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to be scared of getting married because I'm fat?(105 Posts)
I am losing some weight, trying to at least but I will always be on the bigger side my body doesn't lend itself to smallness, 5'8+ size 10 feet broad shoulder etc.
But I am dreading getting married as I am convinced everyone will be sneering and making comments about me and my dress or comparing me to my bridesmaids (much prettier) or my SIL (again much prettier) , I'm dreading the photos (even if I was skinny I look like a bulldog chewing a wasp).
I went shopping with DM the other month and spent the entire fitting talking about how good she would have looked in those dresses, and saying 'well you're on about loosing more weight aren't you?' I felt like I didn't want to get married coz well if my own mother can't make me feel okay and pretty on my wedding day I'm screwed.
I feel sick with worry and the whole idea makes me sick , dreading what should be the happiest day of my life and its got worse the closer I get.
I know this is a rant but I feel like I am going to erupt or runaway I need to spill somewhere. please diplomatic I'm on the verge of tears atm.
Do I need a shake, AIBU to dread my wedding day and think everyone will be sneering at me?
I've been to 2 weddings recently with larger ladies. Both looked absolutely stunning. Pick a beautiful dress, have an amazing hairstyle and wear beautiful jewellery and makeup and you will look fantastic, believe me. One of the weddings I went to the bride had her beautiful long hair in a top bun, all plaited around the bun. She was gorgeous.
I had negative comments about my dress from my parents. They said it wasn't what a wedding dress was supposed to look like. It was a 2-piece, duchess cream satin, long sleeved dress from Ritva Westenius. It was stunning!!!! I remember sitting in the changing room crying because they totally spoilt it for me and a really nice lady popped her head round and said, honestly love, you look fantastic in that dress. It was made for you.
I love weddings but I never attend them for fashion. Normally they are fashion free zones with shrugs and satin galore
Anyone even vaguely fashionable looks out of place and is whispered about as "odd"
I've always gone to weddings to wish the couple well and have fun. The food is 90% gopping. The wine is almost always warm or of the cooking variety.
For all future reference Mothers are insane. Mad a snakes around weddings and during wedding planning.
So what if you are fat and tall.
Or short and skinny
So what! My best bet is that you are what you are now and you'd be better embracing that than hating yourself or feeling self conscious
Wear what you like and what you think looks nice and is comfortable
To be brutally honest lots of brides look beyond daft on their wedding day(s) It has nothing to do with height or girth. We all just go a bit dolally. Very crazily stylish people I know would have looked better in onsies than the dresses they wore. My problem was my hair and make up, whilst lovely in the comedically expensive photographs, made me look like it was covering a beard on the day.
I was married twice and looked a fright on BOTH occasions. I wish I had had the confidence to just be me.
Focus on having the most cheesy wedding disco of all time that's the good stuff to remember
Please tell your mother how she made you feel. she should feel awful she made you feel that way; it wasn't very nice and she should think twice about doing it again. You are going to be a beautiful bride and your fiance's jaw will drop when he sees you at the altar because he thinks you are gorgeous.
Broad shoulders are GREAT- they mean you are an hourglass and can work the whole va-va-voom thing, and not an apple, which is harder to dress.
And on the bridesmaid thing, my gorgeous sister was my bridesmaid. She was stunning. However, only one person said to me that she "showed me up" and it was such a wankerish thing to say that it was easy to write him off as an idiot from then on. It's such a rude thing to say that it is easier for it to be "water off a duck's back" IYSWIM?
Have a wonderful day!
Lisanthus- that is awful, I hope you slapped them did they say it to your face? truth be told I can guarantee someone will say that to me.
Ex ratty, I hope I don't look too daft I'm having soft curls no tiara! and I'm doing my own make up so fingers crossed,
Aw that shopper was nice.
If she brings up dresses etc I think I will mention it it may sow a seed, the seamstress was nice but kept mentioning it was a 'bigger dress' 'you need some underwear to do the job'
and a pattern she picked up in my measurements were waaay bigger than my normal dress size and announced it loudly pfft.
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Cool place, good bar, great drinks and paintings that keep an eye on you! Recommended any day of the week. It's got a nice Art Deco feel to it with redwood paneled walls.
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. . .you have to have style. Being a trendsetter, good looking, and gainfully employed is key here. Drinks are not cheap and after parking or valet, you are on your way to spending a couple hundred easy. Now if you throw in reserving a table, it's an expensive night, but well worth it. This is a must-see in San...
One of my favorite bars in San Francisco. Enjoyed a Smokey Guava Margarita with some fries and just felt divine! A MUST in San Francisco.
We went to the Redwood Room on Dec. 29th 2014. Having flown in that day we didn't feel like venturing out too far but rather to get settled into our suite.
The food was okay but with the Velvet Room now not open you can tell that the wait staff was a bar/lounge staff and not food. My med. rare...
I like the dark, widely separated seating alcoves. The drinks were actually made off site and the actual bar counter and display case for the liquor were empty. Maybe there were cleaning/remodeling?? Still, a comfy place to have good drink in an old world setting.
Great bar to kick back in and relax. Every trip to San Francisco, this is now on the place to go list. The decor, the vibe, great music to relax and have a good night. Looking forward to my next trip so I can kick back at Redwood Bar and The Clift.
I make at least one visit to the Redwood Room every time I'm in SF. It's a great place to take friends, and I've never seen it less than vibrant. Great, old-school decor, friendly staff and great drinks make a bar. There's no real pretense here, either, although there certainly could be.
Must see when in SF. Check out the...
Love this place. VERY high ceilings with redwood pillars give it that "I'm in a forest" (or large log cabin) look and feel! lol. It also looks like an old Library but without the books. Great electronic portraits on the wall which every now and then wink at you or move making it feel a little like hogwarts from harry...
Went here for a cocktail before enjoying a play at ACT. The lounge is beautiful, quiet though busy, and the cocktails we ordered were perfect. Pineapple Express and the Razz-Mary. This will be one of my requested must-do's now!
We had a quick cocktail at The Redwood Room, having seen it recommended as one of the best bars in the city. It's certainly an impressive room, art deco styling and modern moving art framed pictures combining to unusual effect. As one would expect it was quite expensive but the drinks were good and the service attentive. Worth a visit.
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Ownage Pranks called a guy who was selling his Acura TSX. He absolutely hates getting low offers for his car.
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Scandal Links
This page will direct you to the latest news and best sites about ABC Network's Scandal show
About Scandal
When you get into trouble – life-ruining, headline-making trouble – there's only one person to call … Olivia Price. Olivia (Kerry Washington) is a professional Fixer who makes problems go away before anyone even knows they exist. For the moneyed, the powerful and even the President, Olivia is a legend in her field. Her spectacular success is mostly due to her unbreakable rule of always trust your gut. No matter how careful you are, when you do damage control for a living, you're bound to cause some damage to your own life.
News Articles about ABC Networks Scandal
TV Guide 5/20/15 Mega Buzz: Could Huck Team Up with Rowan on Scandal?
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TV Guide 5/15/15 Scandal's Guillermo Diaz on Huck's Fate: Part of Him Wants to Die
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Randall Hoven at The American Thinker has a thought or two on that question."Everyone knows" there were no Weapons of Mass Destruction (WMD) in Iraq when Bush decided to invade in 2003. If there were any doubts about that, surely they were laid to rest by the Duelfer Report, the official findings of the Iraq Survey Group (ISG) headed by Charles Duelfer, Special Advisor to the Director of Central Intelligence.Take your pick of excerpts from Duelfer's report.• On nuclear weapons: "Saddam Husayn [si … [Read more...]
No WMD? Hang on a second!
The Joyful Face of Freedom
Our friend over at Mystery Achievement has a picture that you really must see. It speaks volumes about the joy the Iraqi people are taking as they exercise their right to vote - a right taken for granted by too many in this country, a right too frequently perverted, as we have seen in Wisconsin and Washington State, and elsewhere.The face of freedom. What joy!You cannot look at that face and believe that any of our troops died "for nothing" as John Kerry would say.You cannot look at that face … [Read more...]
A letter from Baghdad, and related items
From Sgt. Thomas Foreman Jr. writing from the center of the storm:Every Iraqi I talk to has hope. I've written several times on the power of hope, and right here is a living, breathing 24-million-strong testament to it. As long as some hope endures for the Iraqi people, my time here will not have been wasted.It will not be perfect. This very well could be the most dangerous period we face while we are over here. There will be some violence against election workers, voters, even the candidates … [Read more...]


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Former QU Men's Ice Hockey Stand-out Jeremy Langlois Signs One-Year Contract With NHL's San Jose Sharks June 29, 2015 Former Quinnipiac men's ice hockey stand-out Jeremy Langlois signed a one-year deal with the National Hockey League's San Jose Sharks, as announced by Sharks General Manager Doug Wilson on Saturday, June 27, 2015. | Read Full Release
QU Men's Ice Hockey's Matthew Peca Highlighted On CollegeHockeyInc.com May 26, 2015 Former Quinnipiac men's ice hockey captain Matthew Peca was featured as a player to watch in the National Hockey League in 2015-16 by CollegeHockeyInc.com. The article "Smaller Stars Shining in NHL" discusses the success of professional... | Read Full Release
Quinnipiac Men's Ice Hockey Announces Class of 2019 May 21, 2015 Quinnipiac University men's ice hockey head coach Rand Pecknold has announced the Bobcats' incoming class for the 2015-16 season. Pecknold welcomes six freshmen to his squad that returns 21 players from the 2014-15 season that qualified... | Read Full Release
Quinnipiac Men's Ice Hockey's Soren Jonzzon Named To Capital One Academic All-District 1 Men's At-Large First Team May 15, 2015 Quinnipiac men's ice hockey junior Soren Jonzzon (Mountain View, California) was named to the 2015 Capital One Academic All-District Men's At-Large NCAA Division I First Team, as selected by the College Sports Information Directors of American... | Read Full Release
Shameal Samuels Women's Outdoor Track & Field Women's outdoor track and field junior Shameal Samuels was named Quinnipiac's May Female Athlete of the Month.
Vincent Guglietti Baseball Senior Vincent Guglietti was named Quinnipiac's May Male Athlete of the Month.


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Plum is located in Allegheny County, PA. On this city guide, you will find all kinds of helpful information about hotels, real estate, careers and much more.
Searchers recovered more bodies Friday, a day after a passenger ferry capsized shortly after leaving port in the Philippines, killing 59 people, authorities said. The Philippine coast guard said 140… Sat, 04 Jul 2015 03:26:43 GMT
Officials with the 3 Rivers Regatta have announced that they are cancelling all water activities due to disappointing and dangerous river conditions. Fri, 03 Jul 2015 22:47:57 GMT
A Nebraska girl who died of brain cancer Tuesday at age 3 helped save the lives of two Pennsylvania children through organ donation. Fri, 03 Jul 2015 22:44:40 GMT
There are 20 apartments found in and near the Plum area.


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2014 could go down as a "breakout" year for Kentucky's economy. Economists and workers in about every occupation imaginable were waiting for the effects of the "Great Recession" of 2008 to fade. State Economist Manoj Shanker says a significant uptick has happened over the past eleven months. Shanker says he has been expecting growth and recovery in the Kentucky labor market for the last two years, but it just hasn't happened. "This year, suddenly things aligned themselves just right, and it did take off," said Shanker.
As this week's rainfall has knocked many leaves off of trees, Lexington leaders Tuesday got a briefing on this year's leaf collection efforts. As in past years, vacuum trucks will roll through Lexington neighborhoods. Streets and Roads Director Rob Allen says a new interactive map is now available so residents can know when to expect leaf pickups. "Citizens will now know their subzone in a more accurate start time for collection, so the leaves don't sit on the grass, kill the grass, turn to mud, blow in their neighbors yard," said Allen.
State tourism officials are always working to make Kentucky a common vacation destination. The Commonwealth will next week be a popular site for golf fans.


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Director Craig Brewer's remake of the '80s dance classic Footloose opens in theaters today (you can read our review of the film HERE as well our interview with Brewer HERE). Perhaps the most challenging role to cast for the remake was the one that catapulted Kevin Bacon into super-stardom – back when the original film was released.
The role of Ren Mccormack in Brewer's re-imagining eventually went to Boston dancer Kenny Wormald. Wormald had been a back-up dancer for Justin Timberlake and when the casting directors for Footloose asked J.T. for a recommendation he immediately passed them on to Wormald.
Take a look at the interview below.
Red Carpet Interview with Footloose Star Kenny Wormald:
For those who are unfamiliar, here is the official synopsis for Footloose 2011:
Writer/Director Craig Brewer ("Hustle & Flow," "Black Snake Moan") delivers a new take of the beloved 1984 film, "Footloose." Ren MacCormack (played by newcomer Kenny Wormald) is transplanted from Boston to the small southern town of Bomont where he experiences a heavy dose of culture shock. A few years prior, the community was rocked by a tragic accident that killed five teenagers after a night out and Bomont's local councilmen and the beloved Reverend Shaw Moore (Dennis Quaid) responded by implementing ordinances that prohibit loud music and dancing. Not one to bow to the status quo, Ren challenges the ban, revitalizing the town and falling in love with the minister's troubled daughter Ariel (Julianne Hough) in the process.
Footloose opens in theaters today, Friday, October 14th.
Craig Brewer directs a cast that includes Kenny Wormald, Julianne Hough, Dennis Quaid and Andie MacDowell.
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This is a DELICIOUS basic recipe. I have been doing a similar one for years. I also, prefer adding a few more spices TO THE BREAD CRUMBS,like basil, oregano, garlic powder, salt, fresh cracked p...
This was an extremely easy, very tasty recipe. As many others suggested, I only put sauce on the bottom of the chicken and then spooned a little over the top when serving. I think the recipe c...
I BRINED my chicken in 4 cups water , 1/2 cup kosher salt (1/4 table salt) ½ cup sugar for 30 minutes. No need to brine if you are using quick frozen chicken that has been enhanced. Kosher chick...


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Your Life: For teen addicts, life after rehabilitation requires support
On Oct. 9, the Oklahoma Outreach Foundation will host a fundraiser. Keynote speaker for the event will be former NBA and Boston Celtic star Chris Herren, whose career and life have been affected by alcohol and drug abuse. Tickets are available. Donations are tax deductible.
Teenage drug and alcohol abuse is not a problem that affects one family. It affects our community. You can help by supporting this organization, which believes with love, perseverance and a strong knowledge of the disease of addiction, families can heal.
Charlotte Lankard is a licensed marriage and family therapist in private practice. Email her at firstname.lastname@example.com.


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Mario Lopez gets his body painted gold for an underwear photo shoot.
You know it's a going to be a good week when Chrissy Teigen is getting naked on a Monday.
Magic Mike XXL is almost here! In honor of the movie's upcoming release date, we've picked Channing Tatum as Celebuzz's #ManCrushMonday!
Kim Kardashian left her bra at home this weekend. …


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Video: Armed law student's argument with police goes viral
A law student – who was apparently visibly toting a gun around town – is seen on a mobile phone video arguing with police
Editor's Note:
Editor's Note: We've seen this movie before. These cops did a great job. They were reasonable and professional and knowledgeable. After you read the short news item, I encourage you to check out my commentary on this encounter in particular, on this issue in general, and on the Top 10 things to keep in mind about encounters with open carry advocates.
— Doug Wyllie, PoliceOne Editor in Chief
By PoliceOne Staff
Video taken from a student's mobile phone shows a conversation develop after he was stopped by an officer who had received calls of concern from the public.
The footage starts with the student stating that he does not consent to any searches or seizures.
The officer calmly responds, "I'm not going to search you," and asks permission to take the gun so that they can have a conversation.
The dialog escalates as the student refuses to give the officer any identification and demands to speak to a supervisor, as he cites several legal cases as reasons that he cannot be stopped for carrying a gun unless suspected of committing a crime.
The squad in the background of the video indicates that the police are from Portland, Maine, though that has not been confirmed.
The student is eventually given his gun and allowed to leave.
Recommended Patrol Issues
Police warn public against using iPhone cases shaped like guns
FBI: No civil rights violations in Calif. shooting of teen carrying replica AK-47
Join the discussion
PoliceOne top 5
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- 5 Former LA cop involved in OIS shares lessons on deadly force


text: We booked here for its close proximity to the train station. It's close to the town centre and has lots of shops near by . Debbie was very welcoming and friendly . Good parking at the rear of the property. It's on a main road , our room was downstairs and we didn't hear any traffic noise. The room was... More


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ASSAULT Read the full story here http://www.mv-voice.com/story.php?story_id=5718 posted Friday, December 25, 2009, 12:00...Original post made on Dec. 24, 2009
Last comment by The Eye, on Dec 24, 2009 at 3:18 pm | 1 comment | 1708 Views
SCHOOLS & KIDSWriting better with a buddy
For more than a decade, young students in Mountain View have been working on their literacy skills with local seniors in...Original post made on Dec. 24, 2009
Last comment by Tony Fanning, on Dec 24, 2009 at 3:53 pm | 1 comment | 1890 Views
AROUND TOWNWinning lottery ticket still unclaimed
A winning California Lottery MEGA Millions ticket worth more than $150,000 remains unclaimed a month after it was purchased...Original post made on Dec. 28, 2009
Last comment by , on Dec 28, 2009 at 5:45 pm | 1 comment | 1947 Views
OTHER ISSUESHoliday Fund helps domestic violence victims
The holiday season can make a bad situation even worse for a battered woman, say staff members at Support Network, a Sunnyvale...Original post made on Dec. 30, 2009
Last comment by Claudia Hevel, on Dec 30, 2009 at 12:28 pm | 1 comment | 1747 Views
AROUND TOWNArrest warrant issued in foundation theft case
An arrest warrant was issued Dec. 24 for a former Silicon Valley Community Foundation employee suspected of stealing $100,000...Original post made on Dec. 30, 2009
Last comment by Tom Delany, on Dec 30, 2009 at 2:55 pm | 1 comment | 1587 Views
AROUND TOWNMartello takes interim gig in Los Gatos
Mountain View city attorney Michael Martello was all set to retire at the end of December, leaving public service behind...Original post made on Dec. 30, 2009
Last comment by the299crew, on Dec 30, 2009 at 2:46 pm | 1 comment | 1700 Views
AROUND TOWNMountain View's top 10 stories of 2009
Like most California communities, Mountain View felt the pain when the nation's and the state's economies fell apart in the...Original post made on Dec. 30, 2009
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OTHER ISSUESAnalysts: Guv's goals appropriate, but unlikely
In his State of the State address Wednesday, Gov. Arnold Schwarzenegger discussed prisons and priorities while pushing a...Original post made on Jan. 7, 2010
Last comment by Doug Pearson, on Jan 7, 2010 at 11:32 pm | 1 comment | 1636 Views
OTHER ISSUESTop high speed rail executive to retire
Mehdi Morshed, the executive director of the California High-Speed Rail Authority, announced Thursday that he will retire...Original post made on Jan. 8, 2010
Last comment by Rodger, on Jan 8, 2010 at 5:18 pm | 1 comment | 1665 Views
OTHER ISSUESThe buzz on caffeine
Recently, you may have picked up the newspaper or turned on the TV news to see yet another report about caffeine. The debate...Original post made on Jan. 12, 2010
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AROUND TOWNCouncil kills grocery store proposals
Hopes for a new downtown grocery store were diminished Tuesday night when the City Council rejected two proposals for building...Original post made on Jan. 15, 2010
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AROUND TOWNCities work to stop another state money grab
Last year, state legislators ordered California cities to cough up millions to help them make up a huge budget shortfall....Original post made on Jan. 15, 2010
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OTHER ISSUESSecond $50,000 match offered for Haiti relief
A local drive to raise $50,000 to help victims of the Jan. 12 earthquake in Haiti has been accomplished, the Silicon Valley...Original post made on Jan. 18, 2010
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AROUND TOWNHeavy rain, high winds expected to last
Monday's heavy rain and high winds are expected to last through the week and bring nearly 10 inches of rain to the Bay Area,...Original post made on Jan. 19, 2010
Last comment by HandyAndy, on Jan 19, 2010 at 9:04 am | 1 comment | 1596 Views
AROUND TOWNKing Tuttles
Four members of The Tuttles with AJ Lee — a five-piece bluegrass group playing this weekend at First Presbyterian Church...Original post made on Jan. 24, 2010
Last comment by Anonymous, on Jan 24, 2010 at 1:02 am | 1 comment | 1744 Views
OTHER ISSUESStolen car crashes in Los Altos, driver flees
An unidentified driver fled after crashing a stolen car into a tree in a residential Los Altos neighborhood early Sunday...Original post made on Jan. 28, 2010
Last comment by anonymous resident, on Jan 28, 2010 at 9:37 pm | 1 comment | 1680 Views
OTHER ISSUESAlvarez case: 'Evil killer' sentenced to death
Convicted cop-killer Alberto Alvarez showed little emotion in a packed Redwood City courtroom Monday morning as a judge handed...Original post made on Feb. 9, 2010
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AROUND TOWNLos Altos police seek man in July sex assault
Police in Los Altos are investigating the sexual assault of a teenage girl while she was out jogging in July 2009. Read...Original post made on Feb. 18, 2010
Last comment by clyde, on Feb 18, 2010 at 1:50 pm | 1 comment | 1328 Views
OTHER ISSUESCouncil to consider Pot Club ban again
Mountain View (acting) City Attorney Janie Quinn (of San Jose) has submitted for vote an ordinance banning Medical Cannabis...Original post made by B.D. on Feb. 22, 2010
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AROUND TOWNEl Camino Hospital board member steps down
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La Roche-sur-Foron Vacations
La Roche-sur-Foron is within easy reach of many of Annemasse's attractions. Among the most interesting places to explore are the marvelous Grand-Bornand Ski Lift and the remarkable La Patinoire Ski Lift. And don't miss the Beauregard Ski Lift and the Cret du Merle Ski Lift.
There are many sites and attractions to visit near La Roche-sur-Foron. Be sure to set aside enough time to see as many as possible during your visit. Notre-Dame-de-Liesse Church in Annecy offer those exploring Annemasse the opportunity to better understand the religious history of the area.
One of the best ways to experience the great outdoors is to grab your golf bag and head to the area's challenging golf courses like the Serves Golf Club in Saint-Genis-Pouilly and the Lake Annecy Golf Course in Talloires.
If you enjoy skiing and snowboarding, round up the family and head to the La Clusaz Ski Resort in La Clusaz, the Morillon Ski Resort in Morillon and the Gentianes Ski Lift for the best slopes around La Roche-sur-Foron.
Finding somewhere handy to stay within La Roche-sur-Foron is easy. The Holiday Inn Express Geneva Airport, Meyrin, the Hotel Royal, Geneva and the Hotel Auteuil, Geneva are just some of the best places to stay while you are enjoying this special area.


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Semin, Staal lead Hurricanes past Sabres, 4-3 - 0 Comments
RALEIGH, N.C. — The Carolina Hurricanes' top line made things easier for Justin Peters in his first game filling in for injured staring goalie Cam Ward.
Alexander Semin had a goal and two assists, linemate Eric Staal added three assists and the Hurricanes beat the Buffalo Sabres 4-3 on Tuesday night.
Carolina was playing for the first time since Ward went on injured reserve following a torn MCL that will require a recuperation of six to eight weeks.


text: Diversions Yoga Twists Its Way to Olympic Spotlight June 27, 2008 Competitive yoga is trying to shove its way into the Olympic spotlight. But not all practitioners agree that it's a good idea for yoga. April Baer of Oregon Public Broadcasting reports on the raging debate in the yoga community. Listen Loading… Playlist Download Embed Embed Close embed modal <iframe src="http://www.npr.org/player/embed/91975547/91975514" width="100%" height="290" frameborder="0" scrolling="no">


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Rep. Robinson selected for Emerging Leaders ProgramJune 22, 2015
Rep. June Robinson
The Milbank Memorial Fund and the Reforming State Group have selected Representative June Robinson to participate in the 2015 Emerging Leaders Program. The program helps legislators gain skills and policy tools that are essential to advocating for healthy communities. Participants from a wide variety of backgrounds are accepted in to this program, including legislators and executive branch officials with experience in medicine, law, and finance. Rep. Robinson will represent Washington as a legislator and bring her experience working in public … Continue reading
Keeping people with mental illness out of emergency roomsJune 16, 2015
Rep. June Robinson
Mental illness affects us all – we all know someone, or have ourselves, been touched by mental illness. Everyone deserves to be treated with respect and dignity, including our family members, friends and neighbors who suffer from mental illness. When a person is experiencing a mental health crisis, we know that getting them appropriate treatment is important. Instead of ending up at specially created facilities that have the resources and support to address mental health issues, too many people end … Continue reading
A consequence of the personal belief vaccine exemptionJune 12, 2015
Rep. June Robinson
Recent reports show that nearly 11 percent of kindergarteners in Washington do not have up to date vaccination records on file with their schools. In this KOMO News report, Rep. June Robinson discusses the personal belief exemption and her work to increase immunization rates in Washington. Rep. Robinson introduced a bill during the 2015 legislative session to eliminate the personal belief exemption. The bill, HB 2009, did not pass.
Investing in education means investing in educators and other news from OlympiaMay 27, 2015
Rep. June Robinson
Special Session We are nearing the end of the first special session and, if a budget deal is not reached by Thursday, May 28, we will go into a second 30 day special session. The House and the Senate have been hard at work negotiating a new budget, but significant obstacles remain in the way. One of the most important differences is how we fund education. In the House, we are working hard to increase teacher pay and fully fund … Continue reading
Is Boeing moving more jobs out of Washington?May 1, 2015
Rep. June Robinson
Boeing to Oklahoma City: Give Us $6m and We'll Send More Washington Jobs OLYMPIA— As the Washington State Legislature considers legislation that would link Boeing's record $8.7 billion in tax credits to job creation and retention, the company is quietly offering to ship more Washington jobs to Oklahoma City for a $6 million incentive from that city. In total, over 3100 jobs have been exported from Washington since the November 2013 passage of the unprecedented Boeing tax breaks. These jobs … Continue reading
Olympia Address:
PO Box 40600
Olympia, WA
(360) 786-7864
Email June
Toll-free Hotline:
Community Development, Housing & Tribal Affairs (Vice Chair)
Health Care & Wellness


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Mix 30 Liquid Feed is a "high energy" protein supplement created from a combination of corn and soy based co-products. This proprietary blend of ingredients results in a palatable, consistent, nutrient-rich product that supplies a judicious combination of both protein and energy for all ruminant diets. Morales Feed & Supply is pleased to be a Mix 30 dealer and to provide this quality cattle feed supplement to ranches and farmers in the south Texas communities.
Call Morales Feed & Supply at 830-665-9358 to schedule delivery of your Mix 30 feed today!


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"Our team did a very good job of finding Danielle and our seniors showed great leadership down the stretch. Sarah Lowe did a tremendous job of finding Danielle and then after she hit one, did a good job of finding her again. That strategy of going to and finding the hot hand worked. Danielle had the guts to step up and want to win the game. She wasn't tentative or hesitant and played like a senior."
Related quotes
"If we as a team had to pick a representative it would clearly be Sarah. She is extremely team-oriented and unselfish."
"Sarah is our team leader, both on and off the court. She is a model student-athlete and has turned into a really solid player."
"Devin and Sarah did an excellent job in the tournaments this season. They are both seniors, and they just played with a lot of maturity."
"But I think Sarah is one of the only characters that's not an essential part of the five, and breaking up the five would not be a good idea. So that kind of left my character dangling out there for a chance to either leave the show or spin off. And they chose to spin off."
"For the most part, there have been a lot of good things. Rachel Gable and Sarah Finkel have both been hitting .300, which is some of the places we've been getting help."
"Swimming has changed drastically for Clay over the years. My hopes for Sarah are that she continues to have the spirit that she has. She's unbelievable. She's not one who is 'all about me.' She's very team-oriented and she's not cocky whatsoever. That makes me really proud."


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This is the first time we stayed in castle hotel and the experience is very unique. The location , room view, restaurant, design and service are all very well. This hotel makes our trip have more good memory.
Set amongst the stunning Umbrian countryside and surrounded by amazingly beautiful views, The Abbazzia sits both peacefully and confidently on the top of a hill, tucked away like a the treasure it is.
There is a simple beauty throughout and the hotel is spacious, clean and well-presented both inside and out. Lovely pool and outside area. Fabulous for relaxing and...
We truly enjoyed our stay here. The property, a former Franciscan monastery, is tucked away and the drive through well paved, woodsy roads made me feel I was driving towards my own private castle. Everything was excellent, the room, the property, the views- truly breathtaking. The manager, Lorena went out of her way to make sure we got everything we...
Dear Guest
Thank You To choosen ABBAZIA COLLEMEDIO for your staying , We hope you will take this memories with you up to see you once more in a next future.BEST WISHES.
The location, the staff, the food, everthing was as expected: great!
The diner was every evening of a very high quality.
Maybe one minor remark: the quality of the juices given for breakfast was below zero!
We stayed at this hotel during May 2013, it was, my wife and I, traveling with our 4 kids. The place is perfect for a relaxing weekend. You do not have to expect a lot from the rooms, but the rates are very competitive. Rooms could use a good face-lift and bathrooms need somewhat of a renovation, but overall it...
beautiful location. Very good food and very clean.
The staff is very friendly


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Evan Turner Wins Wooden Award
Posted: 04/09/2010 - LOS ANGELES (AP) - Ohio State's Evan Turner has won the John R. Wooden Award, claiming yet another trophy as the nation's top basketball player.
Posted: 04/09/2010 - LOS ANGELES (AP) - Ohio State's Evan Turner has won the John R. Wooden Award, claiming yet another trophy as the nation's top basketball player.
Posted: 04/09/2010 - AVONDALE, Ariz. (AP) - A.J. Allmendinger has earned his first NASCAR Sprint Cup Series pole.
Posted: 04/09/2010 - WASHINGTON (AP) - Alex Ovechkin has joined Wayne Gretzky and Mike Bossy as the only players to reach at least 50 goals in four of their first five NHL seasons.
Posted: 04/09/2010 - JOHANNESBURG (AP) -- A FIFA executive says a terrorist threat has been made on the World Cup.
Posted: 04/09/2010 - DETROIT (AP) -- Wisconsin forward Blake Geoffrion, the grandson of Hockey Hall of Famer Bernie "Boom Boom" Geoffrion, received the Hobey Baker Memorial Award on Friday night as college hockey's top player.
Posted: 04/09/2010 - ORLANDO, Fla. (AP) -- A witness has taken responsibility for tossing a glass at a woman at an Orlando nightclub, according to the lawyer for Pittsburgh Steelers receiver Santonio Holmes who was first accused of attacking the woman.
Posted: 04/09/2010 - ROCKVILLE, Md. (AP) -- Washington Wizards guard Gilbert Arenas began serving his sentence Friday night for bringing guns into the team's locker room.
Posted: 04/09/2010 - SPARKS, Nev – UC Davis turned in a six-stroke victory over the Nevada women's golf team on Friday afternoon at the UC Davis-Nevada Challenge at the par 72, 6,048-yard Red Hawk Golf Course.
Updated: 04/09/2010 - RENO, Nev. – The Nevada softball team came back from four runs down to tie the game against San Jose State but the Wolf Pack fell short in eight innings, 7-6.
Updated: 04/09/2010 - Pittsburgh Steelers quarterback Ben Roethlisberger will not be charged in an alleged sexual assault case in Georgia, ESPN is reporting.
Posted: 04/09/2010 - MIAMI (AP) - The case against Miami Dolphins defensive end Randy Starks has been resolved with the charges being reduced to a misdemeanor traffic violation.
Posted: 04/09/2010 - MESA, Ariz. (AP) - Former NBA player Isaiah Rider has been arrested on suspicion of assaulting his fiance and reneging on a $150 cab fare.
Posted: 04/09/2010 - AUGUSTA, Ga. (AP) - England's Lee Westwood has grabbed a share of the lead at the Masters with a 3-under 69, pulling even with countryman Ian Poulter.
Posted: 04/09/2010 - CINCINNATI (AP) - Bronson Arroyo's lower left leg was doing much better, a day after the Cincinnati Reds' right-hander got hit by a batted ball.
Posted: 04/09/2010 - AUGUSTA, Ga. (AP) - It took just three holes for Fred Couples' feel-good story at the Masters to unravel.
Posted: 04/09/2010 - SOUTH ORANGE, N.J. (AP) -- Former Seton Hall basketball coach Bobby Gonzalez has sued the university over his firing last month.
Posted: 04/09/2010 - HARRISBURG, Pa. (AP) - A celebrity boxing promoter has been charged in Pennsylvania with fixing fights and not having a license when he staged a bout between "Partridge Family" television star Danny Bonaduce and a comedian from the Howard Stern show.
Posted: 04/09/2010 - LAS VEGAS (AP) - A co-defendant in the robbery and beating of former Oakland Raiders wide receiver Javon Walker has taken a plea deal in Las Vegas.
Posted: 04/09/2010 - INDIANAPOLIS (AP) -- College basketball fans may get another chance to watch Duke and Butler.
Posted: 04/09/2010 - ATLANTA (AP) -- To the surprise of no one, Derrick Favors is leaving Georgia Tech after only one season to enter the NBA draft.
Posted: 04/09/2010 - MILLEDGEVILLE, Ga. (AP) -- A district attorney in Georgia plans to announce Monday whether he will file charges in a case of sexual assault accusations against Pittsburgh Steelers quarterback Ben Roethlisberger.
Posted: 04/09/2010 - SAN ANTONIO (AP) -- Manu Ginobili finally convinced the San Antonio Spurs his best days aren't yet behind him.
Posted: 04/09/2010 - RENO, Nev. — Most Valuable Player Luke Babbitt headlined the team awards Nevada presented at its season-end Starting Five Dinner on Thursday, April 8 at the Silver Legacy in Reno.
Updated: 04/09/2010 - Armon Johnson will forego his senior season at Nevada and enter the 2010 NBA Draft, the University announced on Friday.
Posted: 04/08/2010 - PITTSBURGH (AP) Sidney Crosby made certain the last regular-season game in the NHL's oldest arena would be remembered for more than a pregame celebration and a whole lot of nostalgic flashbacks.


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Audibility of a CD-Standard A/DA/A Loop Inserted into High-Resolution Audio Playback - September 2007
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Sound Board: Food for Thought, Aesthetics in Orchestra Recording - April 2015
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Reflecting on Reflections - June 2014
4 comments
AES E-Library
Experiences with Multichannel Sound for HDTV
The deficiencies of two channel stereo have led many to question its suitability for use with high definition television (HDTV). To address these issues, the BBC has been producing multichannel sound for HDTV programmes over the last three years and this paper describes some of the results of that work and the further problems, yet to be addressed, which have come to light.
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Computer Classes
Wilson County Public Library offers free computer classes throughout the year. Please contact the circulation desk at 252-237-5355 for information about upcoming classes.
*Unfortunately classes are not being offered during the months of June & July 2015. Please check back for an update at the end of July.


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New phones suck!
by Wes McKane
posted May 11 2009 6:51AM
It was a sad day. I had to part ways with my Blackberry.....in a way. I got a new one, but I had really grown quite comfortable with the old one. Think of all the stuff we went through together: My 1st "qwerty" keyboard. It took me FOREVER to learn how to text with it! I learned the "joys" of the internet on your phone (dirty sites A-W-E-S-O-M-E!) anytime any place!
And I dropped her in a urinal...and it still worked!
Now I get the joy of trying to learn a brand new phone. It's the same phone but they updated SO much on it. You know half the numbers didn't transfer...so I get to give the awkward line "who's this?" "oh sorry! got a new phone." and now I have to re-type all of my swear words so it recognizes them all over again!
Sad day.
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The best (and worst) times to be on the road in Ramadan
Put on your seatbelts, here we goJune 23, 2015 9:00
Register for our free newsletter
Saudi's Mobily to reissue 2014, Q1 2015 results after regulator probe
Dubai Holding appoints new managing director, CEO
HSBC Bank Oman agrees to sell Pakistan business to Meezan Bank
European tour operators evacuate thousands from Tunisia after attack
French group to invest at least $150 mln in Saudi's Kingdom Holding
Gold ticks up from 2-week low as market eyes Greece
Car bomb aimed at UAE officials kills three Somali soldiers in Mogadishu
Abu Dhabi's Etisalat jumps 13.8 pct on looser ownership curbs
RSE, Qatar teaming up to buy stake in Formula One
Qatar building boom proves a challenge for foreign construction firms
Things seem to be going from bad to worse at EIDA, with applicants taking to camping outside centers and travelling to northern Emirates.
December 23, 2010 2:33 by Eva Fernandes
Dr Ali Al Khoury, Director General of Eida told Gulf News, "We rectified the 40,000 applications so far by contacting the applicants [in required cases] but it was surprising to find that 10,000 applicants had given wrong phone numbers." What's become of the other 40,000? Your guess is as good as ours.
With the backlog of applications in typing centers dramatically increasing, centers are taking to keeping the passports of applicants despite warnings that individuals should be wary of such practices. Although we last reported having to leave our passport at the center for five days, one of Kipp's co-workers was asked to leave her passport at such a center for an incredible 45 days.
As the saga of the quest for an ID continues, some are taking to camping outside the centers overnight while others are travelling across the Emirates to find a center that will process them. Philip M told Emirates 24|7 that he has been travelling the lengths of Dubai, Sharjah and Umm Al Quwain in search of a center that was accepting applications: "Finally someone told me a typing centre in Ajman was accepting last minute applications provided we pay an extra amount of Dh60 for each application. I finally submitted all the five passports [presumably for his family] by paying an additional amount of Dh300 (…) at the end of the day typing centres have made a lot of money."
As the New Year approaches and the looming deadline seems more and more unrealistic, Kipp can only hope that the EIDA's New Year's resolution will include a new, thorough administrative system. Alternatively, they could just give up on the whole thing.
Pages: 1 2
All is Sunny in Saudi
December 23 2010
2009 vs. 2010
December 23 2010


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They do sandbag alright. Their guidance for Q1 EPS was $1.21 - $1.26 and they came in with $1.37 or $1.33 if you subtract the one time benefit of $0.04. So that's +7.7% better than what the midpoint of their own guidance was!
By the way, the consensus estimate for comparable store sales was +3.4% and ROST came in with +5% vs their own guidance of 2% - 3%, considerably better (2x at the midpoint).
Yeah this should pop but even if the market decides to be obtuse in the short term, I'm in it for the long haul anyway.
Actually now that I think about it, it isn't so shocking that cnbc avoids ROST since Dana Telsey got her analysis on ROST bass ackwards wrong a while back and now since she is a friend of the show they cannot talk about ROST. Fair and balanced wall street analysis......NOT!
It shocks me the way cnbc is so obsessed with TJX and GPS and APO and M and JCP and..........., and rarely if ever mentions ROST............on second thought maybe that's a good thing........
Nice call. Well she probably is sandbagging as usual but she increased the FY EPS guidance by about 2% at the midpoint and tightened the range a bit.
Share buybacks do not boost revenue and they reported $2.938B vs $2.89B consensus.
Even adjusting for the 0.04, 1.33 still beats consensus of 1.28 and the way the stock has been trading lately, that beat was definitely not baked in as there has been a lot of negativity regarding retail stocks as proven by the way the pop it got on the TJX results was rapidly taken away.


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1 of 2 people found the following review helpful
If you need to go straight,
Verified Purchase(What is this?)
This review is from: Bosch PCL 10 Cross Line Laser Level (DIY & Tools)
Excellent addition to the DIY tool kit. You do need a tripod though to get the best out of this tool, I've use my camera tripod though if you need to go higher you'd best buy the Pole.I also thought that you could use it for "lining" up the side of the stair case say for hanging pictures... but not so! Its still good though.
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Initial post: 26 May 2014 14:18:30 BDT
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Lining up pictures down a staircase? - I thought the clue would have been in the Self Levelling bit?
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FIG. 1 is a top perspective view of a desk showing my new design;
FIG. 2 is a back plan view thereof;
FIG. 3 is a left side view thereof, the opposite side view being a mirror image thereof;
FIG. 4 is a bottom view thereof; and,
FIG. 5 is a bottom perspective view thereof.
The broken lines are for illustrative purposes only and form no part of the claimed design.


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|Home | About | Journals | Submit | Contact Us | Français
The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins. The essential role of IGF axis in hepatocellular carcinoma (HCC) has been illustrated in HCC cell lines and in animal xenograft models. Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC. Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation. This review describes the most up-to-date understanding of this complex axis in HCC, and provides relevant information on clinical trials targeting the IGF axis in HCC with a focus on anti-IGF-1R approach. IGF axis is increasingly recognized as one of the most relevant pathways in HCC and agents targeting this axis can potentially play an important role in the treatment of HCC.
Hepatocellular carcinoma (HCC) is the 5th most common neoplasm worldwide with more than 600,000 cases per year and the 3rd leading cause of cancer-related death [1,2]. For the past 3 decades, the incidence of HCC in the US has tripled, yet the 1 year survival rate of HCC remains less than 50% [3]. Currently sorafenib is the only medication that shows overall survival advantage compared to placebo in patients with advanced HCC [4,5]. However, the benefits with sorafenib are moderate and its toxicities can be challenging to manage. For patients who fail or cannot tolerate sorafenib, there are currently no standard treatments. Therefore, there is an urgent need to search for novel effective therapies in advanced HCC. Recently, the insulin-like growth factor (IGF) axis has emerged as an important pathway in the development and progression of HCC and as a potential therapeutic target.
Here we review the complexity of IGF axis, the supporting preclinical and clinical data highlighting the significance of this pathway in HCC, and the early clinical trials of targeting this axis in advanced HCC.
The insulin-like growth factor (IGF) pathway has highly conserved function in mammals and plays a critical role in energy metabolism and cell renewal in response to nutrients [6-11]. IGF pathway is not only involved in cell growth in tissue culture [12,13], but it also promotes cell proliferation, migration and transformation into malignant clone [12,14]. The IGF-1 pathway revolves around 4 essential components.
The first component contains the IGF ligands, which include both insulin-like growth factor 1 (IGF-1) and IGF-2. Their names are based on the observation that both IGF-1 and IGF-2 are peptides, similar to insulin, and they share 40% homology with proinsulin [15,16]. They are, however, slightly different from insulin structurally by containing an additional domain, which could account for their dramatically different role in neoplasms in comparison with insulin [16].
The IGF ligands bind to the second component of the IGF axis, the receptors which include IGF-1 receptor (IGF-1R), IGF-2 receptor (IGF-2R), insulin receptor and hybrid receptors consisting of IGF-1R and insulin receptor hemireceptors (IGF-1R/insulin receptor) (Figure (Figure1).1). IGF-1 and IGF-2 both bind to IGF-1R with high affinities, and IGF-2 is the only ligand for IGF-2R [6,12,15]. IGF-1 only binds to insulin receptor at extremely high doses, as IGF-1 has 100 fold higher affinity for IGF-1R compared to insulin receptor [16]. IGF-2 usually binds to insulin receptor during fetal development, as later in development when IGF-1R is expressed, IGF-2 binds to IGF-1R more tightly [16,17]. Each IGF-1R/insulin receptor hemireceptor only contains one α and one β subunit; IGF-1 is the preferred ligand for IGF-1R/insulin receptor hybrid receptors compared to insulin, as IGF-1 can tightly bind in the presence of only one α subunit of the hemireceptor, while insulin requires two β subunits of the hemireceptor to provide optimal binding [16].
The third component of the IGF axis refers to the insulin receptor substrate (IRS) and Shc proteins, which are the major signals downstream of IGF-1R activation [16]. There are 4 types of IRS and the important ones include IRS-1 and IRS-2.
The last key component of the IGF axis consists of IGF binding proteins (IGFBPs). There are 6 members of IGFBPs with high affinities for IGF-1 and IGF-2. For instance, IGFBPs 1-4 bind both IGF-1 and IGF-2 with similar affinities, yet IGFBP-5 and 6 strongly prefer IGF-2 as their ligand.
The majority of IGF-1 is synthesized in the liver under the influence of growth hormone, which is a major promoter of postnatal growth [18]. However, deletion of liver specific IGF-1 gene in mice showed no difference in growth compared to wild type animals, even though serum IGF-1 level was reduced by 75% [18-20]. Such observations came with no surprise when later on IGF-1 was found to be produced in other organs such as the kidneys, muscle and bone [16]. IGF-1 can act as an autocrine, paracrine or endocrine growth factor, therefore even minimal amount of IGF-1 could still exert its function on postnatal growth [18-20]. Nutrition depletion reduced IGF-1 levels and risk of cancer [12,21], whereas infusion of IGF-1 abolished the protection against carcinogenesis provided by dietary restriction [22]. Epidemiology studies also indicate that IGF-1 is involved in the risk of cancer development. Several studies suggest that height and weight at birth are proportional to the level of IGF-1 in the umbilical cord, and that infants with higher percentile of height and weight at birth tend to develop more common cancers such as breast, prostate and colorectal later in life [22-28].
IGF-2 shares 60% homology with IGF-1. Similar to IGF-1, it is also mostly produced in the liver [6,16] and acts in an autocrine, paracrine and endocrine fashion. It is abundant in fetal development, yet its quantity sharply diminishes after birth [16]. IGF-2 knockout mice develop normally except all of them have stunted growth after birth [16], indicating that IGF-2 is critical in growth.
Both IGF-1 and IGF-2 bind to IGF-1 receptor 1(IGF-1R), a tyrosine kinase that is structurally similar to insulin receptor (IR) (Figure (Figure1).1). After IGF ligand binding, the β subunit of IGF-1R undergoes conformational change which causes autophosphorylation of its own tyrosine kinase domain, which leads to the full activation of IGF-1R. IGF-1R induces anti-apoptosis and increases tumor cell mobility. The anti-apoptotic property of IGF-1R was shown in its response to p53, the tumor suppressor gene that promotes apoptosis. Wild type p53 expression inhibited the gene expression of IGF-1R, while mutant p53 increased the gene expression of IGF-1R [16,29]. Oncogenes such as Src kinase and Akt kinase both stimulated the gene expression of IGF-1R, providing more evidence that IGF-1R is vital in carcinogenesis [16,29-31]. In addition, IGF-1R also stimulates cell mobility, as demonstrated by its activity in melanoma cell lines [32].
Another important role of IGF-1R in carcinogenesis is its ability to transform and maintain the transformed phenotype [33]. Mouse embryo fibroblasts possess an extremely strong tendency to spontaneously transform in culture without any additional factors [33], which was no surprise given IGF-1R overexpressed in mouse embryo fibroblasts led to transformation [33-36]. However, when IGF-1R gene in mouse embryo fibroblasts was disrupted, these fibroblasts failed to transform, even in the presence of the most potent oncogenes such as SV40 T antigen, Ha-ras oncogene and activated c-Src [33,37-41]. An even more noteworthy observation was that when IGF-1R was reintroduced, these mouse embryo fibroblasts again restored their ability to rapidly transform.
IGF-1R is required for anchorage independent growth, and inhibition of IGF-1R causes apoptosis without toxicities in vivo. Human prostate cancer cells usually form anchorage independent growth, however; when IGF-1R was abolished, these cells failed to grow in culture, and the same model showed no tumor formation in mice [33,42-45]. These observations indicate that IGF-1R is an essential requirement for anchorage independent growth, a pattern common in cancer cell proliferation. In animal models with transformed tumors where IGF-1R was overexpressed, strategies that caused IGF-1R downregulation such as antisense against IGF-1R produced profound tumor apoptosis and massive reductions of metastases [46,47]. Interestingly, IGF-1R is not required for normal cell growth, as its absence provided no growth inhibition on monolayer cell culture [45], eluting to the possibility that anti-IGF-1R strategies could produce minimal side effects on normal tissues.
There are no known downstream signals related to IGF-2R activation and it appears that IGF-2R mainly serves as a clearance site for its only ligand, IGF-2 [6]. Most of the effects of IGF ligands are mediated through IGF-1R, a transmembrane tyrosine kinase [6,12,16].
Among the substrates of IGF-1R, IRS plays a prominent role in exerting the activity of IGF-1R by activating downstream signals [16]. After IGF-1R activation, additional tyrosine residues are then phosphorylated, which act as docking stations for substrates such as the insulin receptor substrate (IRS) and Shc adaptor proteins (Figure (Figure2).2). IRS and Shc adaptor proteins then recruit additional factors to yield activations of two major cascades, the phosphatidyl inositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK), both result in cell differentiation, proliferation and anti-apoptosis [16,22]. There are currently 4 types of IRS proteins [48], the effects of IRS-1 and 2 are opposite to that of IRS-3 and 4 [16]. IRS-1 is the most well understood IRS, and it is essential to the activation of IGF-1R. When IRS-1 was abundant, it promoted cell size growth, activated p70 S6K, a kinase that promotes cell proliferation and leads to transformation [49]. Meanwhile, IRS-1 turned off IGF-1R's stimulation for differentiation through its phosphotyrosine binding (PTB) domain, therefore inhibited differentiation and stimulated transformation [50]. When IRS-1 was inhibited or malfunctions, such as the case when there was a mutation of its PTB domain, transformation no longer continued and these cells tend to undergo differentiation. The inhibitor of p70S6K such as rapamycin, which is an inhibitor in the mammalian target of rapamycin (mTOR) pathway, also produced similar effects as the mutated PTB domain, thus cells exposed to rapamycin tend to grow slowly with good differentiation [51].
One of the key regulators of IGF expression is the family of IGF Binding Proteins (IGFBPs) [6]. The predominant form of IGFBPs is IGFBP-3, which comprises of 90% of all IGFBPs in serum [15,16], and it binds to the majority of circulating IGF-1 and IGF-2. IGFBPs that include IGFBPs 1, 3, 4 and 6 usually limit IGF access to IGF-1 receptor, therefore decrease the availability of IGFs and diminish their effects on cancer progression [6].
In human HCC tissues, IGF-1 mRNAs were expressed at lower levels than the surrounding normal liver tissues [18,53]. This could be related to the observation that growth hormone receptor level was low in HCC tissues [18,53], and growth hormone stimulation thus was low, and the downstream signals such as IGF-1 level would be accordingly low.
IGF-2 has been reported to be overexpressed in animal models of hepatocarcinogenesis and in human HCC [50,54-60]. IGF-2 has been linked to carcinogenesis by providing a stimulatory effect on cell proliferation and angiogenesis, both critical in HCC development. In a study using 2 human HCC cell lines, high levels of IGF-2 were demonstrated, and anti-sense oligonucleotides used to target IGF-2 mRNA showed reduction of IGF-2 mRNA and protein levels, which corresponded to a remarkable decrease in cell proliferation [18,61]. In a study of molecular profiling of human HCC samples, overexpression of IGF-2 was related to a cluster of gene signature that downregulates apoptosis [62], indicating a potent anti-apoptotic effect of IGF-2. The relationship between IGF-2 and angiogenesis was demonstrated in human HCC cell cultures. Under hypoxia environment, IGF-2 mRNA levels in human HCC tissue increased, and IGF-2 overexpression directly increased vascular endothelial growth factor (VEGF) mRNA and protein levels [63]. It suggested a pro-angiogenic effect of IGF-2, an important pathway in HCC development and metastasis.
In rodents, diethylnitrosamine (DEN) induced 100% development of glycogen rich hepatic lesions, which are precursors to HCC, and up to 98% of such lesions expressed IGF-2 mRNA [54,64]. These results highlight a vital role of IGF-2 early in hepatocarcinogenesis. The expression of IGF-2 has been shown to be a common pathway leading to hepatocarcinogenesis regardless of the species or the process of HCC development [65]. In transgenic mice where IGF-2 levels were persistently 20 times higher than normal control mice, a diverse spectrum of tumors were seen at a much higher frequency than the controls, and HCC was the most common malignancy by 18 months of age [66].
The expression of IGF-2 is very unique in fetal development, as it is maternally imprinted; therefore it is monoallelic [6,18]. In adults, IGF-2 becomes biallelic [18]. In fact, IGF-2 overexpression in HCC showed re-emergence of fetal IGF-2 by the identification of fetal promoter activation [67]. In all 15 samples of human HCC tested in a study, the overexpression of maternally imprinted fetal IGF-2 was demonstrated [51]. In a study from Hong Kong, 30 HCC samples from patients examined using northern blot analysis showed more than 93% of the adult promoter IGF-2 transcripts were repressed, while 93% of the adult type IGF-2 transcripts were detected in nontumourous tissues [68,69].
The importance of IGF-2 in HCC development is further demonstrated in its relationship with risk factors of HCC such as hepatitis B and C [70]. In patients with chronic hepatitis C and cirrhosis, the overexpression of IGF-2 was clearly related to hepatitis C viral replication [71]. In patients with chronic hepatitis B, HBV X protein stimulated IGF-2 expression by binding to the fetal promoter of IGF-2, therefore directly stimulating fetal transcript expression of IGF-2 in HCC [72]. Furthermore, aflatoxin has been shown to be synergistic with hepatitis B in the carcinogenesis of HCC, and p53 gene mutation induced by aflatoxin increased the expression of IGF-2 in HCC patients with hepatitis B infection [73].
In a study where 10 HCC cell lines (including PLC HCC cell line) were tested, all of them showed elevated IGF-1R mRNA [50]. Furthermore, the addition of both IGF-1 and IGF-2 to the PLC HCC cell line induced increased cell proliferation in a dose dependent manner, showing that the major tumor promoting effects of IGF ligands on HCC are exerted through IGF-1R [46].
In a model utilizing pancreatic islet transplantation into the livers of diabetic rats, a well established series of events led to development of HCC from preneoplastic foci [74]. When HCC developed from preneoplastic foci in this animal model, the expression of IGF-1R significantly increased, which could explain the phenomenon that the increase in mitotic activity was more than the increase in the rate of apoptosis [18,75]. IGF-1R is therefore crucial in both the development of and the growth of HCC, making IGF-1R an ideal target in the treatment of HCC.
IGF-2R is closely associated with transforming growth factor β (TGF-β), a very potent growth inhibitor [76]. For instance, in human HCC tissues, the levels of both TGF-β and IGF-2R protein were reduced compared to those in adjacent normal liver tissues [66]. The expression of IGF-2R was significantly lower in several HCC cell lines in vitro, in HCC animal models and in human HCC tissues [77,78]. The role of IGF-2R in IGF axis appears to serve as a site for IGF-2 clearance, therefore reduces the availability of a potent ligand for IGF-1R, the major gateway for carcinogenesis, tumor growth and proliferation. IGF-2R therefore provides an indirect inhibitory effect on IGF-1R.
The overexpression of IRS-1 has been described in human HCC cell lines and tissues [79]. IRS-1 leads to activation of downstream mitogens such as PI3K and MAPK. In human HCC cell lines, IRS-1 developed acquired resistance to apoptosis, indicating a potent role of IRS-1 in the promotion of continued cell growth in HCC [79].
IRS-2 is a major downstream signal of insulin pathway in the liver, and its function in hepatocarcinogenesis is demonstrated in animal models. When SV40 large T antigen or DEN was applied in murine models, IRS-2 overexpression was detected in both preneoplastic foci and HCC lesions, with higher levels in HCC nodules [47]. A similar observation was reproduced in human HCC cell lines and tissue specimens, suppression of IRS-2 levels led to increased apoptosis. Together with IRS-1, IRS-2 also contributes to hepatocarcinogenesis, as demonstrated by its early emergence in preneoplastic lesions, and its anti-apoptotic property. IRS-1 and 2 therefore create an optimal environment for HCC growth.
In a study comparing IGFBP-3 levels in human normal liver, cirrhotic liver and HCC, the expression of IGFBP-3 mRNA levels was significantly reduced in HCC [80]. In a human HCC cell line, addition of exogenous IGFs stimulated mitosis, but this mitogenic effect was greatly reduced by IGFBP-3 [46]. Furthermore, addition of recombinant human IGFBP-3 induced growth inhibition of the human HCC cell lines HepG2 and PLC [81]. The role of IGFBP-3 on tumor growth inhibition can be further explained by IGFBP-3's induction by p53, a tumor suppressor gene essential in apoptosis and cell cycle arrest [15].
In a study examining radiation induced HCC mouse model, northern analysis showed decreased expressions of IGFBP-7 (a low affinity IGFBP) in HCC compared to normal liver tissues, which was inversely related to anchorage-independent growth in HCC cell lines [82]. A similar trend of reduced IGFBP-7 level was seen in human HCC tissues. When IGFBP-7 cDNA was injected to radiation induced HCC mouse model, the volume of HCC was greatly reduced. IGFBP-7, although has relatively low affinity toward IGF-1 and IGF-2, exerts a similar anti-tumor effect as its high affinity IGFBP counterpart IGFBP-3.
Metalloproteinase belongs to IGFBP proteases that degrade IGFBP-3. In a transgenic murine HCC model overexpressing the inhibitor of metalloproteinase (TIMP1), IGFBP-3 degradation was reduced, and serum level of IGFBP-3 was subsequently increased, which decreased the bioavailable IGF-2 ligand and its downstream signalling. This resulted in reduced liver hyperplasia, despite the activation of IGF-2 by a strong oncogene such as SV40 T antigen [83]. It provided evidence that IGFBP proteases and IGFBPs are equally important in the regulation of IGF ligand bioavailability and their downstream effects on IGF axis activation.
There are several strategies in the therapeutic considerations involving IGF axis in the treatment of HCC and other tumors. The first method targets the ligand to reduce its activity, the second inhibits the function of the receptor, and the third modulates the downstream signals of IGF-1R pathways (Table (Table11).
One of the first drugs to be tested was somatostatin. However, as it only lowered serum IGF-1 level to a modest degree without achieving desired reduction, it showed no anti-neoplastic activity [84]. Metformin lowered insulin levels in patients with hyperinsulinemic states such as in obesity, a major risk factor for HCC. The reduction of insulin was significant, yet its effect on IGF-1 and IGF-2 was minimal, making metformin a weak candidate in the treatment of HCC [85]. Ongoing studies utilizing growth hormone antagonists or IGF ligand specific antibodies have demonstrated some activity in prostate and breast cancer cell lines, suggesting their potential in the treatment of HCC [86,87]. MEDI-573 is a first in human neutralizing antibody against both IGF-1 and IGF-2, has shown promising activity in vivo based on its inhibition of downstream IGF signalling [88], and is now being tested in phase I solid tumors.
The majority of anti-IGF strategies focused on IGF-1R, the key component of IGF axis that provides mitogenic signal for tumor growth. The most common strategy utilized is the receptor-specific antibodies. For instance, pharmacodynamic studies of MK-0646 (Merck) on neoplastic tissues demonstrated reduction of phosphorylated AKT and phosphorylated S6 kinase, two downstream targets of IGF-1R. MK-0646 also decreased tumor proliferation as shown by reduction in the proliferation marker Ki67 [89,90]. This observation provided a rationale to use this class of antibodies in the treatment of HCC, and it was supported by additional data generated using IMC-A12 (Imclone), a human monoclonal antibody that blocks IGF-1R, both in vitro and in vivo [91]. In hepatoma cell lines, 2 hour incubation with IMC-A12 completely blocked downstream signalling of IGF-1R as shown by the suppression of phosphorylated AKT and phosphorylated S6 kinase [91]. In addition, 10 day treatment with IMC-A12 in HCC xenografts led to 40% reduction of tumor volume and 40% prolongation of overall survival without additional toxicity compared to control animals [91]. In a phase I study of refractory solid tumors using IMC-A12 as a single agent, a patient with HCC had stable disease for up to 9 months [92].
One of the most studied IGF-1R antibodies is CP-751871 (Pfizer) and it showed rather promising activity in a phase II study in patients with advanced non-small cell lung cancer. When it was added to carboplatin and paclitaxel as a first line regimen, the response rate increased from 32% to 46%. What was even more impressive was in patients with squamous histology, the response rate was as high as 71% [93]. The most common side effect in this phase II study was hyperglycemia. The subsequent ambitious Phase III study looked at patients with stage IIIB or IV non-small cell lung cancer, and randomized them to receive carboplatin and paclitaxel either with or without CP-751871. This study was halted in late 2009 due to unexpected increase in fatal events in the experimental arm [93], and it could be partially explained by the most common side effect of hyperglycemia. The consequence of IGF-1R inhibition leads to compensatory increase of growth hormone stimulation that promotes liver gluconeogenesis, resulting in hyperglycemia [94]. What we could learn from this surprising result is that there are subsets of patients who could potentially benefit from IGF-1R inhibitors such as CP-751871 [95]. For instance, in the experimental arm, patients with low IGF-1 levels (< 5 pg/ml) before treatment with CP-75871 were more likely to suffer fatal events within 60 days of treatment. The same group of patients also had much shorter median overall survival compared to the ones with higher pretreatment IGF-1 levels (7 months vs. 10.4 months). Conversely, for patients with higher pretreatment IGF-1 levels, those who received the experimental treatment that included CP-751871 had a trend toward higher median overall survival compared to those who received the standard chemotherapy (10.2 months vs. 7 months). Further analysis from the phase II study also showed that IGF-1R was present in the highest level in patients with squamous histology, which could explain the observed high response rate in squamous cell patients who received CP-75871 [96]. Such observation was consistent with a presentation at ASCO GI in 2011, in which data of 288 patients with HCC were analyzed. In this study, pretreatment lower plasma IGF-1 and higher plasma VEGF levels significantly correlated with advanced clinicopathologic parameters and poor overall survival, with an optimal cut off point of 26 pg/mL and 450 pg/mL, respectively. The combination of low IGF-1 and high VEGF predicted median overall survival of 2.7 months compared with 19 months for patients with high IGF-1 and low VEGF (p < 0.0001) [97]. Such information provided insights into the specific patient subsets in HCC where IGF-1 levels would offer additional prognostic significance. Whether baseline plasma IGF-1 levels could be used to predict response to IGF axis inhibition in HCC remains to be explored.
IMC-A12 was studied as a single agent in patients with advanced HCC as a front line systemic therapy. This study unfortunately was terminated due to futility. The pre-planned primary endpoint of progression free survival rate at 4 months was only 30% and median overall survival of 8 months [98]. Up to 46% of patients developed grade 3-4 hyperglycemia, similar to what was seen in the phase II NSCLC study of CP-751871 [93], thus raising the possibility that hyperglycemia could be the dose limiting toxicity of IGF-1R monoclonal antibodies. Hyperglycemia and its subsequent increase of growth hormone could also contribute to the disappointing activity of this class of drugs. BIIB022 (Biogen-Idec) is an anti-IGF-1R monoclonal antibody that blocks binding of both IGF-1 and IGF-2 to IGF-1R [92]. It does not contain Fc effector function, therefore can potentially minimize toxicities in healthy tissues expressing IGF-1R [92]. This agent does not appear to cause hyperglycemia, a common side effect of receptor specific antibodies [92]. Hyperglycemia has been attributed to insulin resistance secondary to high levels of growth hormone, a compensatory reaction to IGF-1R antibodies [94,95]. The class of IGF-1R monoclonal antibodies share similar side effect profiles, including minimal dose limiting toxicities. These favorable safety profiles make them ideal candidates in the combination therapy with current available chemotherapy or biologic therapy [6]. BIIB022 showed inhibition of tumor growth in HCC cell line HepG2, and this inhibitory effect was enhanced by addition of sorafenib [92], the only FDA approved medication for patients with advanced HCC. A planned phase I/II study comparing sorafenib with or without BIIB022 in patients with advanced HCC was terminated due to a business decision of Biogen-Idec. AVE-1642 (Sanofi-Aventis) is another IGF-1R antibody that was initially studied in advanced HCC patients in a phase I study in combination with sorafenib [99], the study was terminated not related to either efficacy or toxicity concerns. Although IMC-A12 lacks single agent activity in HCC, its combination with sorafenib could potentially yield synergy. It is currently undergoing phase I study in combination with sorafenib in patients with HCC, the result of this clinical trial may help understand the clinical benefits of combining IGFR-1R monoclonal antibodies and sorafenib in HCC.
A major advantage of small molecule inhibitor is its ability to inhibit both IGF-1R and insulin receptor. Such ability was demonstrated in several human tumor cell lines, where phosphorylated IGF-1R and its downstream proteins, including ERK and p70s6k were all effectively inhibited by OSI-906 (OSI) [100]. In addition, it inhibited phosphorylated insulin receptor in both primary human hepatocytes and HCC cell line HepG2. IGF-1R and insulin receptor interaction has been seen in many human tumor cell lines after the appearance of IGF-1R monoclonal antibodies. For instance, when IGF-1R phosphorylation was reduced with the treatment of IGF-1R monoclonal antibody, phosphorylated insulin receptor also increased [100].
Even though IGF-1R plays a dominant role in the activation of IGF axis, insulin receptor becomes very important when IGF-1R is blocked, such as the case with IGF-1R monoclonal antibodies. When IGF-1R is blocked, all the IGF-1 and IGF-2 (ligands for IGF-1R) are available to bind insulin receptor. There are 3 ways how insulin receptor activates the IGF axis. First, when IGF-1 levels increase with IGF-1R inhibition, its binding to insulin receptor also increases, which leads to more insulin receptor activation. Second, IGF-2 usually binds to insulin receptor with very low affinity, however; when IGF-2 fetal transcripts are reactivated, such as in HCC, the affinity of IGF-2 for insulin receptor increases dramatically. Additional insulin receptor is therefore turned on through IGF-2. Third, the overexpression of insulin receptor was demonstrated in numerous human cancers including HCC, and its overexpression was linked to tumor growth and cell survival [101].
Several small molecule tyrosine kinase inhibitors of IGF-1R such as BMS-554417 (Bristol-Myers-Squibb) are under development [102-107]. There have been encouraging in vitro and in vivo data in broad range of cancers with activated IGF axis. Current phase I data on drug tolerability will provide more information regarding the feasibility of such medications in the potential treatment for advanced HCC.
OSI-906 (OSI) is a potent tyrosine kinase inhibitor of both IGF-1R and insulin receptor. The unique advantage of OSI-906 over previous class of anti-IGF drugs is its ability to minimize the activity of IGF-2 where IGF-1R inhibition alone will not be sufficient. In cancers such as adenocortical carcinoma and HCC, where insulin receptor binds to IGF ligands with higher affinity, OSI-996 is able to inhibit both insulin receptor and IGF-1R to achieve maximum inhibition of the IGF axis [108-110]. A phase III study using OSI-906 in patients with adenocortical carcinoma is ongoing. OSI-906 is therefore considered one of the desirable drugs to be tested in patients with HCC.
AMP-activated protein kinase (AMPK) pathway is one of the upstream signalling pathways above mTOR [6]. The AMPK activation effects are quite complex, and although experimental models of AMPK activators demonstrate their anti-proliferation effects, they could also potentiate cell survival after exposure to stress [110-113]. Additional studies on activators of AMPK are required to understand the role of such class of medications prior to its use as anti-neoplastic agents. Another active downstream signal of IGF axis is the mTOR pathway, which is downstream of PI3K/AKT signal. Everolimus (Novartis) is being studied in patients with sorafenib refractory HCC in a phase III trial. A third active pathway involves MAPK, and inhibitors of this pathway are currently in very early phase of investigation [114].
As most of IGF-1R inhibitor molecules have minimal dose limiting toxicities in phase I studies, and IGF-1R activation reduces responsiveness of antineopalstic therapies [6], it is possible to combine IGF-1R inhibitors with certain chemotherapies. For instance, IGF-1R overexpression has been associated with resistance to epidermal growth factor receptor (EGFR) inhibitors and mTOR inhibitors [115,116]. The idea of combining IGF-1R inhibitors and agents such as erlotinib or everolimus could be a promising strategy in the management of advanced HCC.
In recent years, the understanding of IGF pathway in cancer has led to development of IGF inhibitors which show promising anti-cancer signals in early phase I studies. According to the World Health Organization, more than 50% of cancers come from countries where obesity is a prominent risk factor, and that cancer mortality now is more than that of tuberculosis, malaria and AIDS combined [117]. In the next 3 decades, the incidence of HCC in the US is expected to be among the fastest growing cancers partly due to the increasing incidence of obesity [6,12]. IGF axis is an essential pathway in the development of hyperinsulinemia, a condition closely related to obesity, which in turn increases the risk for HCC [6]. Agents that target the IGF axis, an active pathway in carcinogenesis and progression of HCC, provide an alternative strategy in the management of HCC. We are only in the beginning era of realizing the complexities of IGF pathway, additional research in the understanding of both basic science and clinical applications of anti-IGF agents will provide insights into the value of IGF inhibition in the treatment of HCC.
HCC: hepatocellular carcinoma; IGF: insulin-like growth factor; IGF-1: insulin-like growth factor 1; IGF-2: insulin-like growth factor 2; IGF-1R: insulin-like growth factor 1 receptor; IGF-2R: insulin-like growth factor 2 receptor; IRS: insulin receptor substrate; IGFBPs: insulin like growth factor binding proteins; PI3K: phosphatidyl inositol 3-kinase; MAPK: mitogen-activated protein kinase; PTB: phosphotyrosine binding; mTOR: mammalian target of rapamycin; VEGF: vascular endothelial growth factor; DEN: diethylnitrosamine; TGF-β: tumor growth factor beta; AMPK: AMP-activated protein kinase; EGFR: epidermal growth factor receptor.
The authors declare that they have no competing interests.
JW contributed to the collection and interpretation of data, helped drafting the manuscript. AXZ conceived and designed the study, provided critical revisions of its intellectual content, and gave final approval of the version to be published. All authors read and approved the final manuscript
We thank Biogen-Idec and OSI for providing essential information on BIIB-022 and OSI-906, respectively.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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By JOHN McCALLUMEditor
Cheney council reviews six-year facilities plan, repeals and replaces animal codes at Feb. 11 meeting
February 20, 2014 | Vol. 117 -- No. 44
The Feb. 11 Cheney City Council meeting covered more subjects than what to do about a interim zoning ordinance regarding the location of marijuana production, processing and retail outlets in the city.
Besides wrapping up a public hearing and approving moving Ordinance W-18 along the process towards becoming part of the city's municipal zoning code, the council also took action on a pair of resolutions and ordinances. The measures dealt with a variety of functions from surplusing equipment to Cheney's six-year project wish list.
According to a Planning Department staff report on the latter, the Capital Facilities Plan, the projects list is required by the state's Growth Management Act as an inventory of existing facilities, locations and capacities that will be needed to handle projected growth over a 20-year period. Some projects, such as the $334,000, six-year water well rehabilitation work show funding coming from fees while others like the $718,045 annual water main replacements are paid for through grants.
A $619,856 Mullinix Road 12-inch water line extension from SR 904 to Salnave Road would be funded by "growth." Most of the projects on the list, which ranged from water and sewer to electrical and parks and included $800,000 pool work in 2015 and a $3 million fire station remodel in 2019 showed no funding sources. Council approved the first reading of the facilities plan ordinance, with readings two and three and final passage scheduled for later.
The council approved all three readings and final passage of Ordinance W-26 to repeal a section of the city's municipal code pertaining to dogs and cats and adopt in its place Spokane County Code Title 5. The action was required as part of a memorandum of understanding signed between Cheney and Spokane County Regional Animal Protection Service (SCRAPS) to provide animal control in the city, and also deals with future updates to the county code.
"(It's) so we don't have two laws running at the same time (in the city)," Cheney Police Chief John Hensley said.
Council unanimously approved a resolution authorizing Mayor Tom Trulove to sign a supplemental amendment to the city's agreement with the Washington State Department of Transportation for engineering services on the upcoming North Sixth Street Preservation Project. The amendment obligates additional federal funding of $29,205.94 for the maximum amount for construction administration services with Taylor Engineering and changes the fixed overhead rate to 134.4 percent; a move Public Works Director Todd Ableman said reduces the amount of overhead to the city.
Finally, council unanimously approved the surplusing of two pieces of Street Division equipment: a 1975 IHC water truck and a LECO mosquito fogger. Ableman told the council the fogger had never been used, while parts for the 40-plus year old water truck are becoming more difficult to find.
"The only thing good on it is probably the (water) tank," Trulove said.
Prior to adjourning the meeting, council went into executive session to consider the minimum price for a possible real estate sale. No action was taken after the executive session ended and public meeting resumed.
John McCallum can be reached at email@example.com.
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Russell's Salsa
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Author Notes: When I asked my brother, Russell, what sort of food he likes to make for gatherings. He told me about this salsa that he claims is "freakin good" on account of the tequilla he adds to it. —midnitechef
Serves 4 (you will probably have to make more)
Tags: party,spicy,ForTequilaLovers
- This recipe was entered in the contest for Your Best Dish in the Raw
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