text:
You missed it This great deal for YogaBody Chino Hills is over. But don't despair, we've got more great deals every day.
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inside FITBODY Bootcamp Studio
3560 Grand Avenue, Suite C, Chino Hills, CA 91709
909-992-2525 | get directions


text:
Thanks for helping us sort this video!
Thanks for helping us associate the correct Pornstars to this video!
Помогите нам: эти порнозвезды присутствуют в этом видео?
Pornstar Name:
Yeah! This is what hookers are for. I remember my first sex with a prostitute. I was in the army for only two weeks and my mates and I desperately needed a fuck. That night we drove to Arnhem red light district. Some of the guys had been there before, but for me it was my first visit to a whore. A sweet Latin girl gave me a great fuck. I still remember the condom full of my cum. I felt like a superstar! From that moment there was no turning back. Paying for sex more or less became a lifestyle.
she is cute an he is cute for kissing her after he come..nice
she dosn´t look happy at all....she needs a new job! he is cute!
zomaar komt die andere bemoeien!
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subset: commoncrawl


text:
St. Alphonsus Liguori
Prospect Heights, IL
Mass Times
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Bulletin, Kiosk, Narthex, Display Items
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FORMED: "Catholic Netflix"
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priority is given to pastor's requests.
All inserts
be reviewed and scheduled by the Bulletin Editor.
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by you
and brought to the Parish Office no later than Thursday morning for that weekend's bulletin.
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At Saint Alphonsus Liguori, all bulletin or display activities and events must follow Catholic teachings. Items for the bulletin must be received as early as possible as space is limited.
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. Please send the original document in either Microsoft Word or Publisher. Include a contact number and the dates you would like it to appear in the bulletin.
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Coming soon
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text:
The Hollywood actor Sylvester Stallone has opened an art exhibition at the Russian Museum in St Petersburg – where the main attraction is a retrospective of 40 years of his own work.
The collection of "very serious paintings from a very serious artist" has been entitled simply: "Sylvester Stallone. Painting. From 1975 until Today", and features pieces such as "Finding Rocky", "Hercules O'Clock" and "Untitled (Michael Jackson)".
There have been murmurs of discontent among the more conservative branches of the Russian art world, who see it as something of an outrage that a hobbying painter – particularly one whose most famous films have been described as outright anti-Soviet propaganda – could be given pride of place in one of Russia's most prestigious museums.
The collection of 36 original Stallones will appear in the Ludwig arm of the museum, alongside pieces from "his contemporaries" Jean-Michel Basquiat and Andy Warhol.
"If my visit is a challenge for somebody, let it be so," Stallone said at a press conference heralding the start of the exhibition.
The museum has a heavy focus on Russian art, making it all the more surprising that it should feature work from a man more famous for starring in the Rambo, Rocky, and The Expendables film franchises.
While promoting his latest film Escape Plan in which he co-stars with Arnold Schwarzenegger, Stallone himself told Good Morning America it was a "really odd" decision.
"It's very, very flattering because there are so many great artists in the world," he said. "But for some reason, they chose me to go over there and show this 40-year retrospective of all the paintings from the beginning up until now."
He told an assembled audience of curators, critics and privileged early visitors on Sunday: "I love all of you," and added that if he had to choose, he would prefer to spend his life working on his painting and sculpting rather than starring in action movies.
The listing for the exhibition on the Russian Museum website explained how, long before "his ascension to the cinematic Mount Olympus", Stallone had attended an art course in Switzerland and had wanted to pursue it as a career.
The museum added: "Stallone's paintings can seem beautiful or savage, skillfully done or not, but they do not leave viewers indifferent, as within them lives the mystery of experience."
This is not the first time Stallone's work has appeared at a major art gallery – some pieces of his sold for between $50,000 and $120,000 at Art Basel Miami Beach 2009, a fleeting annual exhibition satirised for its excesses in the Tom Wolfe novel Back to Blood.
Museum director Vladimir Gusev said Stallone's paintings "show the character of a passionate man", and were not simply "the work of an amateur". According to AFP, he told journalists: "This is a real artist." The exhibition will run until 13 January 2014.Reuse content


text:
Anthology: The Writer & His Music [CD & DVD]
- Artist: Deitrick Haddon
- Release Date: 08/23/2011
Best Buy is dedicated to always offering the best value to our customers. We will match the price, at the time of purchase, on a Price Match Guarantee product if you find the same item at a lower price at a Designated Major Online Retailer or at a local retail competitor's store.Here's how:
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- Don't Leave Me Now [Original Version]
- Well Done [Blessed & Cursed Version]
- I Gotta Praise (Holy One)
- Take Rest In Me
- Heaven
- Don't Leave Me Now [Blessed & Cursed Version]


text:
Need Help? Call us at 865-521-0000
Thank you for donating to Second Harvest Food Bank of East Tennessee. We greatly appreciate your caring and compassionate support. We ensure that 95 cents of every dollar will go directly to feeding the hungry in our 18 county service area. Again, thank you for your donation and joining the fight to end hunger in our communities.


text:
New Pre-Made Costumes are coming soon~
Update will be posted on SHOP | Blog | Facebook.
Princess White Rose from SaGa Frontier
Costume made by Cosaru | Cosaru Chae
Photo by Simply Frank Productions (facebook | website)
Photo by COSARU | AnimeNEXT 2015 (Somerset, NJ)
LoveLive! School Idol Project
Ayase Eli by midsummer cosplay | Toujou Nozomi by Mara


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05/11/00- Updated 11:47 AM ET
Poll: Bush leads presidential race
LOS ANGELES (AP) - Republican George W. Bush leads Democrat Al Gore by 8 percentage points in the race for president, according to a nationwide Los Angeles Times poll published Tuesday.
Bush, the presumed GOP nominee, now leads the vice president, the presumed Democratic nominee, among registered voters by 51% to Gore's 43%, the poll showed. Five% of respondents said they didn't know who to vote for.
The Times poll surveyed 1,211 registered voters between May 4-7. It has a margin of sampling error of plus or minus 3 percentage points.
The figures changed little when participants were polled on Ralph Nader, the Green party nominee, and Patrick J. Buchanan, the likely Reform party nominee.
In the four-way matchup, Bush drew 47% to Gore's 39%, with 4% for Nader and 3% for Buchanan.
Several polls recently have shown Bush with a slight lead in the race, but polling evidence has been mixed.
Gore and Bush were tied in a poll released Tuesday by the Pew Research Center for the People and the Press. Bush had 46% and Gore had 45% in the poll of 940 registered voters taken May 2-6. It had an error margin of plus or minus 4 percentage points.
In the Times poll, Bush, the Texas governor, drew 48% of female voters to Gore's 46%. Women have been a Democratic stronghold in recent years, with President Clinton leading by 16 percentage points among women in the 1996 election, exit polling found.
Among men, Bush leads Gore by 55% to 39%, and is even attracting about one-fifth of Democratic men.
Bush also has solidified a broad base of support among Republicans, while support for Gore among Democrats has weakened. Bush is winning about nine in 10 GOP partisans, while Gore is winning only five of every six Democrats, the poll said.
In addition, Bush is successfully courting centrist swing voter groups, who were crucial to Clinton's two victories.
Among Democrats who consider themselves moderates or conservatives, Bush is taking one in five voters, while Gore is winning only one in seven moderate Republicans.
Bush leads among self-described independents overall by 16 percentage points, the Times poll found.
© Copyright 2002 USA TODAY, a division of Gannett Co. Inc.


text:
Poll: Who are the ten best Naruto fanfic authors? Vote Now!
Author has written 5 stories for Naruto.
Age: Old enough to drink legally.
Gender: Male
Likes: Anime, Manga, and I've recently taking a liking to writing. and many more things
Dislikes: well lots of things :)
copy and paste:
FRIENDS: Never ask for anything to eat or drink.
FRIENDS: Call your parents by Mr. and Mrs. and Grandpa, by Grandpa.
FRIENDS: Would bail you out of jail.
FRIENDS: Have never seen you cry.
FRIENDS: Asks you to write down your number.
FRIENDS: Borrows your stuff for a few days then gives it back.
FRIENDS: Only know a few things about you.
FRIENDS: Will leave you behind if that is what the crowd is doing.
FRIENDS: Would knock on your front door.
FRIENDS: You have to tell them not to tell anyone.
FRIENDS: Are only through highschool/college. (aka: drinking buddies)
FRIENDS: Will be there to take your drink away from you when they think you've had enough.
FRIENDS: Would ignore this letter
╔═╦╦══╦══╦╗╔╦══╦══╗╔╗ x ╔╗╔╦══╦═╦╦══╦══╦══╗╔╗
Quote section updated 11/16/10
"There's a fine line between pride and stupidity and your border lining retarded!" Me
If you absolutely cannot stand the mere thought of Naruto and Sakura as a couple, copy and paste this into your profile.
If you believe that Naruto and Hinata are the greatest pairing, copy and paste this into your profile and add your name to the list: SilentSinger948, Leaf Ranger, Thymistacles, Tenshi Namikaze, Arashigan16, Gravity The Wizard, Kyuubi123, Kingkakashi, Zentary
If you think Masashi Kishimoto is ruining Naruto and agree, copy this, put it in your profile, and add your name to the list. The Fifth Rider of Armageddon, Hiroshima Namikaze, Zaara the black, desuta, Reikson, D-reaper X-20, blackstardragon624, chinoodin, The Silver Blossom, RasenganFin, Raidentensho, Knives91, Kingkakashi, DarkSamuraiX1999, THE HEE-HO KING, Wirespeed91, Naruto 21, GraityTheWizard, GuyverZero, durwin, Hakkyou no Yami, VFSNAKE, Stormrunner56, Haru Kitsune, DragonMaster4381, Demon Wraith, Leaf Ranger, Zentary
My view on harems.
I dislike harems I'll read them every now and then, but none of this 6 girls+ shit. 3 girls max, is all I'll read and I honestly don't care how good people say the story is. Harems are like the amount of Yaoi on this site. There is far to much of it and it gets old fast. I've actually seen a lot of people say the same thing about harems. There was one harem class manga that i loved reading and that was 'Love Hina' although that's because the main character loved only one of the girls. Most of the stories that concern harems on this site is that Naruto just tries to bed every girl in the harem which is honestly boring after a short while.
oh i hate Sakura so if she's in the harem I'm def not going to read it.


text:
Скачать Operating System Concepts - 7th Edition бесплатно
10 апреля 2009 | Автор: Admin | Рубрика: Компьютерная литература » Програм-ние и разработка » Программирование | Комментариев: 0
Operating System Concepts - 7th Edition - by Silberschatz, Galvin, Gagne
ISBN: 0471694665 | Publisher: Wiley | Publication Date: 2005 | Pages: 944 | Format: Pdf (scanned, no OCR) | 56 MB
Another defining moment in the evolution of operating systems
Small footprint operating systems, such as those driving the handheld devices that the baby dinosaurs are using on the cover, are just one of the cutting-edge applications you'll find in Silberschatz, Galvin, and Gagne's Operating System Concepts, Seventh Edition.
By staying current, remaining relevant, and adapting to emerging course needs, this market-leading text has continued to define the operating systems course. This Seventh Edition not only presents the latest and most relevant systems, it also digs deeper to uncover those fundamental concepts that have remained constant throughout the evolution of today's operation systems. With this strong conceptual foundation in place, students can more easily understand the details related to specific systems.


text:
super sixes
Who doesn't love a list? These are our pick of the best events from beginner triathlons to the toughest 10k's.
A challenging, multi-terrain course of 2.5 mile run, undulating 11 mile on-road cycle, 2.5 mile run. A relay is also possible consisting of teams of two people: one person doing both the runs and 1 person doing the bike leg. Please note that cycle helmets must be worn for the bike section.
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text:
Space Ship Wallpapers
by: Dena Irunckel • 0
All Android applications categories
by: Dena Irunckel • 0
Space Ship Wallpapers and Theme Application
An unidentified flying object, or UFO, in its most general definition, is any apparent anomaly in the sky (or near or on the ground, but observed hovering, landing, or departing into the sky) that is not readily identifiable as any known object or phenomenon by visual observation and/or use of associated instrumentation such as radar. These anomalies were referred to popularly as "flying saucers" or "flying discs" during the late 1940s and early 1950s.
This app will add a few search access points on your device. If you do not want to use this new search page, you can either ignore it or delete it. If you do use it, we get a few cents and it will help us a lot to keep developing more apps. If you don't, you can delete it and no harm is done (our app remains the same, no need to uninstall it!). Thank you.
Tags: space ship themes
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All Night Sweet Love Combo
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Monday, April 22, 2013
Happy Earth Day
These days, it's pretty crucial to do what we can to help the earth. Here are my favorite little ways to make a difference, listed out for MyHabit. Click on over HERE to read. xo
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User name:
Remember me.
Results ( 8 ) : 2016 - 1.
The Totalitarian Temptation Deliver Us from Evil
citation manager
Authors: S. Crosby
The New Police and Criminal Justice Data Protection Directive. A First Analysis
Authors: P. De Hert, V. Papakonstantinou
The European Court of Justice: A "Quasi-Constitutional Court" in Criminal Matters? The Taricco Judgment and Its Shortcomings
Authors: E. Billis
Abstract: A main task of the CJEU is to ensure the uniform interpretation and effective application of EU legislation. In the case Taricco and Others, the Court provides for the strengthening of the protection of the financial interests of the EU by emphasis...ing the immediate effect and precedence of primary EU law in criminal matters. At the same time, the CJEU functions as a quasi-constitutional court. It does so by ordering a national court to directly disapply domestic criminal law provisions on limitation periods in a pending case. Legality and legal certainty are at stake here. The judgment of the CJEU indicates, furthermore, the evolution of a "constitutional" relation between the EU judiciary and national criminal courts.hide
Variable Vulnerabilities? Comparing the Rights of Adult Vulnerable Suspects and Vulnerable Victims under EU Law
Authors: S. Van Der Aa
Abstract: EU instruments regulating the rights of adult vulnerable victims and vulnerable suspects differ in their conceptualisation of 'vulnerability'. The Victim Directive mainly focuses on persons who are vulnerable to secondary victimisation due to exter...nal factors, while vulnerability in the Recommendation on procedural safeguards for vulnerable persons suspected or accused in criminal proceedings hinges on endogenic factors, such as the suspect's mental or physical condition. The aim of the latter instrument is to remedy the suspect's inability to understand and to effectively participate in criminal proceedings. These different conceptualisations have resulted in different guarantees for vulnerable victims and vulnerable suspects. The Recommendation contains provisions that – once adopted in a victims' rights instrument – could considerably strengthen the current protection of vulnerable victims and vice versa. In order to provide for a more comprehensive protection the EU should embrace both perspectives in its dealings with vulnerable persons, regardless of whether they are victims or suspects.hide
The Concept of Criminal Law in the Opinions of the Advocates General: Justification of Punitive Powers and Human Rights
Authors: A. Rosanò
Abstract: The article deals with the definition of criminal law as developed over the last twenty years in the Opinions presented by Advocates General before the European Court of Justice. Two notions will be identified here. The first is linked to national ...experiences and the need perceived by every State to protect fundamental national values, as considered in several cases in the nineties and in the first years of the new millennium. The second– now prevailing – is the outcome of the phenomenon of cross-fertilisation between the case law of the European Court of Justice and the European Court of Human Rights, and appears to relate more to the protection of human rights. The article analyses single trials, starting from 1991, and aims at finding reasons why the second notion should be preferred in a legal system such as the European Union in light of its link to the European Convention on Human Rights and the relevance of the protection of fundamental rights in the European Union legal framework.hide
Victims with Intellectual Disabilities through the Spanish Criminal Justice System
Authors: J. Cendra López, M. Recio Zapata, A. Martorell Cafranga
Abstract: This research is the result of analysing twenty-nine cases of persons with intellectual disabilities who were victims of some type of mistreatment or abuse and who, after filing a complaint, were processed through the criminal justice system – not ...always with all the recommended support. The study analyses the experiences of these alleged victims of crime to determine the source and scope of the primary obstacles blocking their access to proper and effective protection under the law, in order to assess Spain's compliance with Directive 2012/29/EU of the European Parliament and the Council of 25 October 2012, which establishes minimum standards for the rights, support, and protection of victims of crime. Based on the report's conclusions, the authors formulate a number of recommendations for lawmakers.hide
The Limitation Period of Crimes: Same Old Italian Story, New Intriguing European Answers – Case Note on C-105/14, Taricco
Authors: F. Giuffrida
Abstract: Following a request for a preliminary ruling from an Italian judge, the Court of Justice of the European Union issued a groundbreaking decision in the Taricco case (C-105/14). In this judgment, the Court states that domestic judges are entitled, or... even obliged, to disapply national legislation on the prescription of crimes, when such legislation impairs an effective fight against frauds to the detriment of EU finances. This case note offers an overview of the most problematic aspects of this decision, as well as its implications at the EU level. Moreover, the effects of the Taricco judgment on the Italian system are briefly discussed, especially from the perspective of the possible violations of the principle of legality.hide
Exchanging Information on Road Traffic Offences: A Measure of Police Cooperation or Transport Policy? – Case Note on C-43/12 Commission v Parliament and Council
Authors: N. Vavoula
Abstract: The present case note examines the judgment of the CJEU concerning the legal basis of an EU instrument establishing an information exchange system for road-traffic offences (C-43/12 Commission v Parliament and Council). The case arose from the inte...rinstitutional battle between the Commission on the one hand and the Parliament and Council on the other, whereby the former considered that such a scheme forms part of the EU transport policy, while the latter opined that it constitutes a standard police cooperation measure. In this context, this case note maps the historical background behind the case from the release of proposal for a directive by the Commission to the adoption of a Framework Decision instead and the institution of infringement proceedings before the CJEU. Then, the conflicting opinions of the parties, the Advocate General and the Grand Chamber are analysed, followed by commentary.hide


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Aleena Moore is haunted by Jared Holt. It's been six years since she's seen her brother's best friend, the self-destructive bad boy she secretly loved in high school. As the years pass, she knows it's time to move on. Time to decide between a practical nursing degree and her true dream as an artist. Time to get over Jared and give another guy a chance…Just when she opens her heart to her friend, Gabe, Aly returns home to find Jared sleeping on her couch. The teenage boy she loved has grown into a man she can't resist.
A second chance at life. A second chance at love. Jared Holt never thought he deserved either - until he found both in the arms of Aly Moore. Aly has loved Jared for as long as she can remember, and she's more than ready for the future they're making together. But Jared can't help remembering his own family. And he'll never forgive himself for what happened to them. How can he allow himself the very happiness he once destroyed?


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Rich, creamy pumpkin risotto is gluten-free and vegan. I spiced it up with warm Indian spices and smoked sea salt. This is an easy, unusual side to bring or serve on Thanksgiving.
Stuffed portobello mushrooms
Serve these stuffed mushrooms either as an appetizer using smaller portobellas, or use 2-4 full-size portobella mushrooms for entree portions. Either way, it's a hearty, tasty dish with a nutty, savory filling. Read on for the surprise grain I used.
Pressed tofu satay
Pressing firm tofu creates a meaty texture that holds up to grilling like satay. Spicy sunflower seed sauce and Thai-style cucumber salad make for a refreshing meal.


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The Water Diviner
A father's love knows no bounds
The Water Diviner
Rating & Content Info
Why is The Water Diviner rated R? The Water Diviner is rated R by the MPAA for war violence including some disturbing images.This additional information about the movie's content is taken from the notes of various Canadian Film Classification boards:
- Portrayals of non-graphic violence.
- Brief explicit violence.
- Depictions of beating, shooting, stabbing, explosion and dismemberment.
- Frequent portrayals of hand-to-hand and weapons violence in a battlefield context, with blood and intense detail,
- Domestic violence.
- Gory and grotesque images.
- Upsetting and disturbing scenes.
- Some scenes may frighten children.
Sexual Content:
- Brief buttock nudity shown in a non-sexual context.
- Mild sexual references
- Infrequent use of scatological slang, vulgar expressions, and mild cursing.
- Limited use of slurs
Alcohol / Drug Use:
- Tobacco use.
Page last updated May 13, 2016
|Rating Descriptor
|British Columbia
|Not Recommended For Young Children,Violence, Language May Offend.
|Violence, Disturbing Content.
|Not Rated
|Canadian Home Video
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News About "The Water Diviner"
Cast and Crew
The Water Diviner is directed by Russell Crowe and stars Russell Crowe, Jai Courtney, Olga Kurylenko, Isabel Lucas .
This movie makes reference to one of World War I's most tragic Allied Troupes' defeats. Learn more about the Battle of Gallipoli.
Home Video
The most recent home video release of The Water Diviner movie is July 28, 2015. Here are some details…
The Water Diviner releases to home video on July 28, 2015.
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Russell Crowe also plays a concerned father in Cinderella Man and a vigilante in Robin Hood.


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text:
I MADE an early call on West Ham simply because Betfred's 7-5 on them to win at Sunderland looks too big.
I accept there's no such thing as an away banker in the Premier League but the Hammers have a 100 per cent record on the road having defeated big guns Arsenal, Liverpool and Man City.
A trip to Sunderland will hold no fears but will represent a different challenge. Slaven Bilic's men go there as favourites so how do they handle that and they should have more possession so less counter-attacking which they like?
On the upside for the Hammers is the fact Sunderland are rank rotten and rock bottom and boss Dick Advocaat must be wishing he'd quit in the summer.
Fabio Borini, Jermain Lens, Younes Kaboul and Yann M'Vila looked decent buys but haven't gelled and the defence is as solid as Celtic's featuring Efe Ambrose.
Dimitri Payet has been exceptional for the Hammers and Diafra Sakhko continues to bang in the goals. They've got pace to burn and I'm on the away as well as West Ham -1 Asian Handicap at 29-20 with 888sport. That's void if the Hammers win by one.
If goals bets are your preference the match to target is Norwich v Leicester. The Foxes are the only side in England whose matches have featured both scoring in every game.
Last week's 5-2 home loss to Arsenal could have been 8-5 but that's the way they play and Claudio Ranieri's offer of pizza for a clean sheet is likely to go begging another week.
Norwich have settled well into life in the Premier League and also score and concede. Back both teams to score at 8-13 with McBookie and over 2.5 goals at 3-4 with bet365. A 2-2 draw has a nice feel to it so try over 3.5 goals at 21-10 with McBookie.
Man City will be lifted by their first Champions League win in midweek and should take care of a Newcastle outfit they've beaten 5-0, 4-0 and 4-0 in the last three seasons at the Etihad. City minus two pays 13-8 at Paddy Power.
Chelsea are no gimmes at home to Southampton and I'm on both to score for the fourth season running at 4-5 (bet365).
I'd have backed Bournemouth if they hadn't lost star man Callum Wilson to injury. Glenn Murray's a ready-made replacement but isn't as good and I can see them drawing with a Watford side who lost 2-0 at Dean Court last season and drew 1-1 the year before.
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Inhibition of eIF2α dephosphorylation inhibits ErbB2-induced deregulation of mammary acinar morphogenesis
The ErbB2/Her2/Neu receptor tyrosine kinase is amplified in ~30% of human breast cancers. Phosphorylation of the translation initiation factor, eIF2α inhibits global protein synthesis and activates a stress signaling and growth suppressive program. We have shown that forced phosphorylation of eIF2α can suppress head and neck, colorectal carcinoma and multiple myeloma tumor growth and/or survival. Here we explore whether ErbB2 modulates eIF2α phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis.
We tested whether ErbB2 signaling influenced eIF2α signaling and whether enhanced phosphorylation of the latter affected ErbB2-deregulated mammary acinar development. We obtained stable MCF10A cells overexpressing wild-type (Wt) Neu/ErbB2 or a constitutively active (CA) variant via retroviral delivery or mammary tumor cells from MMTV-Neu tumors. Western blotting, RT-PCR and confocal microscopy were used to analyze the effects of ErbB2 activation on eIF2α signaling and the effect of the GADD34-PP1C inhibitor salubrinal. Wt- and MMTV-Neu cells formed aberrant acini structures resembling DCIS, while CA-ErbB2 overexpression induced invasive lesions. In these structures we found that CA-ErbB2 but not the Wt variant significantly down-regulated the pro-apoptotic gene CHOP. This occurred without apparent modulation of basal phosphorylation of PERK and eIF2α or induction of its downstream target ATF4. However, inhibition of eIF2α dephosphorylation with salubrinal was sufficient to inhibit Wt- and CA-ErbB2- as well as MMTV-Neu-induced deregulation of acinar growth. This was linked to enhanced CHOP expression, inhibition of proliferation, induction of apoptosis and luminal clearing in Wt-ErbB2 and to inhibition of cyclin D1 levels and subsequent proliferation in CA-ErbB2 cells.
Depending on the strength of ErbB2 signaling there is a differential regulation of CHOP and eIF2α phosphorylation. ErbB2 uncouples in basal conditions eIF2α phosphorylation from CHOP induction. However, this signal was restored by salubrinal treatment in Wt-ErbB2 expressing MCF10A cells as these DCIS-like structures underwent luminal clearing. In CA-ErbB2 structures apoptosis is not induced by salubrinal and instead a state of quiescence with reduced proliferation was achieved. Treatments that stabilize P-eIF2α levels may be effective in treating ErbB2 positive cancers without severely disrupting normal tissue function and structure.
The receptor tyrosine kinase ErbB2 is over-expressed in approximately 30% of human breast carcinomas
The initiation factor eIF2 participates in a rate-limiting step during the initiation of translation, namely the formation of the ternary complex (TC) and AUG initiation codon recognition. The role of eIF2α phosphorylation during transformation by oncogenes like ErbB2 is poorly understood. GTP-bound eIF2 interacts with the initiator methionyl tRNA to form a ternary complex (TC) followed by binding to the 40S ribosomal subunit. Phosphorylation of the α subunit of eIF2 at Ser-51 sequesters it in an inactive GDP-bound complex with its GTP-exchange factor, eIF2B, resulting in attenuation of translation initiation
Cancer cells can enhance general and preferential translation of specific mRNAs coding forproteins that stimulate proliferation or inhibit apoptosis (reviewed in
The role of eIF2α in oncogenesis has been established by studies which demonstrated that overexpression of a non-phosphorylatable mutant of eIF2α
ErbB2/Neu disruption of normal mammary acinar morphogenesis
We generated MCF10A cells stably expressing either a wild-type
Figure 1
Characterization of ErbB2 overexpression in normal MCF10A mammary epithelial cells
Characterization of ErbB2 overexpression in normal MCF10A mammary epithelial cells. (A) Phase-contrast micrographs (a, b, c) or representative DAPI-stained equatorial confocal sections (d, e, f) of acinar structures formed from stable MCF10A cells infected with retrovirus expressing empty vector or the wild-type rat Neu/ErbB2 (Wt-ErbB2) or the constitutively active V664E Neu/ErbB2 mutant (CA-ErbB2) after 8-9 days of growth in Matrigel. Scale bars = 20 μm. (B) Western blots of whole-cell lysates from monolayer cultures of MCF10A cells expressing empty vector, Wt-ErbB2 or CA-ErbB2 constructs probed with the indicated antibodies to downstream targets of ErbB2 signaling. GAPDH was used as loading control.
Effect of ErbB2 activation on basal eIF2α phosphorylation and expression of ATF4 and CHOP/GADD153
Using the model described in Fig.
Figure 2
ErbB2 overexpression does not modulate phospho-eIF2α signaling under basal growth conditions
ErbB2 overexpression does not modulate phospho-eIF2α signaling under basal growth conditions. (A, B) Western blots of whole-cell lysates from monolayer cultures of MCF10A cells expressing empty vector, Wt-ErbB2 or CA-ErbB2 constructs for phospho-and total PERK (A, top panels) or phospho- and total eIF2α (A, bottom panels) or ATF4. Total eIF2α or GAPDH was used as loading control respectively. Bottom panels depict relative intensities quantified by scanning densitometry and normalized to vector control. The averages of three or more independent experiments are shown; ± SEM. (C) Equatorial confocal sections of 10-day vector control (a) or wild type (Wt) ErbB2/Neu (b) or constitutively activated (CA) ErbB2/Neu (c) structures labeled with an anti-CHOP antibody (green) or DAPI nuclear stain (blue). Arrows point to CHOP-positive cells in the acinar structure. Scale bars = 25 μm. (D) Graph showing the percentage of cells per acinar structure that stained positive for CHOP. Values are representative of four independent experiments performed on different days (8-10) of growth in Matrigel; mean ± SEM. Statistical significance was determined using the unpaired t-test with p < 0.05 defined as statistically significant. N.S - not significant.
We next determined whether expression of the downstream target of eIF2α signaling CHOP/GADD153 might be modulated by ErbB2 overexpression in MCF10A cells. Acini that were grown for 8-10 days in Matrigel, when luminal clearing is initiated and apoptosis is evident
Salubrinal increases phospho-eIF2α levels and significantly restricts ErbB2-deregulated acinar growth
The downregulation of CHOP in CA-ErbB2 structures suggested that perhaps ErbB2 signaling uncouples eIF2α phosphorylation from CHOP induction and its growth inhibitory function. However, the cells might still be sensitive to higher levels of eIF2α phosphorylation. Thus, we next tested whether ErbB2 oncogenic signaling could be counteracted upon forced eIF2α phosphorylation or whether it might still bypass the growth inhibitory function of this pathway
Additional file 1
Supplementary figure 1. (A) Western blot for GADD34 from lysates of cells grown in monolayer conditions. GAPDH was used as loading control. (B) Graph showing viability of cells treated with vehicle or 10 μg/ml salubrinal in adhered conditions for the indicated time points, using Trypan blue exclusion. Points indicate average ± SD. (C) Graph showing the effect of salubrinal on 2D cellular proliferation. Cells were treated with vehicle or 10 μg/ml salubrinal in adhered conditions for the indicated time points before detachment and counting using a hemocytometer. Bars indicate average ± SD.
Click here for file
Figure 3
Salubrinal increases basal phospho-eIF2α levels and significantly limits ErbB2-induced acinar growth
Salubrinal increases basal phospho-eIF2α levels and significantly limits ErbB2-induced acinar growth. (A) Phase-contrast micrographs of control and ErbB2-expressing acini untreated (top panels) or treated with salubrinal (10 μg/ml) from Day 4-day 10 in Matrigel (bottom panels). Note the reduced acinar size of salubrinal treated ErbB2-expressing acini. Scale bars = 60 μm. (B) Western blots showing the increase in phospho-eIF2α levels in empty vector, Wt-ErbB2 or CA-ErbB2 cells untreated or treated with salubrinal under adhered monolayer conditions for the indicated time points. Total eIF2α was used as loading control. (C) Acinar volume was quantified on day 8 in Matrigel after daily treatment with salubrinal (day 4 onwards) for vector, Wt-ErbB2 or CA-ErbB2 acini. Acinar volume was estimated by measure two perpendicular diameters per acinus, assuming an ellipsoid structure. Between 50-100 acini were quantified and results are representative of experiments repeated at least three times. Statistical significance was determined using the unpaired t-test with p < 0.05 defined as statistically significant. (D) Graphs showing the distribution of acinar sizes over several volume ranges to depict the increase in acinar size upon ErbB2 activation, mean ± SD. Note that salubrinal treatment causes a shift in the percentage of acini falling within the smaller size ranges.
Differential proliferative and apoptotic responses to Salubrinal by Wt vs. CA-ErbB2 expressing acini
The decrease in acinar sizes observed with salubrinal could result from decreased cell proliferation, increased apoptosis or a combination of both. To test whether salubrinal caused a reduction in cell proliferation, vector, Wt and CA-ErbB2 acini were treated with salubrinal from day 4-10 in Matrigel, fixed and stained for Ki-67 (proliferation marker). The percentage of Ki-67 positive cells per acinus was estimated using standard immunofluorescence and LSCM
Figure 4
Induction of eIF2α phosphorylation by salubrinal inhibits ErbB2-induced hyperproliferation
Induction of eIF2α phosphorylation by salubrinal inhibits ErbB2-induced hyperproliferation. (A) Representative confocal images of equatorial cross-sections through day 10 vector control, wild type and constitutively active ErbB2 acini stained for Ki-67 (red) or the corresponding images stained with DAPI (blue). Untreated acini (panels a, c and e) and salubrinal treated acini (panels b, d and f). Note Ki-67-positive cells in the outer basal layer of cells in untreated vector control acini (outlined in dotted lines in some structures where edges are not obvious) compared to those occupying the central luminal space in untreated ErbB2-over-expressing acini. Scale bars = 40 μm. Inset (panel d) depicts a smaller salubrinal-treated Wt-ErbB2 acinus with many Ki-67 positive cells. (B) Graph showing distribution of the percentage of wt-ErbB2 cells per acinus that stained positively for Ki-67 at days 6, 8 and 10 (left panel) or phospho-H3 at day 6 (right panel); horizontal red line indicates the median. Statistical significance was determined using the unpaired t-test with p < 0.05 defined as statistically significant. N.S - not significant. Salubrinal treatment significantly decreases the percentage of Ki-67 positive cells in WT-ErbB2 acini only early at day 6.(C) Graph showing distribution of the percentage of cells per acinus that stained positively for Ki-67 cells; mean ± SEM. Statistical significance was determined using the unpaired t-test with p < 0.05 defined as statistically significant. N.S - not significant. Note the increase in percentage of Ki-67 positive cells in untreated CA-ErbB2 expressing acini compared to vector controls. Salubrinal treatment significantly decreases the percentage of Ki-67 positive cells in CA-ErbB2 acini.
In Wt-ErbB2 acini decreased acinar size could only be partially explained by reduced proliferation in response to salubrinal treatment. Thus, we tested whether apoptosis was being modulated by sustained eIF2α phosphorylation. In this case cleaved caspase-3 staining was used as a marker of apoptosis
Figure 5
Salubrinal treatment induces apoptosis and accelerates luminal clearing in control and wild type ErbB2 acini
Salubrinal treatment induces apoptosis and accelerates luminal clearing in control and wild type ErbB2 acini. (A) Two representative confocal images of equatorial cross-sections of day 10 vector control, wild type and constitutively active ErbB2 acini stained for cleaved caspase-3 (c-casp-3; green) or DAPI (blue). Untreated acini (panels a, c and e) and salubrinal treated acini (panels b, d and f). Note increase in c-caspase-3 stained cells within the luminal space in salubrinal-treated vector and Wt-ErbB2 acini. Scale bars = 25 μm. (B) Graph showing distribution of the percentage of cells per acinus that stained positively for c-caspase3; mean ± SEM. Statistical significance was determined using the unpaired t-test with p < 0.05 defined as statistically significant. N.S - not significant.
We next tested whether the effect of salubrinal was limited to the MCF10A model. Treatment with salubrinal of control normal mammary epithelial cells from FVB mice were grown in Matrigel. In these cells, like in parental MCF10A, salubrinal had minor effects on morphogenesis in 3D (not shown). Further, in agreement with our results in MCF10A cells overexpressing ErbB2, MMTV-Neu cells obtained from spontaneous tumors that arose in these mice formed dramatically enlarged structures devoid of proper tissue architecture and with a filled lumen (Fig.
Figure 6
Salubrinal normalizes the deregulated acinar morphogenesis of MMTV-Neu mammary tumor cells
Salubrinal normalizes the deregulated acinar morphogenesis of MMTV-Neu mammary tumor cells. Single epithelial cells isolated from MMTV-Neu mouse mammary tumors were grown in 3D organotypic/Matrigel cell culture over a period of 10 days. (A) Size of vehicle control (CTRL) and salubrinal 5 ug/ml treated acini was calculated following the equation [(Length × width2)/2 = acini volume (mm3)] and plotted; Mann Whitney test p < 0.0001, n = 30. (B) Representative confocal images of equatorial sections through control and salubrinal treated MMTV-Neu acini stained with DAPI at day 10 in Matrigel. Salubrinal treatment reverted the tumorigenic phenotype of MMTV-Neu acini by promoting formation of normal lumens in growth arrested acini (lower panel) as compared to untreated acini showing luminal filling and increased size (upper panels).
Salubrinal-mediated inhibition of acinar growth correlates with increased expression of CHOP and reduced cyclin D1 levels
We first tested whether salubrinal might affect total ErbB2 protein levels. Western blot analysis showed that salubrinal had no effect on ErbB2 protein expression or its downstream targets Akt and Erk1/2 (Fig.
Figure 7
Salubrinal may restrict growth by increasing expression of CHOP and suppressing cyclin D1 levels
Salubrinal may restrict growth by increasing expression of CHOP and suppressing cyclin D1 levels. (A) Western blots for total ErbB2, phospho-Ser473 and total Akt levels after 24 hr salubrinal treatment (10 μg/ml) of cells grown in monolayer conditions. GAPDH was used as loading control. (B) Graph showing quantification of the percentage of CHOP positive cells per acinus, mean ± SEM. Statistical significance was determined using the unpaired t-test with p < 0.05 defined as statistically significant. N.S - not significant. Note the modest increase in CHOP expression in salubrinal-treated vector control and Wt-ErbB2 acini but not in CA-ErbB2 acini. (C) Western blots (top panels) for cyclin D1 levels after 72 hr salubrinal treatment (10 μg/ml)of cells grown in monolayer conditions. GAPDH was used as loading control, N.S-non-specific band. Bottom graph, Cyclin D1 protein levels were quantified by scanning densitometry and normalized to GAPDH.(D) Schematic depicting the growth-inhibitory effects of increased eIF2α phosphorylation on aberrant acinar morphogenesis induced by ErbB2.
CHOP induction is dependent of eIF2α phosphorylation, mediates ER stress-induced growth arrest and apoptosis and can be up-regulated by salubrinal treatment
Cyclin D1 has previously been shown to be a major mediator of ErbB2-induced tumor cell proliferation and oncogenesis
We established a model where acquisition of phenotypes that resembled DCIS or invasive carcinoma can be mimicked by expressing the Wt-ErbB2 and a CA-ErbB2, respectively. In this model we set out to determine whether ErbB2 over-expression was linked to modulation of eIF2α phosphorylation and downstream pathway induction. Our results show that there is a dependence of ErbB2 signaling on eIF2α phosphorylation to promote deregulation of mammary acinar morphogenesis in 3D cultures. We found that both WT- and CA-ErbB2 did not significantly modulate basal PERK or eIF2α phosphorylation. Consistently, the expression of an eIF2α downstream target ATF4 also remained unchanged. Conversly expression of the ATF4 target gene CHOP, was decreased but only in invasive CA-ErbB2 expressing structures. Possible explanations for this uncoupling are that ATF4 activity may be reduced by ErbB2 signaling, that other transcription factors that regulate CHOP expression, such as ATF6
We found that as opposed to normal MCF10A or mouse MECs, ErbB2 overexpressing human or mouse (MMTV-Neu) MECs were very sensitive to enhanced eIF2α phosphorylation. This was supported by the fact that Salubrinal treatment and increased eIF2α phosphorylation strongly inhibited Wt- or CA-ErbB2 deregulation of MCF10A acinar morphogenesis. This was also evident in MMTV-Neu induced structures that cavitated and reduced their size upon Salubrinal treatment. However, depending on the intensity of ErbB2 signaling, salubrinal treatment achieved inhibition of the deregulated acinar morphogenesis via different mechanisms. In Wt-ErbB2 over expressing acini, which resemble structures observed in DCIS, salubrinal treatment was largely associated with early inhibition of proliferation (days 4-6) that was lost at later time points (days 8-10) of morphogenesis when a strong induction of apoptosis was detected. Interestingly, this apoptosis occurred mostly in the luminal population of cells, stressing the specificity of this signal to the luminal compartment. Notably, salubrinal treatment could accelerate the normal process of luminal clearing which fails to occur during ErbB2 oncogenesis
In CA-ErbB2 acinar structures, which resembled invasive lesions, salubrinal treatment also strongly inhibited growth but mainly through inhibition of proliferation. Apoptosis although induced, was of a much lower magnitude. Activated ErbB2 cells showed stronger activation of Akt signaling that was not affected by salubrinal treatment (Figs.
We recently showed that chronic inhibition of eIF2α phosphorylation by PERK dominant negative mutants in MCF10A cells results in acinar deregulation and hyperplastic benign growth
We conclude that while ErbB2 signaling does not seem to significantly modulate eIF2α phosphorylation at Ser51 tumor cells overexpressing this oncogene are highly sensitive to the effects of hyper-phosphorylated eIF2α levels. In contrast, normal MECs are marginally sensitive to Salubrinal treatment. We recently showed that doses of salubrinal that have no effect on basal multiple myeloma viability greatly sensitize these cells to bortezomib (Velcade) treatment in conjunction or after bortezomib treatment
Cell culture and generation of stable cell lines
MCF10A cells and the culture conditions in 2D or 3D cultures were described previously
Reagents and Antibodies
Salubrinal was obtained from Calbiochem. Anti-phospho-ErbB2 (pTy1221/1222), anti-phospho- and total PERK (P-Thr 980) and eIF2α (P-Ser 51), anti-phospho-Akt (Ser473), cyclin D1 and anti-cleaved caspase-3 were from Cell Signaling (Danvers, MA). Anti-total ErbB2 and anti-total Erk 1 was from BD Biosciences. Anti-ATF4, anti-CHOP/GADD153 (sc-575), anti-GADD34 and anti-phospho-Erk 1/2 were from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-Ki-67 was from Invitrogen (Carlsbad, CA) and anti-GAPDH from Calbiochem. Secondary antibodies were described previously
Western analysis and viability assays
Cells were washed with ice-cold PBS, lysed in RIPA buffer containing protease and phosphatase inhibitors (Roche) and processed for immunoblot analysis as described previously
Immunofluorescence and Laser Scannin Confocal Microscopy (LSCM)
Processing of MCF10A cells grown in 3D Matrigel for 8-10 days was done as described previously
Statistical analyses
Statistics were performed using MS-Excel or GraphPad Prism 5.0 software (San Deigo, CA) and P values were calculated using one-way ANOVA followed by the Bonferroni multiple comparison post test or the unpaired t test with p < 0.05 considered statistically significant. N.S = not significant.
eIF2: eukaryotic translation initiation factor-2; GADD: growth arrest and DNA damage-inducible protein; ER: endoplasmic reticulum; CHOP: C/EBP homologous protein.
Authors' contributions
SJS: developed transgenic cells, performed a majority of the experiments, interpreted the data and wrote the paper. WHC: performed experiments related to MMTV-Neu tumor and mouse MECs and to detection of Ki67 in WT-ErbB2 cells. AAV: performed experiments related to phospho- and total-PERK detection as well as detection of Ki67 and phospho-H3 in WT-ErbB2 cells. EFF: provided the MMTV-Neu transgenic model and participated in the experimental design and data interpretation of the experiments. JAAG: participated in conceptual and experimental design, interpretation of the data and writing of the paper. All authors read and approved the final manuscript.
We thank Drs. Antonis Kourtidis, Douglas Conklin (SUNY Albany) for assistance with the retroviral delivery system and Dr. Lisa Petti (Albany Medical College) for the retroviral ErbB2 constructs. We also thank Liliana Ossowski (MSSM) for critical reading of the manuscript. This work is supported by grants from the Samuel Waxman Cancer Research Foundation Tumor Dormancy Program (to JAG), the NIH/National Cancer Institute (grant CA109182 to JAG and grant CA119018 to EFF) and a New York State Stem Cell Science (NYSTEM) Grant to JAG.
HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review
Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene
The biology of erbB-2/neu/HER-2 and its role in cancer
Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors
Insights from transgenic mouse models of ERBB2-induced breast cancer
Modelling glandular epithelial cancers in three-dimensional cultures
ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini
The ErbB receptors and their role in cancer progression
A multifactor complex of eIF1, eIF2, eIF3, eIF5, and tRNA(i)Met promotes initiation complex assembly and couples GTP hydrolysis to AUG recognition
Regulated translation initiation controls stress-induced gene expression in mammalian cells
Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2
The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice
The role of translation in neoplastic transformation from a pathologist's point of view
HER2 signaling enhances 5'UTR-mediated translation of c-Myc mRNA
ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis
Translational control by an upstream open reading frame in the HER-2/neu transcript
Down-regulation of c-neu receptors by nerve growth factor in PC12 cells
A novel mechanism for integrin-mediated ras activation in breast carcinoma cells: the alpha6beta4 integrin regulates ErbB2 translation and transactivates epidermal growth factor receptor/ErbB2 signaling
Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes
Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells
Mutants of the RNA-dependent protein kinase (PKR) lacking double-stranded RNA binding domain I can act as transdominant inhibitors and induce malignant transformation
Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation
Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival
Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy
Transformation of mortal human fibroblasts and activation of a growth inhibitory pathway by the bovine papillomavirus E5 oncoprotein
Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene
Oncogenic activation of p185neu stimulates tyrosine phosphorylation in vivo
A point mutation in the neu oncogene mimics ligand induction of receptor aggregation
Diseases of the breast
The role of autophosphorylation in modulation of erbB-2 transforming function
The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini
PERK mediates cell-cycle exit during the mammalian unfolded protein response
Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression
A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro
Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis
Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway
Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II
Oncogenic Ras-mediated downregulation of Gadd153/CHOP is required for Ras-induced cellular transformation
GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor
Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway
Dominant negative retinoic acid receptor initiates tumor formation in mice


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Las Vegas Office of Snell & Wilmer Grows its Bankruptcy Practice Group by Adding Bob Olson
Bob Olson joins Snell & Wilmer's Bankruptcy and Reorganization practice group in their Las Vegas office.
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easy to get to the train station." Near to public transport, according to 100%." enjoyed the restaurants & bars nearby." liked the proximity to shopping." Great parking, according to 100%." City centre within easy reach, said 100%." liked the proximity to sightseeing."
wifi quality was great." great value."
staff to be very friendly." happy with the room service." service was very professional." Housekeeping was great, according to 94%."
rooms were small." Air conditioning was criticizedby 64%." too noisy."
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On Saturday 07 April 2007 18:50, Roland Weber wrote: > The safe way is a clean room implementation: let person A > analyse the GPLed code and write a specification of the protocol. > Then let person B, who never looked at the GPLed code, implement > the protocol "in a clean room", based exclusively on the spec > written by person A. How can the "specification of the protocol" not be derivative work, and there would also need to be GPL'd?? IP rights are not limited to a particular medium, form or format. Cheers -- Niclas Hedhman, Software Developer I live here; http://tinyurl.com/2qq9er I work here; http://tinyurl.com/2ymelc I relax here; http://tinyurl.com/2cgsug --------------------------------------------------------------------- DISCLAIMER: Discussions on this list are informational and educational only. Statements made on this list are not privileged, do not constitute legal advice, and do not necessarily reflect the opinions and policies of the ASF. See <http://www.apache.org/licenses/> for official ASF policies and documents. --------------------------------------------------------------------- To unsubscribe, e-mail: email@example.com For additional commands, e-mail: email@example.com
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Hotel Argos
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TripAdvisor Reviews Hotel Argos Oostduinkerke
Travel Blogs from Oostduinkerke
Waiting for the ferry, plus free entertainment
... the deck. Ouch. There's quite a lot of pushing and shoving. This is good entertainment. Can't wait for a car to get hit. There's a guy in a suit with them – must be the manager – holding a tall can of drink. I am guessing this is either Monster energy drink or beer. I hope it's beer because that would be just splendid.
Early morning
Today we were up at 1 am, ready for the dawn service. We were all layered, warm and ready to go. All was good when we arrived, but surely enough it started to rain and it got colder, to which we almost got hypothermia. After seeing our fellow ...
Poison in Paris
... br>
Instead, have a look at this 188cm idiot demonstrating how tiny the inhabitants of this city must have been in the recent past.
If that's not a desperate attempt at humour, I don't know what is!
Depending on whether I can get Wen out of bed, we'll talk from Ghent tomorrow.
In Bruges, Europe's Most Medieval City
... aesthetic. Eventually, the wooded areas give way to cobblestone streets and quaint buildings that suggest a time at least three centuries removed. The center of the city is even a UNESCO World Heritage Site. Maybe it's just an image that's upheld to maintain tourist interest (and it does interest tourists), but there's no denying that it's a beautiful environment to wander through.
After exiting the park, we stopped by the Begijnhof, ...
Delightfully Wonderous Bruges
... my favourite beer Leffe began that way.
As I wall through the perfectly preserved and manicured medieval town I am struck by how very spoiled I have been so far. It is extraordinarily beautiful. I had heard so much of the beauty of Brugge, the fairytale medieval city. And it is.
But it brings to mind Warsaw old town, a perfectly reconstructed medieval city in Poland next to whose beauty lurks a music scene that ...
Other places to stay in Oostduinkerke
Hof Ter DuinenAlbert I Laan 141, Oostduinkerke | 3 star hotelfrom $141


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The Guests
First Prince Albert wearinggrey slacks, black shoes with a white puffy styled shirt with a blue embrodered octagon that had a teardrop shaped diamond in the middle of it. He came with Princess Arica who was wearing a light grey dress with pale pink ruffle along the bottom and a pink embrodered rose under her shoulder. They carried a fairly large package wrapped in greenish colored tissue paper, which was the same color as their eyes and they both had short golden curly hair.
Next came King Johnathan wearing pale yellow slacks, light brown shoes, a deep dark orange short sleeved shirt and a shiny blue cape with red trim. Queen Shara was wearing a bright yellow dress with white dasies on the collar and grean leaves and stems connecting them. They carried with them a brown and yellow package.
After them came Prince Edward, he was wearing a white and blue striped shirt with dark blue pants which matched his eyes. With him came Princess Maria, she was wearing a rose red dress with a pink carnation embrodered below her right shoulder. They carried a shiny black package which matched their hair.
Then Prince Mathew came in wearing a pair of bunny rabbit brown pants and a sunshine yellow shirt. His hair was mousy brown and curly, his eyes were greeny grey and in his shirt pocket was a little orange package. Matt was helping William the priest wheel in a large wheelbarrow full of gifts. Will was wearing a long brown robe which matched his eyes and accented his blong curly hair.
After they all came up, placed their gifts by Cristy's chair (Matt and Will left the wheelbarrow by the throne) and curtsied or bowed to the royal family, they all sat down to a fair sized feast.


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Part One
Whoever lands on the role of Adam, must stick to whatever goes on.
Justin sends a text to Adam and Diego after school saying: Meet me at my place. Diego immediately gets the text and starts to head out of his house, Adam too. While Justin was waiting for the two to arrive, he reached over and grabbed the pills he had from yesterday. He was lucky his parents weren't home, if they found out about him having sleeping pills in his room they'd think he's suicidal, and he is way too cool to be suicidal. His body stiffened as he trudged downstairs to the kitchen.
Once he'd made it into the kitchen, he opened the cabinet and took out the small bowl and the thing meant for smashing pills properly. He then pulled come coke out of the refrigerator and set it down on the table. Letting out a heavy sigh, he began to pop open the pill bottle. His body began to heat up as he dumped them all into the bowl, then his left hand grew shaky as he picked up the stick.
Meanwhile, Diego was out running over to Justin's house. He was on the cross country team, so he'd probably be about three minutes earlier than Adam, who was getting dressed already. Justin was still in his kitchen, his pulse quickening while he was smashing the pills. Now Adam was out of the door, and Diego was at Justin's door. When he rang the doorbell, it startled Justin.
Justin brushed back his hair as he went to answer the door. Diego looked at him funny, as if he were just out of his mind right now. "Dude, you high?" He asked. Justin grabbed him by the shirt and pulled him in. "Do I look high to you?" He asked back, frowning. Justin was a mess. His eyes were baggy, his skin was whiter than snow, and some of his hair was messy. Diego shook his head, as though he were lying.
"Okay, let's go." Justin said, walking back towards the kitchen. Diego slowly followed him, wondering what was wrong with him. Just then, the doorbell rang again. (Now, play as Adam, be descriptive or no credit for you)


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London, Sept.8 : Formula One racing ace Lewis Hamilton has expressed outrage over him being sensationally stripped of his thrilling Belgian Grand Prix victory last night.
Hamilton received a 25-second penalty for cutting a corner in an amazing duel with world champion Kimi Raikkonen.
The British driver's McLaren team are trying to appeal the decision to rob Hamilton of a stunning victory after the FIA found him guilty of taking a short cut, reports the Daily Star.
Hamilton claimed it was "absolutely wrong" to hand him a retrospective 25-second penalty which demoted him to third place and gave the win to Felipe Massa.
It means Ferrari's Brazilian ace is now two points behind Hamilton in the drivers' championship.
The stipulated punishment is a drive-through penalty, which cannot be appealed, and the 25 seconds was considered appropriate.
Hamilton had taken the chequered flag more than 14 seconds ahead of Massa and McLaren boss Ron Dennis was last night seeking clarification over whether an appeal is possible.


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Andrew displaying his perfect comedic timing on Red Eye, early December 2009 with Loveline, Sex Rehab and Celebrity Rehab host Dr. Drew Pinsky:
"Dr. Drew? …..Um, I have a friend….."
Makes me laugh every time I see it:
Comment count on this article reflects comments made on Breitbart.com and Facebook. Visit Breitbart's Facebook Page.


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Need to give your dog some medicine? Just use reverse psychology.
Adam Rifkin stashed this in Dogs!
Stashed in: Best Videos, Psychology!, Pets!
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The trade-off is countless years of letting your dog disobey your "no" command.


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Photo by John Todd/ISIPhotos.com
By IVES GALARCEP
SEATTLE– Versatility is a trait that can boost any national team prospect's chances, and two players who have used their versatility to secure roles on the U.S. Men's National Team are Seattle Sounders teammates Eddie Johnson and Brad Evan.
When the U.S. take on Panama on Tuesday night in CONCACAF World Cup Qualifying, Johnson and Evans stand a very good chance of starting in front of their home fans at CenturyLink Field, and if they do, the chances are they will be playing positions they don't often play when they are wearing the rave green of the Sounders.
Evans has been one of the biggest surprises during the U.S. team's recent run of matches since taking over the starting right back role. Normally a midfielder for the Sounders, Evans has looked solid at right back in wins vs. Germany and Jamaica.
Johnson has played as a reserve in the team's recent matches, but he stands poised to earn a start against Panama, and there is a good chance he will be deployed on the wing, where his speed and ability to beat defenders one-on-one will come in handy against a Panama side expected to bunker in.
Evans' success at the right back position didn't come as much of a surprise to Sounders head coach Sigi Schmid, who broached the subject of Evans being a potential right back option with U.S. head coach Jurgen Klinsmann last year. Schmid has seen Evans ability to adapt to new positions all the way back to his days as U.S. Under-20 head coach.
"He's just one of the players that whatever position you put him in he just, tactically, plays the position pretty much the way it should be played," Schmid said of Evans. "The only other player I had like that a little bit was Sasha Victorine.
"I've played Brad at center forward. I've played him at centerback, right midfield, left midfield, center midfield, outside back," Schmid said. "Whatever position you put him in, he has a pretty good tactical understanding of what needs to happen there. He's good in a lot of areas.
"What's hurt him at times is he's probably not great in any one thing in particular, but he's so solid in everything else. He's going to fight and his ability to run and cover ground is also outstanding."
"It's just having a positive attitude and being a student of the game and recognizing that that's my role and embracing it," Evans said. "In year's past I really wanted to be a central midfielder, and I thought that's what I thought I was going to be in this league, but things change, lineups change, coaches change, and things like that."
When asked about his performances at right back to date, Evans sound like someone who was more concerned with improving than dwelling on what he has done well (such as his stoppage-time game-winning goal to beat Jamaica last Friday).
"I think I did a decent job in the first two games, and obviously can do better on a number of occasions, but that'll come with time playing the position and learning the position," Evans said. "Still a student, and still learning, but I'll always remember (those games).
"Missed passes. A little bit of timing. Tracking runners. For me it's endless. Those are things that I can remember from games. The ways that I can improve. Not necessarily the good things."
Johnson's versatility has also helped him on the national team. Ever since Jurgen Klinsmann deployed him on the left wing in the last round of CONCACAF qualifying, Johnson has blossomed into a regular contributor for the national team, with much of his time coming on the flank.
"When (Johnson) got the call-up with Jurgen to come into the national team one of the things we talked about is you've got to do whatever it is he asks you to do," Schmid said. "You don't want to say "No, I only do this" or "I only do that", and take away a chance for yourself. You want to get back into the mix, and once you're back in the mix things can happen."
Johnson has taken advantage of his chances to start on the wing, producing two goals and an assist in that role, including his memorable two-goal effort in a qualifying win vs. Antigua & Barbuda last year.
"I've played there and I've two goals and an assist from playing out wide," Johnson said. "We're in this camp for a reason. If the coach is putting me out wide, he does it for a reason, because he sees something in me, or sees that I can be effective out there against the opponent on that given day.
"I like playing with my back to the goal and then sometimes I don't like playing with my back to goal," Johnson said. "I just feel like out wide you get to see a lot more of the field. You get to get the ball in positions where you don't have someone up your back and you're able to play to your strengths.
"It's something I've worked hard at over the past couple of years and be more consistent."
With Graham Zusi suspended for Tuesday's match, Klinsmann could turn to Johnson either as a left winger or right winger. If he does play on the right, he could actually be partnered with Evans.
If the Sounders tandem is called on to start vs. Panama, the packed house at CenturyLink Field will be sure to give Johnson and Evans a warm welcome on a night neither is likely to forget.
"I've thought about it and being home will be something that's extremely special," Evans said. "Not many players get to experience something like this. My first cap as here with the Gold Cup, so I'll always remember that one, and this one, playing in a World Cup qualifier hopefully."
Did everyone forget that beas is normally a left mid and FJ has impressed more as a left back than his showings in the midfield?
Best possible line-up
Yeah, I've been wondering if I'm the only one who's been wondering about DMB and Johnson switching.
Barack Obama
I was wondering if other people wonder what I wonder, especially when i watch the Bolton Wanderers
Old School
I'm Old School and I approve this message.
Travis is Miami
Doesn't sound like you have to wonder about much these days. the answers are just a couple key strokes away.
I agree, maybe Corona for E johnson, idk about Evans but don't think we really have anyone else
Dig it! Right on, right on, right on.
davis for beasley to provide the same type of service that zusi has been providing from the right
OG are not good initials to have if you're a central defender. Call him Omar or something else. You might jinx him.
Forgive me, I am just starting to understand some of the tactical side of the game. If Panama bunkers, will there be space for EJ to use his speed? Seems to me that the offensive third will be compressed with, the defense laying very deep, and not much chance of getting behind anyone.
Your insights would be appreciated. I feel I'm missing something obvious..
My thinking is that the US will be very aggressive early on. Even more so than usual in a home game. With no Blas Perez, Panama's strategy has probably changed to become even more conservative than they were already going to be. I would say the counter to that would be for the US to be ultra aggressive from the start. If they are going to park the bus, make them do it for 90 minutes.
If that does turn out to be the US strategy, then I do think that EJ's speed can still be beneficial early on. I doubt that Panama is going to play 10 men back from the start, so I would say that EJ's speed has the best chance to pay off in the first 30 minutes or, when Panama is still daring to move forward before packing in the defense.
Honestly, even if it turns out that Panama does go the super conservative route and parks the bus early, then the threat of EJ's speed can still help by not allowing Panama to move forward on a counter.
The way I see it, speed will never be a negative. You are right that he might not have as many opportunities, but I think the best chance is to use it early on.
Speed will never be a negative, but it can be mitigated by packing it in and sitting deep. Johnson relies heavily on his speed to create, if Panama is parking the bus it's going to take more than a fast runner to break them down.
divers suck
If Panama chooses to park the bus, remember that Josy and EJ along with Dempsey are huge aerial threats also. You can only play so many players in the back before the hack game starts, leading to more set pieces and possibly PKs. There is really little good that comes out of parking the bus for 90 minutes….
Thats a great question. I think you're dead on, his speed in a tight final third is somewhat useless. By the time he gets up to speed he is dribbling the ball over the endline.
I think this is a big problem with this team. When we aren't clicking and playing more of a half court style (as opposed to counter attack ball) speed really does very little. Zusi is somewhat ineffective in this half court set up (the running Zusi and not the service Zusi). Players like Brad Davis become more effective since you have overlapping backs that are at speed and are difficult to track. Davis or Zusi can lay the ball off, bring the ball inside for a shot, or if they have space they have the ability to hit a decent cross. This really makes them effective. Know I know Zusi isn't playing and EJ may have to fill that roll His awareness in this situation kinda scares me, as does his service. Yes, he is athletic, but I think Americans overestimate that attribute. Just look at David Beckham. Not the most athletic player, won't dribble past people, but he's so smart it makes up for it.
That is my reasoning for not starting EJ as well, his speed will be pretty ineffective against a bunkered opponent. If I had to choose I would give corona the start.
Huh? If they bunker EJ's speed will be negated! The defenders will be sure to keep a line around both boxes. US needs wingers who can whip in an accurate cross or pick out open diagonal runs. Wingers who can hold and dribble in space and work combo passes in small spaces with Dempsey and Altidore.
Speed could be good for long balls but I expect the US to try and possess the ball. Without JJ those defensive third balls to the offensive third will be lacking.
EJ is great going forward in space, there is a reason he is the MLS
You guys are forgetting that Johnson is a big boy.
If you have a very technical team (like Barcelona) then that is your best option against bunkering.
But if you don't, you want to have a diverse attack.
You want to constantly change things up. Switch sides, short passes, crosses, and one on one dribbling.
We will probably find the most success with accurate crosses into the box. Altidore and Dempsey are both excellent headers of the ball.
But to keep the defenses honest, you want to threaten their flanks.
Of course, Johnson will get marked heavily when he tries to dribble into the box. But for every time he gets stripped cleanly, he will probably also draw a foul. This can set up excellent free kick situations for our big men. Also… if the same defenders keep fouling, they will eventually collect cautions, and will be forced to lighten their marking. A passer on one side and a dribbler on the other is never a bad way to go (see Giggs/Beckham).
Somewhat true, but EJ is also very good in the air, and if Panama is bunkering the US will likely have a lot of corners etc where he could grab a chance (more so than a guy like Corona).
also his speed could still create small 1 / 2s around the box to break the bunker.
The best guys at breaking bunkers are ones that are real crafty types/can create for themselves.
Something to be said for that, but I think that EJ's versatility can still be an asset. He is pretty good in the air, can play on both wings, and depending on the flow can easily move up as a striker in a 4-4-2 (moving Deuce to the right wing for a spell).
Corona might be a better RM/RW than Johnson, but that is all he is. If after 60 minutes, EJ isn't working I think it is a lot easier to bring in a Corona or Davis to do the things Johnson struggles with than vice versa, since when EJ would come in as a sub on the wing, Panama would probably be even more compact with the point closer in sight.
just as a quick counter to the why nots, a good quality in beating a bunker is aerial victories, and EJ brings that.
the thing that's intersting also is IF EJ starts out wide, what formation does Klinnsman choose? I don't think EJ has played that spot in a 4 4 2, at least not for the Nats. It's different than in a 4 3 3 or a 4 2 3 1 like he's been dployed in. not saying he can't do it but it's a different challenge, will truly test his versatility. I think he's best off the bench for this team tho, his versatility allowing Klinnsman options with how he uses him depending on how the game goes
If they compress and limit the space behind the D, he will still be useful as a physical presence in the box. He has great hops and an ability to use his speed to get open for crosses in the box. I wouldn't be surprised if he heads one in. If we can score first, they'll need to open up, which would be a great opportunity for him to use his speed in the open field.
Sure, but nobody gets higher up for headers than EJ however.
If it were up to Sigi, it would be Evans and 3 other players on the field, from the sounds of it.
Funny thing is, Brad played up front and attacking center mid in college. Great guy and hard worker. Zot Zot.
Barack Obama
how is that funny
I want to see 6 points from these next two qualifiers in June. We should handily defeat the Panamanians at home in Seattle, no points should be dropped at home, no excuses.
LIl' Zeke
While hopefully not applicable, I think myocardial infarction would be an acceptable excuse
Have you ever seen Panama play? This will not be a cakewalk.
Ricardo Estupinan
You are absolutely right,so fast they are becoming another football,(Soccer,or World Football) Nation.I'm just thinking it's going to be a tough game for the US.,but I'm not to worry,I'm confident in a good end result and waiting for the game to start.
People like to criticize Brad Evans, but that guy is SOLID. Someone who is tactically aware and can run all day should always have a place on the US Bench, if not on the field itself. Was a fan before, and am more so now.
Can someone tell me why Seattle is a turf field? Is it because it's multi-purposed with the Seahawks? I know it rains a lot, but England isn't exactly the desert, and they aphave figured out ways to keep a pitch playable in a soggy climate…
I'm not whining, I'm really curious.
Seattle Seahawks.
Dos a Cero
If Chelsea or Man U had their own American Football teams playing through the winter months at their stadiums they'd have field turf too.
There is apparently a real grass sod carpet that has been laid down over the artificial turf – it is a bit choppy, but serviceable.
I think its a question of how reasonable it is to keep maintained. The MLS and NFL seasons only overlap for a few games at the end of the year. But its not just soggy in the winters, its also actually very dry here in the summers. No one in the area tries to maintain grass fields here. All the schools and facilities (save for a few that only allow people to play on their grass fields a few months out of the year) have turf.
I was actually kind of angry when I went to the game on Saturday and saw the grass laid out. People were sliding all over and it was clear that the sod wasn't completely set. People knock on turf all the time but the new stuff that is coming out is really not that much different and isn't a major detriment to the quality of the game.
What IS a major detriment is rolling in these sod fields for a week and creating terrible surfaces for everyone. I would be very surprised if you don't see people sliding and falling all over tomorrow.
And by a few games at the end of the year, you mean the NFL preseason starts in Aug and the MLS playoffs run to Dec….virtually the whole NFL regular season and preseason.
Over the past two years the UW Huskies have also played their home games at CL, so you're talking about 14 games between September and January (plus some high school games). Additionally, the physical structure of the stadium is such that it blocks out a good portion of the little sunlight that Seattle gets. It also sounds like a lot of the measures required to install grass in CL would put the field out of commission for several months and as it stands the stadium gets pretty steady use year-round
You don't have to be good, you just have to be lucky, and hard working.
I would respectfully disagree in that being exceptionally good is the pre-requisite.
Andrew in tally
You guys are over thinking this. If panama bunkers in we are going need width,someone who can get past the Fb and cross. Ej is among the best one on one players on this team. He also has great chemistry with Dempsey. brad Davis has struggled to create space to cross the ball. Zusi finally started creating that space in the last two games.lets hope we can score at least twice before halftime. I am tired of one goal leads.makes me tired after watching the game.
That really stinks that there is an attendance cap!
No one at the the US Soccer Federation could have figured this out beforehand?!?!
We could have played Panama in Utah on the 11th and then Honduras in Seattle on the 18th when the Mariners are playing in Anaheim, CA!
This is also a lot of lost revenue!
Very poor planning. C'mon Sunil!
Hmm, the cap is there for the tickets are $100 each, rather than $50. 2/3rds or $100 is more than 100% of $50.
The Mariners 5k fans will not influence my decision as to when to leave for the game even by one minute.
If Panama bunkers, the US defense will not be often challenged for possession and that is a good thing for the US. Besler, Evans and Beasley have the speed to get back on counters and Omar can win a lot of the aerial balls into the box. I would be more worried if Panama came out with high pressure and tried to unsettle the back 4, MB and whoever starts for JJ (assuming the reported concussion will keel him out). Absent that pressure, MB and Evans can provide good long service and Johnson&Johnson can dribble at people.