patients with MM. © 2011 Japanese Society for Investigative Dermatology.
New concept of the pathogenesis of atopic dermatitis: Interplay among the barrier, allergy, and pruritus as a trinityKenji Kabashima
Volume 70, Issue 1, April 2013, Pages 3-11
Atopic dermatitis (AD) is a common skin condition, characterized by a complex, heterogeneous pathogenesis, including skin barrier dysfunctions, allergy/immunology, and pruritus. When the skin barrier is disrupted by, for example, the filaggrin gene mutation and/or environmental factors, the skin is predisposed to being penetrated by external stimuli. Foreign antigens can be subdivided into two subsets by size: haptens (including metals) and protein antigens. It is known that a single hapten challenge provokes Th1 initially, but that repeated elicitation with haptens results in a shift toward Th2-dominated responses. On the other hand, exposure to protein antigens directly induces Th2-dominant conditions via the thymic stromal lymphopoietin (TSLP) receptor on Langerhans cells. Recently, it has been revealed that Th2 cells produce IL-31, which provokes pruritus, and that Th2 cytokines decrease filaggrin expressions by keratinocytes. These findings suggest that Th2 conditions lead to pruritus and barrier dysfunctions. In this review, we will examine the highly complex interplay among skin barrier abnormality, allergy/immunology, and pruritus as a trinity in the development of AD. © 2013 Japanese Society for Investigative Dermatology.
Epidemiology and comorbidities of psoriasis patients in a national database in TaiwanTsen Fang Tsai | Ting Shun Wang | Sheng Tzu Hung | Phiona I Ching Tsai | Brad Schenkel | Mingliang Zhang | Chao Hsiun Tang
Volume 63, Issue 1, July 2011, Pages 40-46
Background: Recent findings in psoriasis research have shown that psoriasis is frequently associated with systemic comorbidities. Objectives: This study aims to describe the epidemiology of psoriasis and the prevalence of comorbidities in patients with psoriasis in Taiwan. Methods: Patients who had at least one outpatient visit or admission with ICD-9-CM diagnosis code 696.0-1 in the Taiwan National Health Insurance (NHI) claims database during 2006 were identified as psoriasis cases. The cases were further classified into moderate to severe psoriasis (sPsO) for those who had previously received systemic therapy during the study period and mild psoriasis (mPsO) for those who had not. The cases were matched in a 1:4 ratio with controls from a sample cohort of 997,771 enrolees representative of the Taiwan population. Matching variables included age, gender and residential area. Prevalence of comorbidities was assessed using prevalence relative risk (RR) based upon a Cox proportional regression model. Results: 51,800 psoriasis cases were identified (prevalence = 0.235%; mean age = 46.4 ± 18.6; male:female = 1.6:1) and 17.5% of cases were sPsO type. Psoriasis was associated with a significantly increased prevalence ratio (RR; [95% confidence interval]) for hypertension (1.51; [1.47, 1.56]), diabetes (1.64; [1.58, 1.70]), hyperglyceridaemia (1.61; [1.54, 1.68]), heart disease (1.32; [1.26, 1.37]), hepatitis B viral infection (1.73; [1.47, 2.04]), hepatitis C viral infection (2.02; [1.67, 2.44]), rheumatoid arthritis (3.02; [2.68, 3.41]), systemic lupus erythematosus (6.16; [4.70, 8.09]), vitiligo (5.94; [3.79, 9.31]), pemphigoid (14.75; [5.00, 43.50]), pemphigus (41.81; [12.41, 140.90]), alopecia areata (4.71; [2.98, 7.45]), lip, oral cavity and pharynx cancer (1.49; [1.22, 1.80]), digestive organs and peritoneum cancer (1.57; [1.41, 1.74]), depression (1.50; [1.39, 1.61]), fatty liver (2.27; [1.90, 2.71]), chronic airways obstruction (1.47; [1.34, 1.61]), sleep disorder (3.89; [2.26, 6.71]), asthma (1.29; [1.18, 1.40]), and allergic rhinitis (1.25; [1.18, 1.33]). Conversely, psoriasis was not associated with an increased risk of Crohn's disease. Conclusions: Psoriasis was associated with a significantly increased risk of comorbidities, especially for those patients with moderate to severe disease. These health associations should be taken into consideration when evaluating the burdens of psoriasis and designing effective treatment plans. © 2011 Japanese Society for Investigative Dermatology.
Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: A phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL)Tsen Fang Tsai | Ji Chen Ho | Michael Song | Philippe Szapary | Cynthia Guzzo | Yuang Kuang Shen | Shu Li | Kwang Joong Kim | Tae Yoon Kim | Jee Ho Choi | Jai Il Youn
Volume 63, Issue 3, September 2011, Pages 154-163
Background: Ustekinumab has been evaluated in Caucasian patients with psoriasis, but no studies have been conducted in Asian patients. Objective: To assess the efficacy and safety of ustekinumab in Taiwanese and Korean patients with moderate-to-severe psoriasis. Methods: In this 36-week, multicenter, double-blind, placebo-controlled study, 121 patients with moderate-to-severe psoriasis were randomized (1:1) to receive subcutaneous injections of ustekinumab 45. mg at weeks 0, 4, 16 or placebo at weeks 0, 4 and ustekinumab 45. mg at weeks 12, 16. Efficacy endpoints at week 12 included the proportion of patients achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75; primary endpoint), proportion of patients with Physician's Global Assessment (PGA) of cleared or minimal, and change from baseline in Dermatology Life Quality Index (DLQI). Results: At week 12, the proportion of patients achieving PASI 75 was 67.2% and 5.0% in the ustekinumab 45. mg and placebo groups, respectively (p< 0.001). PGA of cleared or minimal was achieved by 70.5% (ustekinumab) and 8.3% (placebo; p< 0.001), and median DLQI changes were -11.0 and 0.0, respectively (p< 0.001). Efficacy was maintained through week 28 in ustekinumab-treated patients. Adverse event (AE) profiles at week 12 were similar between the ustekinumab and placebo groups: 65.6% and 70.0%, respectively, had at least one reported AE. Through week 36, no disproportionate increase in AEs was observed, with the exception of abnormal hepatic function, which was related to concomitant isoniazid treatment for latent tuberculosis. Injection-site reactions were rare and mild. No deaths, malignancies, or cardiovascular events were reported. Conclusions: Treatment with subcutaneous ustekinumab 45. mg offers a favorable benefit/risk profile for Taiwanese and Korean patients with moderate-to-severe psoriasis. The efficacy and safety profile is consistent with the global phase III studies of ustekinumab in psoriasis. © 2011 Japanese Society for Investigative Dermatology.
Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healingNicholas S. Greaves | Kevin J. Ashcroft | Mohamed Baguneid | Ardeshir Bayat
Volume 72, Issue 3, December 2013, Pages 206-217
Cutaneous wound healing ultimately functions to facilitate barrier restoration following injury-induced loss of skin integrity. It is an evolutionarily conserved, multi-cellular, multi-molecular process involving co-ordinated inter-play between complex signalling networks. Cellular proliferation is recognised as the third stage of this sequence. Within this phase, fibroplasia and angiogenesis are co-dependent processes which must be successfully completed in order to form an evolving extracellular matrix and granulation tissue. The resultant structures guide cellular infiltration, differentiation and secretory profile within the wound environment and consequently have major influence on the success or failure of wound healing. This review integrates in vitro, animal and human in vivo studies, to provide up to date descriptions of molecular and cellular interactions involved in fibroplasia and angiogenesis. Significant molecular networks include adhesion molecules, proteinases, cytokines and chemokines as well as a plethora of growth factors. These signals are produced by, and affect behaviour of, cells including fibroblasts, fibrocytes, keratinocytes, endothelial cells and inflammatory cells resulting in significant cellular phenotypic and functional plasticity, as well as controlling composition and remodelling of structural proteins including collagen and fibronectin. The interdependent relationship between angiogenesis and fibroplasia relies on dynamic reciprocity between cellular components, matrix proteins and bioactive molecules. Unbalanced regulation of any one component can have significant consequences resulting in delayed healing, chronic wounds or abnormal scar formation. Greater understanding of angiogenic and fibroplastic mechanisms underlying chronic wound pathogenesis has identified novel therapeutic targets and enabled development of improved treatment strategies including topical growth factors and skin substitutes. © 2013 Japanese Society for Investigative Dermatology.
Epithelial-mesenchymal transition in the skinMotonobu Nakamura | Yoshiki Tokura
Volume 61, Issue 1, January 2011, Pages 7-13
Epithelial-mesenchymal transition (EMT) plays important roles not only in the morphogenesis but also in wound repair, tissue fibrosis and cancer progression. Recently, regulatory mechanism of this process has been elaborately elucidated. EMT can be a new therapeutic target for treating skin ulcer, fibrosing alopecia, and malignant cutaneous cancers, including squamous cell carcinoma and melanoma. © 2010 Japanese Society for Investigative Dermatology.
Angiogenesis and oxidative stress: Common mechanisms linking psoriasis with atherosclerosisApril W. Armstrong | Stephanie V. Voyles | Ehrin J. Armstrong | Erin N. Fuller | John C. Rutledge
Volume 63, Issue 1, July 2011, Pages 1-9
Shared angiogenic and oxidative mechanisms underlie the pathophysiology of psoriasis and atherosclerosis. During the pathogenesis of both diseases, stimuli such as injury or local hypoxia trigger the release of pro-angiogenic factors including IL-8, HIF-1α, ETS-1, and VEGF. These factors stimulate increased permeability and encourage leukocyte transmigration into areas of inflammation by enhanced expression of cell adhesion molecules. Psoriasis and atherosclerosis also share common enzymatic sources of reactive oxygen species (ROS), and these ROS influence several cellular signaling pathways implicated in the pathogenesis of both diseases. Pharmacologic and genetic therapies that target key factors in these pathways could provide innovative approaches to the management of psoriasis and potentially mitigate the cardiovascular complications suffered by psoriasis patients. © 2011 Japanese Society for Investigative Dermatology.
An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathwayGaku Tsuji | Masakazu Takahara | Hiroshi Uchi | Satoshi Takeuchi | Chikage Mitoma | Yoichi Moroi | Masutaka Furue
Volume 62, Issue 1, April 2011, Pages 42-49
Background: Benzo(a)pyrene (BaP) is an environmental contaminant found in cigarette smoke. It is well known that cigarette smoking exacerbates interleukin-8 (IL-8)-related inflammatory skin diseases such as psoriasis, palmoplantar pustulosis and acne. Although BaP has been shown to exert its biological effects via the aryl hydrocarbon receptor (AhR) signaling pathway, the mechanism of its inflammatory effects on skin remains unanswered. Objective: To elucidate whether or not BaP cause AhR activation and subsequent oxidative stress leading to IL-8 production in normal human epidermal keratinocytes (NHEKs). Methods: NHEKs exposed to BaP were analyzed. Immunofluorescence, real-time PCR, Western blotting, ELISA, reactive oxygen species (ROS) detection using H2DCFDA and RNA interference using si (small interfering) RNA were employed. Results: Immunofluorescence analysis clearly demonstrated that BaP induced nuclear translocation of AhR from cytoplasm. The AhR activation subsequently induced CYP1A1 mRNA and protein expression in a dose-dependent manner. In addition, ROS and IL-8 production were coordinately augmented by BaP, whereas this was not the case in IL-1α, IL-6, TNF-α or GM-CSF production. Knockdown of AhR expression using siRNA transfection inhibited BaP-induced-ROS and IL-8 production, suggesting that these responses are strongly dependent on the AhR signaling pathway. Furthermore, the addition of N-acetyl cystein or catalase cancelled the IL-8 production by BaP, indicating that ROS production is essential for IL-8 production. Results: This data highlights AhR-ROS-dependent regulation of IL-8 in NHEKs by BaP, providing a plausible explanation, at least in part, for why cigarette smoking exacerbates IL-8-related skin diseases such as psoriasis, palmoplantar pustulosis and acne. © 2011 Japanese Society for Investigative Dermatology.
Hemidesmosomes and focal contact proteins: Functions and cross-talk in keratinocytes, bullous diseases and wound healingDaisuke Tsuruta | Takashi Hashimoto | Kevin J. Hamill | Jonathan C R Jones
Volume 62, Issue 1, April 2011, Pages 1-7
The outer most layer of the skin, the epidermis, is attached to the dermis via a sheet of extracellular matrix proteins termed the basement membrane zone (BMZ). In the intact skin, adhesion of the keratinocytes in the basal layer of the epidermis to the BMZ is facilitated primarily by hemidesmosomes which associate with the keratin cytoskeleton. Cultured keratinocytes do not assemble bona fide hemidesmosomes although hemidesmosome protein clusters (stable anchoring contacts) are found along the substrate-attached surface of the cells and towards the leading edge of keratinocytes repopulating scratch wounds. Actin cytoskeleton-associated matrix adhesion devices termed focal contacts are not thought to play an important role in the adhesion of keratinocytes to the BMZ in intact skin but are prominent in cultured keratinocytes where they are believed to regulate cell migration. We review the molecular components, functions, dynamics and cross-talk of hemidesmosomes and focal contacts in keratinocytes. In addition, we briefly describe what is known about their role in autoimmune and genetic blistering diseases of the skin. We also discuss recent publications which indicate, contrary to expectation, that certain focal contact proteins retard keratinocyte migration while hemidesmosomal proteins regulate directed keratinocyte motility during wound healing. © 2011 Japanese Society for Investigative Dermatology.
Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: A retrospective clinical analysisMartin Metz | Tatevik Ohanyan | Martin K. Church | Marcus Maurer
Volume 73, Issue 1, January 2014, Pages 57-62
Background: Omalizumab (anti-IgE) therapy is effective and safe in chronic urticaria (CU) in placebo-controlled clinical trials but real life clinical data are scarce. Objective: To better understand the effects of omalizumab in CU patients treated outside of clinical trials. Methods: In this retrospective clinical analysis, we assessed responder rates, optimal dosage, response to up-/downdosing, time to relief of symptoms, rates of return and time of relapse after omalizumab administration, and safety in 51 CU patients, 20 with chronic spontaneous urticaria (CSU) alone, 21 with different forms of chronic inducible urticaria (CindU) and 10 with both. Results: Omalizumab treatment led to complete remission in 83% of CSU and 70% of CindU patients. When starting with 150. mg omalizumab 4 weekly, only 2/15 CSU and 7/17 CindU patients required updosing to achieve complete remission. In CSU, 57% of complete responses occurred within week one, all on the first day. Relapses were 2-8 weeks in all but six patients, where they were <4 months. Omalizumab was safe. Efficacy was not correlated to baseline IgE levels. Conclusion: Clinical experience from more than 1250 injections in 51 patients over four years indicates that omalizumab is a rapidly acting, highly effective and safe drug in CSU and CindU patients. Our observations in a real life clinical setting support the recommendation of current EAACI/GA2LEN/EDF/WAO guideline for the management of urticaria to use omalizumab to treat urticaria patients. © 2013 Japanese Society for Investigative Dermatology.
Clinicopathologic and prognostic significance of SATB1 in cutaneous malignant melanomaHongxiang Chen | Masakazu Takahara | Junna Oba | Lining Xie | Takahito Chiba | Satoshi Takeuchi | Yating Tu | Takeshi Nakahara | Hiroshi Uchi | Yoichi Moroi | Masutaka Furue
Volume 64, Issue 1, October 2011, Pages 39-44
Background: Special AT-rich sequence-binding protein-1 (SATB1), a new type of gene regulator, has been reported to be expressed in several human cancers and may have malignant potential. However, no data on SATB1 expression and its relationship to tumor progression in cutaneous malignant melanoma (CMM) has yet been reported. Objective: We examined the immunohistochemical expression of SATB1 in CMM to determine whether it could serve as a prognostic marker. Methods: A total of 97 samples of primary CMM and controls were immunostained for SATB1. The following clinicopathologic variables were evaluated: age, gender, subtype, SATB1 expression, Breslow thickness, Clark level, presence of ulceration, lymph node metastasis, distant metastasis, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional-hazards model. Results: Forty cases (85.1%) of CMM showed positive staining for SATB1 by immunohistochemistry. The intensity of SATB1 staining was significantly higher in CMM than in nevus NV and normal skin (NS) (P<0.01). High SATB1 expression was significantly correlated with Breslow thickness, Clark level, mortality, presence of ulceration, and lymph node metastasis (P<0.01). Moreover, Kaplan-Meier analysis revealed that SATB1 overexpression was significantly associated with worse survival (P<0.01). Further univariate analysis and multivariate regression analysis indicated that SATB1 expression was an independent prognostic marker for CMM (P=0.03). Conclusions: The overexpression of SATB1 correlated with metastatic potential of CMM and is a novel independent prognostic marker for predicting outcome. © 2011 Japanese Society for Investigative Dermatology.
Quercetin inhibits UV irradiation-induced inflammatory cytokine production in primary human keratinocytes by suppressing NF-κB pathwayFabiana T M C Vicentini | Tianyuan He | Yuan Shao | Maria J V Fonseca | Waldiceu A. Verri | Gary J. Fisher | Yiru Xu
Volume 61, Issue 3, March 2011, Pages 162-168
Background: Topical flavonoids, such as quercetin, have been shown to reduce ultraviolet (UV) irradiation-mediated skin damage. However, the mechanisms and signaling pathways involved in this protective effect are not clear. UV irradiation leads to activation of two major signaling pathways, namely nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) pathways. Activation of NF-κB pathway by UV irradiation stimulates inflammatory cytokine expression, whereas activation of AP-1 pathway by UV irradiation promotes matrix metalloproteinase (MMP) production. Both pathways contribute to UV irradiation-induced skin damage, such as photoaging and skin tumor formation. Objective: To elucidate the underlying mechanism, we examined the effect of quercetin on UV irradiation induced activation of NF-κB and AP-1 pathways. Methods: Primary human keratinocytes, the major skin cell type subjected to physiological solar UV irradiation, were used to study the effects of quercetin on UV irradiation-induced signal transduction pathways. Results: Quercetin decreased UV irradiation-induced NF-κB DNA-binding by 80%. Consequently, quercetin suppressed UV irradiation-induced expression of inflammatory cytokines IL-1β (∼60%), IL-6 (∼80%), IL-8 (∼76%) and TNF-α (∼69%). In contrast, quercetin had no effect on UV irradiation activation of three MAP kinases, ERK, JNK, or p38. Accordingly, induction of AP-1 target genes such as MMP-1 and MMP-3 by UV irradiation was not suppressed by quercetin. Conclusion: Our data indicate that the ability of quercetin to block UV irradiation-induced skin inflammation is mediated, at least in part, by its inhibitory effect on NF-κB activation and inflammatory cytokine production. © 2011 Japanese Society for Investigative Dermatology.
Molecular basis of androgenetic alopecia: From androgen to paracrine mediators through dermal papillaShigeki Inui | Satoshi Itami
Volume 61, Issue 1, January 2011, Pages 1-6
Androgenetic alopecia (AGA) is characterized by vellus transformation of scalp hairs, corresponding to hair follicle miniaturization during repeated hair cycles with shortened anagen phase. This phenomenon is mediated mainly by androgen. Then, the multi-step molecular pathway of androgen can be involved in the pathogenesis of AGA. The expression of type II 5α-reductase is higher in dermal papilla cells from AGA and beard than those from other sites. On the other hand, type I 5α-reductase expression is relatively low. Next, hormone binding assays and RT-PCR demonstrated that androgen receptor (AR) expression is significantly higher in bald dermal papilla cells than non-bald cells. Additionally, AR coactivator Hic-5/ARA55 is highly expressed in dermal papilla cells of hair follicles from androgen-sensitive sites such as AGA and beard. Collectively, the enhanced expression of type II 5α-reductase, AR and Hic-5/ARA55 can upregulate sensitivity to androgen of dermal papilla cells in AGA. Furthermore, in the coculture of AR-overexpressing human dermal papilla cells from AGA and normal human keratinocytes, R1881 suppresses keratinocyte growth through androgen-inducible TGF-β1, indicating that TGF-β1 is one of the key players in pathogenesis of AGA. TGF-β2 and DKK-1 has been reported to be androgen-induced suppressor of growth of follicular epithelial cells. We expect that more pathogenic mediators will be identified in the future, enabling easier understanding of AGA pathogenesis and providing new therapeutic targets from aspect of andrology. © 2010 Japanese Society for Investigative Dermatology.
Development of NC1 and NC2 domains of Type VII collagen ELISA for the diagnosis and analysis of the time course of epidermolysis bullosa acquisita patientsMarwah Adly Saleh | Ken Ishii | Yool Ja Kim | Akihiro Murakami | Norito Ishii | Takashi Hashimoto | Enno Schmidt | Detlef Zillikens | Yuji Shirakata | Koji Hashimoto | Yasuo Kitajima | Masayuki Amagai
Volume 62, Issue 3, June 2011, Pages 169-175
Background: Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune mechanobullous disease. EBA patients possess autoantibodies against type VII collagen which is composed of a collagenous domain flanked by non-collagenous NC1 and NC2 domains. It was reported that major epitopes reside within the NC1 domain and minor epitopes reside within NC2 domain. Objective: The aim of this study is to develop a sensitive and specific ELISA to facilitate the diagnosis of EBA. Methods: We developed ELISAs using recombinant NC1 domain produced by mammalian expression system and recombinant NC2 domain produced by mammalian or bacterial expression system to characterize autoantibodies in EBA. Next, we developed an ELISA using a combination of the NC1 (mammalian expression) and NC2 (bacterial expression). We tested the ELISAs with 49 EBA sera, 55 normal control sera, 20 pemphigus vulgaris and 20 bullous pemphigoid sera. Results: When we evaluated the 49 EBA sera using the NC1 and NC2 ELISAs, 38 (77.5%) reacted with NC1 domain only, 7 sera (14.2%) reacted with both NC1 and NC2 domains, and one serum (2%) reacted with NC2 domain only. Therefore, to increase the sensitivity of the assay, we developed an ELISA coated with a mixture of recombinant NC1 and NC2 domains, resulting in 93.8% sensitivity and 98.1% specificity. By analyzing the time course of two EBA patients, ELISA scores fluctuated in parallel with their disease activity. Conclusion: We conclude that the NC1. +. NC2 ELISA can be a practical assay for the diagnosis and follow up of the antibody titers of EBA patients. © 2011 Japanese Society for Investigative Dermatology.
Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosisWen Hung Chung | Shuen Iu Hung
Volume 66, Issue 3, June 2012, Pages 190-196
Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65-75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas-FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future. © 2012 Japanese Society for Investigative Dermatology.
NF-κB: An essential transcription factor in psoriasisA. M. Goldminz | S. C. Au | N. Kim | A. B. Gottlieb | P. F. Lizzul
Volume 69, Issue 2, February 2013, Pages 89-94
Nuclear factor kappa B (NF-κB) is a protein transcription factor that orchestrates inflammation and other complex biological processes. It is a key regulatory element in a variety of immune and inflammatory pathways, in cellular proliferation and differentiation and in apoptosis. Therefore NF-κB is a crucial mediator involved in the pathogenesis of psoriasis. Psoriasis, an inflammatory dermatosis, is marked by elevated levels of active, phosphorylated NF-κB. Genomic studies have also linked psoriasis with mediators in the NF-κB pathway. NF-κB has been hypothesized to connect the altered keratinocyte and immune cell behavior that characterizes the psoriatic milieu. Several anti-psoriatic therapies, including tumor necrosis factor-α blockers and glucocorticoids, reduce active NF-κB levels and related down-stream elements, and other biologics currently in development, including interleukin-17 blockers, may also target this pathway. Compounds that specifically target NF-κB signaling may be developed as novel therapeutics for chronic inflammatory disorders including psoriasis. However, chronic NF-κB inhibition could also result in immunodeficiencies. Therefore, a delicate balance must be found that maximizes therapeutic potential while limiting harmful effects, and may be achieved through several possible approaches, including localized therapy, selective inhibition of NF-κB signaling in pathologic cells, incomplete pathway inhibition or short treatment durations. © 2012 Japanese Society for Investigative Dermatology.
The flavonoids apigenin and luteolin suppress ultraviolet A-induced matrix metalloproteinase-1 expression via MAPKs and AP-1-dependent signaling in HaCaT cellsYong Pil Hwang | Kyo Nyeo Oh | Hyo Jeong Yun | Hye Gwang Jeong
Volume 61, Issue 1, January 2011, Pages 23-31
Background: Ultraviolet (UV) irradiation causes major changes in skin connective tissues as a result of the degradation of collagen, a major structural component of the extracellular matrix. This process is likely mediated by matrix metalloproteinases (MMPs). Such changes in collagenous skin tissues have been suggested to be causes of cutaneous aging and skin cancer. Objective: We investigated the protective effects of apigenin and luteolin on immortalized human keratinocytes (HaCaT) against UVA damage. We then explored the inhibitory effects of apigenin and luteolin on UVA-induced MMP-1 and investigated the molecular mechanism underlying those effects. Methods: HaCaT cells were treated with apigenin and luteolin for the indicated times followed by irradiation with UVA. Those effects were assessed by semi-quantitative PCR, Western blotting and enzymic activity assays. Results: These two compounds, at concentrations of 1-5μM, increased the viability of, and inhibited ROS production in HaCaT cells exposed to UVA irradiation. Pre-treatment of HaCaT cells with apigenin and luteolin also inhibited UVA-induced production of the collagenases MMP-1. They also suppressed UVA-induced expression of c-Jun and c-Fos and the phosphorylation of three MAP kinases, upstream modulators of AP-1. Furthermore, the same two flavonoids decreased the UVA-induced influx of Ca2+ into HaCaT cells and the phosphorylation of Ca2+/calmodulin-dependent kinases (CaMKs). Conclusion: The results indicate that apigenin and luteolin inhibited UVA-induced collagenolytic MMP-1 production by interfering with Ca2+-dependent MAPKs and AP-1 signaling. They may thus be potentially useful in the prevention and treatment of skin photoaging. © 2010 Japanese Society for Investigative Dermatology.
A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: Possible immunological state of the intrinsic typeRieko Kabashima-Kubo | Motonobu Nakamura | Jun ichi Sakabe | Kazunari Sugita | Ryosuke Hino | Tomoko Mori | Miwa Kobayashi | Toshinori Bito | Kenji Kabashima | Koetsu Ogasawara | Yukiko Nomura | Toshifumi Nomura | Masashi Akiyama | Hiroshi Shimizu | Yoshiki Tokura
Volume 67, Issue 1, July 2012, Pages 37-43
Background: Atopic dermatitis (AD) can be classified into the major extrinsic type with high serum IgE levels and impaired barrier, and the minor intrinsic type with normal IgE levels and unimpaired barrier. Objective: To characterize the intrinsic type of Japanese AD patients in the T helper cell polarization in relation to the barrier condition. Methods: Enrolled in this study were 21 AD patients with IgE < 200. kU/L (IgE-low group; 82.5 ± 59.6. kU/L) having unimpaired barrier, and 48 AD patients with IgE > 500. kU/L (IgE-high group; 8.050 ± 10.400. kU/L). We investigated filaggrin gene (FLG) mutations evaluated in the eight loci common to Japanese patients, circulating Th1, Th2 and Th17 cells by intracellular cytokine staining and flow cytometry, and blood levels of CCL17/TARC, IL-18, and substance P by ELISA. Results: The incidence of FLG mutations was significantly lower in the IgE-low group (10.5%) than the IgE-high group (44.4%) (normal individuals, 3.7%). The percentage of IFN-γ-producing Th1, but not Th2 or Th17, was significantly higher in the IgE-low than IgE-high group. Accordingly, Th2-attracting chemokine CCL17/TARC, was significantly lower in the IgE-low than the IgE-high group. There were no differences between them in serum IL-18 levels, or the plasma substance P levels or its correlation with pruritus. Conclusion: The IgE-low group differed from the IgE-high group in that it had much less FLG mutations, increased frequency of Th1 cells, and lower levels of CCL17. In the intrinsic type, non-protein antigens capable of penetrating the unimpaired barrier may induce a Th1 eczematous response. © 2012 Japanese Society for Investigative Dermatology.
Mesenchymal stem cells delivered in a microsphere-based engineered skin contribute to cutaneous wound healing and sweat gland repairSha Huang | Gang Lu | Yan Wu | Enhe Jirigala | Yongan Xu | Kui Ma | Xiaobing Fu
Volume 66, Issue 1, April 2012, Pages 29-36
Background: Bone-marrow-derived mesenchymal stem cells (BM-MSCs) can contribute to wound healing after skin injury. However, the role of BM-MSCs on repairing skin appendages in renewal tissues is incompletely explored. Moreover, most preclinical studies suggest that the therapeutic effects afforded by BM-MSCs transplantation are short-lived and relatively unstable. Objective: To assess whether engrafted bone-marrow-derived mesenchymal stem cells via a delivery system can participate in cutaneous wound healing and sweat-gland repair in mice. Methods: For safe and effective delivery of BM-MSCs to wounds, epidermal growth factor (EGF) microspheres were firstly developed to both support cells and maintain appropriate stimuli, then cell-seeded microspheres were incorporated with biomimetic scaffolds and thus fabricated an engineered skin construct with epithelial differentiation and proliferative potential. The applied efficacy was examined by implanting them into excisional wounds on both back and paws of hind legs in mice. Results: After 3 weeks, BM-MSC-engineered skin (EGF loaded) treated wounds exhibited accelerated healing with increased re-epithelialization rates and less skin contraction. Furthermore, histological and immunofluorescence staining analysis revealed sweat glands-like structures became more apparent in BM-MSC-engineered skin (EGF loaded) treated wounds but the number of implanted BM-MSCs were decreased gradually in later phases of healing progression. Conclusions: Our study suggests that BM-MSCs delivered by this EGF microspheres-based engineered skin model may be a promising strategy to repair sweat glands and improve cutaneous wound healing after injury and success in this study might provide a potential benefit for BM-MSCs administration clinically. © 2012 Japanese Society for Investigative Dermatology.
Chemokine receptors in the pathogenesis and therapy of psoriasisTomotaka Mabuchi | Timothy W. Chang | Suzanne Quinter | Sam T. Hwang
Volume 65, Issue 1, January 2012, Pages 4-11
Chemokine receptors are G-protein-coupled, seven-transmembrane-spanning surface receptors that play key roles in cell trafficking, cell motility, and survival. These receptors are activated by small molecular weight chemotactic cytokines called chemokines. Chemokine receptors and their corresponding chemokine ligands play roles in the migration and localization of normal T cells (and other cells) during physiological responses in inflamed or infected skin. In psoriasis, the chemokine receptor CCR6 is expressed on the Th17 cells and γδ T cells, which produce a variety of cytokines (IL17 and IL22 among others), that play a role in the immunological activation. CCR6 and its ligand, CCL20, are highly expressed in psoriatic skin lesion and CCR6 is essential for the development of the psoriasiform phenotype following IL23 injection in mouse skin. In this review, we focus on the roles of chemokine receptors, particularly of CCR6, in the pathogenesis of psoriasis and discuss chemokine receptors as novel therapeutic targets for psoriasis. © 2011 Japanese Society for Investigative Dermatology.
Microarray analysis of microRNA expression in cutaneous squamous cell carcinomaMichael Sand | Marina Skrygan | Dimitrios Georgas | Daniel Sand | Stephan A. Hahn | Thilo Gambichler | Peter Altmeyer | Falk G. Bechara
Volume 68, Issue 3, December 2012, Pages 119-126
Background: MicroRNAs (miRNAs) are a novel class of short RNAs that are capable epigenetically regulating gene expression in eukaryotes. MicroRNAs have been shown to be dysregulated in a variety of cancers. The data on miRNA expression in cutaneous squamous cell carcinoma (cSCC) are very limited, and microarray-based miRNA expression profiles of cSCC have not yet been determined. Objective: To describe differentially expressed miRNAs in cSCC. Methods: Seven patients with cSCC were enrolled in the present study. Tumor biopsies (n= 7) were taken from the center of each tumor. Adjacent healthy skin (n= 7) was biopsied as a control (intraindividual control). miRNA expression profiles of all specimens were detected by microarray miRNA expression profiling based on miRBAse 16 scanning for 1205 potential human miRNA target sequences. The microarray results were confirmed by TaqMan quantitative real-time polymerase chain reaction (qRT-PCR). Results: Non-stringent filtering with a non-adjusted p≤ 0.05 revealed thirteen up-regulated and eighteen down-regulated miRNAs. Non-stringent filtering with a non-adjusted p≤ 0.01 revealed three up-regulated (hsa-miR-135b, hsa-miR-424 and hsa-miR-766) and six down-regulated (hsa-miR-30a*, hsa-miR-378, hsa-miR-145, hsa-miR-140-3p, hsa-miR-30a and hsa-miR-26a) miRNAs in cSCC. Conclusion: This study reveals differentially expressed miRNAs that may play a role in the molecular pathogenesis of cSCC and that are excellent candidates for further validation and functional analysis. © 2012 Japanese Society for Investigative Dermatology.
The role of IL-22 and Th22 cells in human skin diseasesHideki Fujita
Volume 72, Issue 1, October 2013, Pages 3-8
Interleukin (IL)-22 is a cytokine that is involved in the modulation of tissue responses during inflammation. It is produced by immune cell subsets such as T cells, while the expression of its receptor is restricted to cells of non-hematopoietic origin, particularly epithelial cells. In the skin, IL-22 induces keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation of keratinocytes, and promotes the production of antimicrobial proteins. Although IL-22 was initially thought to be produced by T helper (Th)17 cells, IL-22 production can also occur in an apparently unique subset of cells, Th22 cells, which lack the ability to produce IL-17 and interferon-γ. Of note, Th22 cells, which express the skin homing chemokine receptors CCR4 and CCR10, reside in the normal skin and are enriched in the lesional skin of inflammatory skin diseases, indicating the importance of IL-22 in skin homeostasis and pathogenesis of skin diseases. Although a critical role of IL-22 was initially highlighted in psoriasis, a growing body of evidence indicates that this cytokine also plays a role in atopic dermatitis and other inflammatory skin diseases. Moreover, emerging experimental data suggest that IL-22 also participates in the pathophysiology of malignancies of the skin. In this review, recent findings regarding the expression, regulation, and function of the IL-22 pathway in various human skin diseases will be discussed. Considering the strong association between excess activation of the IL-22/Th22 pathway and human skin diseases, targeting this pathway may provide promising new therapeutic approaches. © 2013.
Intrinsic aging- and photoaging-dependent level changes of glycosaminoglycans and their correlation with water content in human skinJang Hee Oh | Yeon Kyung Kim | Ji Yong Jung | Jeong eun Shin | Kyu Han Kim | Kwang Hyun Cho | Hee Chul Eun | Jin Ho Chung
Volume 62, Issue 3, June 2011, Pages 192-201
Background: Glycosaminoglycans (GAGs) have various structural and physiological regulatory functions in skin, including tissue water maintenance, due to their high water-holding capacity. Objective: To investigate changes of GAGs during intrinsic aging and photoaging of human skin and their correlations with water content. Methods: Samples of sun-protected buttock and sun-exposed forearm skin were obtained from young male (21-30. years, n= 8) and female (20-33. years, n= 8) subjects, as well as old male (70-78. years, n= 8) and female (70-80. years, n= 8) subjects, and their epidermal and dermal contents of hyaluronic acid (HA), total sulfated GAG (tsGAG), total uronic acid (tUA), and tissue water were measured. HA content was determined by enzyme-linked immunosorbent assay using HA-binding protein, tsGAG by the sulfated GAG assay kit using 1,9-dimethylmethylene blue, tUA by carbazole reaction, and tissue water by subtraction of tissue dry weight from wet weight. Results: In the buttock, HA was higher in dermis than in epidermis, while tsGAG and tUA were higher in epidermis. In intrinsically aged buttock, epidermal HA and dermal tsGAG and tUA decreased. However, when analyzed for each gender, epidermal tsGAG, tUA, and tissue water decreased only in females. Forearm/buttock ratios of each molecule were compared for determination of photoaging-dependent changes. Forearm/buttock ratios of HA, tsGAG, tUA, and tissue water increased in aged dermis, but showed no change in aged epidermis. When analyzed for each gender, ratios of epidermal HA and tissue water increased only in aged females, while ratios of epidermal tsGAG, tUA, and tissue water decreased only in aged males. Correlations of water content with HA, tsGAG, and tUA were found in epidermis, but not with tsGAG in dermis. Conclusion: These intrinsic aging- and photoaging-dependent GAG changes and their correlations with water content provide new insights into the pathophysiology of dry skin in the elderly. © 2011 Japanese Society for Investigative Dermatology.
Tight junction dysfunction in the stratum granulosum leads to aberrant stratum corneum barrier function in claudin-1-deficient miceTomoko Sugawara | Noriko Iwamoto | Masaya Akashi | Taro Kojima | Junzo Hisatsune | Motoyuki Sugai | Mikio Furuse
Volume 70, Issue 1, April 2013, Pages 12-18
Background: Tight junctions (TJs) contribute to the epithelial barrier function by preventing leakage of solutes through the intercellular space. In the skin, TJs occur in the stratum granulosum (SG), where claudin-1 and claudin-4 are expressed as adhesion molecules of TJs. Claudin-1-deficient (Cldn1-/-) mice die within one day of birth accompanied by excessive transepidermal water loss, indicating a critical role of TJs in the epidermal barrier function. However, it has been debated whether the impaired TJ function in the SG also affects the stratum corneum (SC) barrier function or whether it results in skin barrier defects despite a normal SC barrier. Objective: To clarify whether the impaired TJ function affects the SC barrier function in Cldn1-/- mice. Methods: The morphology, barrier function and biochemical characteristic of the SC were compared between Cldn1-/- and Cldn1+/+ mice. Results: Scanning electron microscopy demonstrated abnormally wrinkled and rough corneocytes in Cldn1-/- mice. Notably, the X-gal tracer easily permeated into the Cldn1-/- SC, and water evaporation through isolated Cldn1-/- SC sheets was significantly higher than that through Cldn1+/+ SC sheets. Furthermore, the ceramide composition of the SC lipids and filaggrin processing were altered in Cldn1-/- mice. Conclusion: Cldn1-/- mice exhibited the abnormal SC formation and SC barrier defects. These findings demonstrate for the first time that TJs in the SG play crucial roles in the complete SC formation and SC barrier function. © 2013 Japanese Society for Investigative Dermatology.
Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 statusJindřiška Hammerová | Stjepan Uldrijan | Eva Táborská | Iva Slaninová
Volume 62, Issue 1, April 2011, Pages 22-35
Background: Search for new substances with antiproliferative activity towards melanoma cells is important since malignant melanoma is notoriously resistant to conventional chemotherapy. Benzo[c]phenanthridine alkaloids (BAs) are natural products with significant anti-proliferative activities, therefore they are considered as agents promising for cancer therapy. Objectives: The effects of five BAs (sanguinarine, chelerythrine, chelidonine, sanguilutine, and chelilutine) on human malignant melanoma cell lines were compared. The study focused on BAs effects on DNA, anti-apoptotic and p53 protein levels; and the involvement of p53 in cellular responses to alkaloids treatment. Methods: Melanoma cell lines, two wild types and two with dysfunctional p53 derived from one of them were used. The mechanism of anti-proliferative and pro-apoptotic effects and the effect on DNA was investigated using MTT assay, flow cytometry, Western blot analysis, fluorescence and electron microscopy. Results: All tested alkaloids exhibit strong anti-proliferative activity. CHL, CHE and SA induced apoptosis, which was probably mediated by decreasing levels of anti-apoptotic proteins (Bcl-xL, Mcl-1, XIAP) and was accompanied by mitochondrial membrane potential decrease as well as caspase-3 and PARP cleavage. Although all alkaloids caused DNA damage, which was demonstrated by induction of H2AX phosphorylation, none of the tested alkaloids stabilised p53 and their toxicity in cells with non-functional p53 was comparable to wild type cells. Conclusion: Despite the profound similarity of BAs molecular structures, it is clear that the mechanism of cell death induction is different for each alkaloid. Our results indicate that BAs could be effective in malignant melanoma treatment, including tumours which have lost wild type p53. © 2011 Japanese Society for Investigative Dermatology.


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#2 to #1 - prettypurpledino [OP]
Reply +2(02/23/2012) [-]
sorry.... It's just what I always see on here and I'm new just trying to please the FJ community. I'll try not to use 'le me' in anymore comics. but in all honesty, do you think it's funny? or cool? or what? Also, does it make me weird?
#6 to #2 - thegrizzlyman (02/23/2012) [-]
#3 to #2 - mmajunkie (02/23/2012) [-]
It's hard to tell honestly... The first thing I saw was 'le', so from that point forward I was not happy. If you don't know, 'le' is French for 'the'... so saying "The me" is just retarded. People use it on here for no good reason... Edit this, take out 'le' and I bet you get a **** load of thumbs. I'll check your page for it, and thumb.
#7 to #3 - prettypurpledino [OP] (02/23/2012) [-]
i revised it. i also mentioned you in the description... Hope you don't mind!


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Hunting is too dangerous for kidsNovember 30,2012
Hunting is too dangerous for kids
The story in the newspapers about the 7-year-old child who got lost in the woods after hunting with family is both appalling and terrible parenting. Taking a 7-year-old, or for that matter any child, hunting is risky and inappropriate. In this case the child wasnt shot by accident, as is usually the case in these accidents while hunting, but got lost overnight in freezing cold weather. I wonder where the parents were? Deer hunting is dangerous enough already without exposing your kids to the bullets buzzing by your head from other hunters shooting at everything that moves. Thats not including your own rifle going off by accident and killing your best friend or kids. Just ask Dick Cheney, who shot his buddy while quail hunting. The 78-year-old victim had a heart attack after getting shot by Cheney.
So, leave the kids at home and go hunting yourself if you have to. If people are in the woods with children they better stay close to them.
Tom King
ShaftsburyMORE IN LettersElection-time letters to the papers often sound as though they were written by a machine, but... Full StoryOpposition to the construction of the Dakota Access Pipeline has brought thousands of... Full StoryI am a Berlin School Board member and one of the three members from Berlin on the Act 46, 706B... Full Story
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Live updates
Appeal after man assaulted outside North Wales pub
North Wales Police are appealing for witnesses following an assault on a man in High Street in Holywell.
The incident occurred at around 2.10am on Monday May 2nd, during which a 44 year old man sustained serious injuries.
Anyone with information is asked to call 101.
- ITV Report
Rugby player stalked teenage newspaper-delivery girl
Youngster hears for the first time after life-changing op
Little Amelie Ring is one of the one-in-a-thousand babies born profoundly deaf. A few weeks ago she had a complex operation to try and help.
Today Amelie and her parents Vicky and Rob made the journey from their home near Holywell to a Manchester hospital - to literally switch on Amelie's hearing and give her a new sense - Rob Shelley was there.
Little Amelie hears for the first time after implant op
This is the moment little Amelie Ring heard for the first time. The 20 month old from Holywell was born profoundly deaf and underwent an operation to insert bilateral cochlear implants to enable her to hear. Today was the first time her microphones were switched on and she heard her parents' voices.
Baby born deaf set to hear for the first time
A baby who was born deaf is set to hear sound for the very first time today.
Amelie Ring from Holywell had an electronic device surgically implanted to enable her to hear for the first time.
In December, surgeons has to postpone plans to insert bilateral cochlear implants after the 20 month old stopped breathing after receiving an anaesthetic.
Last week the implants were put in place and Amelie's mother, Vicky, described said it was a day the family thought they may never see.
Amelie was born at 28 weeks and spent her first 102 days in Glan Clwyd Hospital after suffering major blood loss in her mother's womb. She underwent nine blood transfusions and a heart operation while in hospital.
Richard and Adam switch on Holywell Christmas lights
Singers Richard and Adam Johnson from Holywell in Flintshire started the year turning up to a Britain's Got Talent audition just on the off chance.
Since they finished third, they have topped the album charts for four weeks - and now they've got their eye on topping the christmas charts too.
But today they were bit closer to home, as they switched on the Christmas lights of Holywell. Our own Rob Shelley was there to meet them.
Union: 'Holywell high street needs a Crown Post Office'
Andy Furey is the National Officer for Communication Workers Union, which represents staff working in Crown Post Offices.
He told ITV News: "A Welsh town like Holywell needs a Crown Post Office. If we lose it, this could be the death knell for the high street in Holywell."
Delyn MP: 'More detail needed' over Post Office plans
Delyn MP David Hanson has told ITV News more detail is needed regarding proposals to franchise Holywell's Crown Post Office.
"Part of tonight's meeting is to hear from local people as to what they think of the service," he added.
- ITV Report
Campaigners rally to save Holywell Crown Post Office
Crown post offices 'losing £37m a year'
The Post Office says its 370-branch crown network is losing £37million a year, which cannot be sustained.


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AT-A-GLANCE - Horizontal Erasable Wall Planner, 48 x 32, Blue/White - 2016
by AT-A-GLANCE | Item #: 342862 | Model #: AAGPM30028 |
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About this item
Large bold print on bright white background is easy to see and read. Yearly calendar on one side and bordered ruled and unruled space on other side for lots of notes. Write-on, wipe-off surface erases easily with a damp cloth. Shaded weekends contrast with the workweek. Wet erase marker included.
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48 x 32
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Rovio Entertainment, in partnership with Papagei.com, a video language platform, will launch its online, interactive language courses on a new mobile app, titled "Learn English with Angry Birds."
Rovio Entertainment, via its publishing arm Kaiken Publishing, has partnered with more than 20 publishers worldwide to expand the Angry Birds Movie universe.
Rovio Entertainment has partnered with Microsoft for a new range of emojis for Windows Skype messaging, Mac, Android, iOS and the Internet.
Rovio Entertainment has partnered with Brunswick Bowling to bring its Angry Birds franchise to bowling alleys across the U.S.
In honor of Earth Day Friday, Rovio Entertainment's Angry Birds character Red continued to support the United Nations as part of the Angry Birds for a Happy Planet campaign.
Kaiken Publishing, an affiliate of Rovio Entertainment, has acquired the worldwide publishing rights for Toonbox Animation's "Qumi-Qumi" and "Kit^n^Kate."
Rovio Entertainment has partnered with Madame Tussauds to develop, produce and digitally bring Angry Birds to life at the wax museum.
Rovio Entertainment has partnered with Papagei.com, a video language platform, to provide English language learners interactive video courses led by characters from the "Angry Birds" universe.
Rovio Entertainment has created a new affiliate company, Kaiken Publishing, which will continue to build on the gaming studio's current book business.
In anticipation of The Angry Birds Movie, Bulldog Licensing has secured four new licensees for Rovio's "Angry Birds" brand.
Rovio Entertainment is building a blockbuster consumer products program for the upcoming Angry Birds movie, which will hit the big screen in May 2016.
Rovio Entertainment has appointed seven new licensing agencies in EMEA for the "Angry Birds" brand.
Through a series of strategic executive appointments and local partnerships, Rovio Entertainment is amping up the success of its "Angry Birds" franchise in Asia.
©2016 UBM. All rights reserved. A UBM Company.


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