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cmiVFX - C4D: Introduction to Surface Modeling Techniques
English | AVC1 1166x658 | MP3 128 Kbps | 751 MB
Genre: eLearning
Blocking Understanding how to start your model or elements from it is an essential knowledge every modeler or aspiring modeler should know really well. That will define if you are going to cross the easy road of modeling or if you are going to spend endless time trying to get closer to the shape you want. We will go through several examples of the Scarab Machine elements to discuss important usages of blocking in your day to day modeling and how that can help you achieve what you need.
Shape Design: The first time you sit down to model something in 3D is usually a mind opening experience and a very rewarding one! It is like learning how to write again! It is like letting people see the art in your mind! Creating something from scratch, seeing it evolve with time is like nurturing a little seed until it is a full grown tree. In this segment we will use an important shape from the Scarab machine to talk about all the steps , challenges and techniques around the creation of a model from the ground up. Get ready!
Surface Control: The next level of modeling techniques are about adding intricate details inside a surface without losing surface information or shape integrity. Controlling the surface flow and design is one of the most demanding tasks when you come into the refining stage of your model. Your accomplishment in this area will be easily visible if your model has reflective surfaces because they show surface issues like a bright light! Here you will be presented to some important skills to control your surface inside Cinema 4D using one of the most complex areas of the Scarab Machine , the Front Light Hood. It is an integrated part of the model that must fit perfectly the design lines with proper topology flow.
Sometimes you will be facing a challenging element of your model, very detailed and it must be a single piece of geometry. How do you design such thing without losing the ability to easily control the surface? How to make it simple and efficient but at the same time looking complex? Visual complexity is something that we can bring to our models to enrich the renders. Here we will use a very complex and detailed area from the Scarab leg to demonstrate how you can answer those questions. Starting with the blocking up to the final refined element you will understand the delicate process of adding complex details to your surface modeling.
mORE iNFO
_http://cmivfx.com/productpages/product.aspx?name=C4D_Introduction_to_Surface_Mode ling_Techniques
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What if you could have one big miracle to help your creative flow?
Scientists get the big bang, something from nothing and from that point of reference determine everything else. Why not do the same with creative consciousness?
Let's give ourselves the one big miracle and decide without the need for proof or logic (something from nothing) that creative consciousness exists as a flow of energy your brain receives ideas from. Listen to this weeks episode exploring this, lifting the veil, and a few quotes from Elizabeth Gilbert's book Big Magic.
Get updates on future Creative Habits Podcast episodes plus the ever popular Creative Matrix email series! Your information won't be shared and there is an unsubscribe option sent with every email.

subset: commoncrawl


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RockReef gift vouchers are the perfect gift for those people who have everything! Gift vouchers are available to buy for all RockReef and PierZip activities.
If you have booked your Gift Vouchers online, we will send a unique booking reference number to the e-mail address you provide and you can download a Gift Certificate below.
Download & Print Gift Certificates here
If you would like us to send a Gift Card by post, please order by calling 01202 983983, there will be a charge of £1.50 to send the card by post.
If you would like to purchase multiple gift vouchers, please purchase the vouchers in separate transactions, otherwise you will receive just one voucher booking reference for all the gift vouchers selected.
To redeem gift vouchers: The recipient will need to contact RockReef on 01202 983983 and provide the booking reference number. Session times and availability can be found on our booking page.


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Review The Pinemeadow Golf Putter
Every golfer knows that having a decent short game is critical to keeping the score low and sometimes the golf putter is the key,
For years I used an old fashioned Ping golf putter and thought I had a decent putting game. I just figured those three putts were because of my stroke and because I just did not practice enough.
Well a few months ago I played a round with a friend who had this freaky white golf putter. I actually thought it was a woman's club. Anyway he asked me if I wanted to give it a try, so I did. Holy cow, what a difference in the feel over my old ping. It had a really solid feel to it and was a pleasure to stroke. I borrowed it off and on the rest of the round and it seemed to help a little.
I decided at the end of that round that I should check out some new gear as my game had not really improved in years and maybe my antique clubs were holding me back. My only concern was that I did not want to spend a lot of money on new clubs.
I checked out the PGX Pinemeadow Golf Putter on line and discovered it was only about $40 on Amazon. Well that is less than a round of golf so I bought one and am I glad I did. I have managed to shave, on average, about 3 strokes and have almost eliminated those pesky three putts from my game.
I will say one thing though, if you get one, plan on spending some time on the practice green to really get a good feel for this golf putter. The one thing I noticed right away was the weight was much heavier than what I was used to, but it actually seems to help my stroke.
As I said this golf putter is available on Amazon.
Photo Credit: https://www.flickr.com/photos/golf_pictures/4934955881 and Amazon
I am Ketchingup
© 2014 Ketchingup All rights reserved
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From our correspondants: Festa a Venezia #1 & #2
Photocall: 12/06/2005, 10:00am, Il Giardini, 51° Esposizione Internazionale d'Arte della Biennale.
It's all hushed and woody inside the beach shack - bar the blandishments of the paparazzi.
"Miz Blanjet! Ova here Miz Blanjet!!" Frozen half-smile. "Cate!" "Cate!" Inscrutable but intelligent. "Miz Blanjet!" Nothing, almost completely blank, except for the raised, plucked eyebrow visible above the rim of the eyeglasses. "Miz Blanjet" today is oozing hot and brainy, and she and everybody else knows it. Our Cate is waiting with the artist, some sculptor.
From The Art Life


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Stay in Touch
Get sneak previews of special offers & upcoming events delivered to your inbox.
Meet Allison Ripka
Fine jewelry is a family affair for Judith Ripka and her daughter-in-law, Allison. Working alongside Judith, who Allison affectionately calls "Judie," has provided Allison a wealth of knowledge. Plus, it's fostered a lifelong passion for all things jewelry.
QVC: You've known the Ripkas for quite a while-can you tell us the story behind that?
But there was also a very girly side to me that enjoyed everything fashion and jewelry related. I vividly remember Brian and David calling me back to the basketball game after I had sneaked away to see Judie's latest creations. She always took the time to show me what she was working on and wanted to teach me everything-and I wanted to learn. I loved every minute of it! And Judie tells me she loved it when I came over, because it gave her a chance to enjoy "girl talk." In a lot of ways, I was her "daughter" before I became her daughter-in-law. Who knew that Brian and I would end up going to college together and now be looking forward to our 17th wedding anniversary and enjoying our two children, Gabby and Jesse. I guess he and I have come full circle-from basketball hoops to hoop earrings!
QVC: Is that how you became interested in the jewelry business?
QVC: Can you tell us about your role at the company?
QVC: How does your family life blend with your business life?
QVC: What are you most looking forward to during your QVC appearances?
Shop Judith Ripka's 100-Facet Diamonique® TSV® Necklace >


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Bifana Boys, Piri Piri Sauce (Hot) - 355ml
ith the Traditional Portuguese Sauce made by Cavameida, the Bifana Boys will serve a delicious Portuguese Pork Sandwich (Bifana) with Original Sauce, Hot Sauce or Piri Piri.
A local favourite - a wide variety of uses - ENJOY!!
Located in London, Ontario, Bifana Boys operates both a Food Truck and satellite location at the Farmers and Artisans Market at The Western Fair, serving Portuguese fusion food.
We serve a wide variety of dishes, like Piri Piri Chicken, Angry Fries and our signature favourite - the Bifana Sandwhich - "marinated pork slices in a bun". Don't be fooled by its simplicity, this well-made sandwich will zap you with a lightning bolt of flavours, unlike any other bifana available in London.
Ingredients; Vinegar, garlic, hot peppers, olive oil, spices, salt, sugar, spices, black pepper, lemon, chili peppers, xanthan gum


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Instruments: Piano, Voice
Scoring: Piano/Vocal/Chords
Key: A Minor (Transposable)
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Download sheet music and print it instantly, and sync your digital sheet music to the FREE Musicnotes PC, web and mobile apps. Choose from digital sheet music for new and popular songs, including "Never Gonna Break My Faith", , or click the button below to browse all sheet music.
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book, book review, books, read, reading list, reviews, to read
The Captain's Daughter by Jennifer Delamere
Little description:Warm-Hearted Victorian Romance Brings 1880s London to Life
When a series of circumstances beyond her control leave Rosalyn Bernay alone and penniless in London, she chances upon a job backstage at a theater that is presenting the most popular show in London. A talented musician and singer, she feels immediately at home and soon becomes enthralled with the idea of pursuing a career on the stage.
A hand injury during a skirmish in India has forced Nate Moran out of the army until he recovers. Filling his time at a stable of horses for hire in London, he has also spent the past two months working nights as a stagehand, filling in for his injured brother. Although he's glad he can help his family through a tough time, he is counting the days until he can rejoin his regiment. London holds bitter memories for him that he is anxious to escape. But then he meets the beautiful woman who has found a new lease on life in the very place Nate can't wait to leave behind.
Genre: Historical Fiction/ Christian Romance
Find the book on Amazon here.
My thoughts: 5 stars out of 5
Rosalyn Bernay shared her hardship in life: orphaned from the young age, with a father lost at sea, and with two sisters in the same orphanage, she learns to trust God no matter what. At seventeen, she went to another city to earn her living, yet something went amiss with her possition as lady's companion. One unfortunate incident left her without job, penniless and ruined her reputation, stamping her as a thief. Running away for her life, Rosalyn stops in London, the grand city of many great opportunities, but soon she learns, the capital had its dark, ugly side…. Escaping from the brothel, she wanted to keep her dignity intaked…. she finds there is God's hand in everything. With a new job offer, which she come across accidently, she was made a dresskeeper in one of the theaters…
Amazing story of hope and courage, faith in God and hardship of life….
Provided by Litfuse as a complementary copy for my opinion and review.


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List of Nokia Android Smartphones It's been so long we all were guessing about Nokia's most awaited Android versions. Finally Nokia is going to launchRead more
Category: Nokia Updates
Meet the Nokia's first Android Smartphone : Nokia 6
Now finally this is official that Nokia is coming up with Android smartphones. Everyone was waiting for this kind of launch for such a longRead more
Nokia returns, it will launch Android phone
There are a huge amount of android users all over the globe but still there are few people those who are diehard fan of Nokia.Read more


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I recently worked an event where the sports court only provided about 1 meter free zone along the sidelines and less than 0.5 meters along the end lines. The area outside the playing surface was a cement surface. The tournament director instructed officials to allow players to serve from the cement beyond the end of […]Read More | No Comments
Archive for March, 2015
Is this sport court allowable for USAV-sanctioned events?
31 Mar 2015 at 10:52
Closed Poll: Back Row Situation
10 Mar 2015 at 10:07
THE POLL In the scenario pictured below, the setter on the left (#3) is a back-row player and is making the team's second contact. As a referee, what call, if any, would you make? No fault; play continues. (20%) Reaching over by the blockers, team on the left gets the point. (12%) Attack-hit fault on […]Read More | No Comments


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Can you help prepare accounts?
Could you help us prepare our annual accounts? WinACC is looking for an accountant to assist in the preparation of our annual accounts for inspection by an independent examiner. The role is advisory and a modest reimbursement is foreseen. Full details are available from the volunteering website.
Send expressions of interest to our Treasurer Bill Gunyon email@example.com.


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Flies in the Philippines
Learn more about the lifecycle and habits of flies
Call us for a free quote on (02) 333 5888
We have a range of insect light traps to cater different business needs and requirements. All of them use a unique technology to hygienically and effectively capture flying insects. Unlike conventional Electric Fly Killers with high voltage killing grids that simply zap flying insects and leave a litter of insect fragments and contaminated spores, the units we use are safe and hygienic because it uses UV light technology to attract insects and then traps them on a hidden glue board and/or adhesive film.
Also the range we use is completely silent in operation – getting rid of flying insects discreetly. All our units work against all sizes of flying insect, and are quickly and easily serviced by our Service Technicians saving your business time, money and trouble.
Our Electronic Fly Killer range, Luminos, are suitable for a range of internal environments and a wide variety of businesses with specific requirements for highly effective fly control. Each unit in the Luminos range has its own unique feature, but all fly killers are designed to be hygienic, highly effective and meet all legal, health and safety requirements.
They have been scientifically tested using a Half Life Measurement to ensure optimum performance.
Call Rentokil today on (02) 333 5888 or 1800 10 397 3787 (Toll Free) or contact us online for electric fly killers.
Luminos 3 Plus has been specifically designed to offer effective fly control using a unique encapsulation technology. This approach to fly control works by trapping insects on an adhesive film at the bottom of the unit, which automatically winds at regular intervals, to help mitigate the risks of contamination from dead insects.
This unit can be used from medium to high infestation as the unit offers the option to add a rear glue board aligned with the encapsulation to further increase catch rate in higher risk areas.
Luminos 3 Plus is available in silver, white and blue and can be used in public areas.
Luminos Sapphire is a discreet and attractive unit specifically designed for front of house fly control, where both discretion and effectiveness are essential. It has a modern design that offers a stylish and effective way of controlling flying insects in public areas.
It is suitable for light usage or Low risk areas where aesthetics and fit within customer décor is important
*313 tests carried out on 87 units affecting 31300 flies over a 28 month period (2010)


text: All-new HYDROXYCUT HARDCORE ELITE was built from the ground up with one purpose in mind: to provide you with an unbelievable training experience. This formula contains key amounts of Oxylia®, theanine, theobroma and caffeine. It could also enhance your sensory experience. Plus, HYDROXYCUT HARDCORE ELITE could help you support weight loss with the key ingredient (Oxylia® - kidney bean, olive and rosemary), which has been shown to be effective. Add it to your diet and training programme, because now it's time for you to experience what a real weight loss support formula could do for you.


text: Overview Program description Dr. William Worrall Mayo, the founder of Mayo Clinic, began nurse anesthesia education in 1889. Mayo Clinic's nurse anesthesia program is the oldest continuously operating school of nurse anesthesia. The practice of nurse anesthesia at Mayo Clinic involves the management of a patient's anesthetic care by a certified registered nurse anesthetist (CRNA). Most anesthetics are provided within the care team environment. When you successfully complete the Mayo Clinic School of Health Sciences Doctor of Nurse Anesthesia Practice (DNAP) Program, you are able to provide: Preanesthetic preparation and evaluation Explain upcoming medical procedures and anesthesia to patients Assemble and test the medical equipment needed to administer anesthetics Prepare prescribed solutions and start intravenous infusions Perform preoperative physical assessment Anesthesia induction, maintenance and emergence Administer prescribed anesthetics, fluids, blood products and medications Monitor patients to ensure anesthesia is maintained Monitor patients during anesthesia and respond appropriately to vital signs and emergency situations, if necessary Record each patient's vital signs, anesthetic procedures and case management — as well as all anesthetics, fluids and medications administered — before, during and after surgery Postanesthetic care, recovery and assessment Contributions to practice and profession Enhanced evidence-based practice (EBP) Critically evaluate and appraise research Utilize technology to improve patient outcomes Incorporate evidence-based practice principles into anesthetic care Evaluate health care systems and environments for feasibility of clinical practice change Participate in interprofessional and intraprofessional collaboration to affect practice improvement and enhanced patient outcomes Participation in efforts to improve health policy and health care access for various patient populations Mayo Clinic's Department of Anesthesiology uses state-of-the-art equipment and techniques. Approximately 80,000 anesthetics are administered at Mayo Clinic each year in the following areas: Cardiovascular surgery Obstetrics Diagnostic and interventional procedures Ophthalmic surgery Emergency surgery Orthopedic surgery General surgery Otorhinolaryngology surgery Outpatient surgery Outfield procedures Neurological surgery Pediatrics Plastic surgery Thoracic surgery Transplant surgery Ambulatory surgery Accreditation The DNAP Program at Mayo Clinic School of Health Sciences is accredited (October 2013 to 2023) by the Council on Accreditation of Nurse Anesthesia Educational Programs. Council on Accreditation of Nurse Anesthesia Educational Programs 222 S. Prospect Ave. Park Ridge, IL 60068-4001 Phone: 847-655-1160 Fax: 847-692-7137 See accreditation information for Mayo Clinic College of Medicine and Science. Facilities The Mayo Clinic campus in Rochester, Minnesota, includes an extensive outpatient complex, Mayo Clinic Hospital — Rochester (Saint Marys and Methodist campuses), and substantial research and education facilities. This Mayo Clinic site is among the largest, most advanced medical centers in the world. Also, six small rural hospitals in Minnesota, Wisconsin and Iowa are utilized for a senior clinical rotation. Take a virtual tour of Mayo Clinic's campus in Rochester, Minnesota. Graduation and certification After successfully completing the program's coursework and passing the second National Self-Evaluation Exam (SEE), you are awarded a Doctor of Nurse Anesthesia Practice (DNAP) degree from Mayo Clinic School of Health Sciences, a part of Mayo Clinic College of Medicine and Science. Graduates of the program are eligible to take the national certification examination administered by the National Board of Certification and Recertification for Nurse Anesthetists. Hours For the majority of the 42-month program, the learning schedule varies according to your academic, clinical and research schedules. Some weekend and off-shift calls are required. The average program time commitment is 60 hours a week. Class size Each year, Mayo Clinic School of Health Sciences admits up to 26 students in its DNAP Program at Mayo Clinic's campus in Rochester. This ensures you receive a comprehensive educational experience with close instruction. Aug. 01, 2018 Share Facebook Twitter Email Quick facts Program length: 42 months Prerequisites: Must be an R.N. with a Bachelor of Science degree in nursing or a Bachelor of Science or Bachelor of Arts degree in a science-related field. A minimum of one year (more than two years highly preferred) of ICU clinical experience as an R.N. is required. Postanesthesia care unit and emergency room experience is not accepted as the type of ICU experience required by our program. Granted: DNAP degree from Mayo Clinic School of Health Sciences Patient interaction: High Placement outlook: Excellent Related Link Program benchmarks Career information Find out more about working in this area, including career opportunities and earnings potential. Nurse Anesthesia ARC-20282711 Mayo Clinic College of Medicine & Science Mayo Clinic School of Health Sciences Academics Nurse Anesthesia Doctor of Nurse Anesthesia Practice Program (Minnesota)


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22 Wisconsin Ave W, Tomahawk WI 54487 $270,000
Features of 22 Wisconsin Ave W Tomahawk WI 54487
- CommercialProperty
- Status: Active
- County: Lincoln
- Property Taxes: $2,912
- Property Tax Year: 2017
- Listing Company: Re/Max Property Pros - Tomahawk
Property Description for 22 Wisconsin Ave W Tomahawk WI 54487
22 Wisconsin Ave W Tomahawk WI 54487 - WISCONSIN AVE RESTAURANT- This Tomahawk bar & grill is a favorite among locals & visitors and has a reputation for great food & fun atmosphere. Open the doors and maintain the current, successful restaurant model, or try your own fare. It is a meeting place for friends during several big events, including the Fall Harley Rallies, Car Shows, and parades. Completely renovated inside & out since 2009, including the upstairs living quarters/rental units. The large open sun deck w/outdoor serving area and adjacent volleyball court is a feature that few taverns offer. The upgraded kitchen features new flat grill, sandwich bar, dual deep fryers, 6-burner stove, cooling units, ovens, & chinaware! The bar includes 10 beer taps, several coolers, & plenty of seating. Electrical is updated and certified code compliant. Current leagues include volleyball, softball, & baseball teams. Rental income for the upstairs units is currently $450/mo (1BR) & $550/mo (1+BR), and tenants pay heat/electric.
Interior Features
- Heating/Cooling: Central Air, Forced Air
Building and Construction
- Flooring: Laminate
- Roof: Rubber
Land Features
- Waterfront/Access: N
|MLS Number
|New Status
|Previous Status
|Activity Date
|New List Price
|Previous List Price
|Sold Price
|Mar 30 2018 3:22PM
|Sep 4 2015 1:20PM
Estimated Monthly Payment
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Community Homes Near 22 Wisconsin Ave W
The information which is contained on pages with property data is obtained from a number of different sources and which has not been independently verified or confirmed by the various real estate brokers and agents who have been and are involved in this transaction. If any particular measurement or data element is important or material to buyer, Buyer assumes all responsibility and liability to research, verify and confirm said data element and measurement. Shorewest Realtors is not making any warranties or representations concerning any of these properties. Shorewest Realtors shall not be held responsible for any discrepancy and will not be liable for any damages of any kind arising from the use of this site.
REALTOR *MLS* Equal Housing Opportunity


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BRUSSELS (Reuters) – The European Union reached outline agreement on Friday to impose the first economic sanctions on Russia over its behaviour in Ukraine but scaled back their scope to exclude technology for the crucial gas sector.
The EU also imposed travel bans and asset freezes on the chiefs of Russia's FSB security service and foreign intelligence service and a number of other top Russian officials, saying they had helped shape Russian government policy that threatened Ukraine's sovereignty and national integrity.
FSB director Alexander Bortnikov and Mikhail Fradkov, a former prime minister who now heads the foreign intelligence service, were among 15 Russians or Ukrainians and 18 companies and other organizations named in the EU's latest sanctions list.
Also sanctioned were the secretary of Russia's Security Council, Nikolai Patrushev, Chechen leader Ramzan Kadyrov, who the EU said had made statements supporting Russia's annexation of Ukraine's Crimea region and the insurgency in eastern Ukraine, and several Ukrainian separatist leaders.
After months of hesitation, the EU is set to go beyond asset freezes by imposing sanctions on sectors of the Russian economy.
The 28-nation EU toughened its stance towards Moscow following last week's downing of a Malaysian airliner, killing 298 people, in an area of eastern Ukraine held by Russian-backed separatists.
EU ambassadors reached a preliminary agreement on Friday.
Read more at Reuters


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This is a rush transcript from "On the Record," February 14, 2013. This copy may not be in its final form and may be updated.
GRETA VAN SUSTEREN, FOX NEWS HOST: Now to the family members waiting very anxiously to see their relatives get off that ship. The ship is now -- as Jonathan has said, it's in sight. That's good news. this has been the cruise from hell.
Jon Hair's wife is on that cruise. He and his 8-year-old son, Jace, are waiting at the Mobile port. They are joining us live. And Jon's wife, Julie is joining us by phone from on board the ship.
Julie , it must look great if you can see -- can you see the port from where you are, Julie?
JULIE HAIR, PASSENGER (Via Telephone): We can. We can.
VAN SUSTEREN: And how good -- how good is that feeling to be able to see it? Because I can tell you...
JULIE HAIR: Oh, I...
VAN SUSTEREN: ... your son...
JULIE HAIR: Mobile is...
VAN SUSTEREN: Your son and husband are there.
JULIE HAIR: Mobile's the most beautiful city I've ever seen in my life!
VAN SUSTEREN: Jon, how about for you? What's it been like these last five days? Have you talked to your wife? Have you heard what the conditions were like?
JON HAIR, HUSBAND OF PASSENGER: I have not spoken with her since Monday until this afternoon. I can't explain how happy I was to hear her voice again and know that she was OK. I want to say happy Valentine's to my lovely wife and my sweet Julianna.
VAN SUSTEREN: Jace, this is -- obviously, your mother is safe, so that's great news. You're going to see her in just a few moments, as soon as that ship pulls in. But I'm curious. Jace, what do you think happened? What's your understanding about what happened to this ship?
JACE HAIR, PASSENGER'S SON: Well, I heard that it caught on fire and I was worried. But now I know that they're safe and I'm glad...
VAN SUSTEREN: She is safe. Julie, tell me, what's it like to hear your son and husband's voice?
JULIE HAIR: Oh! Yes, oh, that's so unbelievable. I haven't cried because I didn't want to upset my little girl, but here now, that's brought tears to my eyes for sure.
VAN SUSTEREN: Well, they are very excited to see you, and all the family members who are gathered and they're watching around the country as this ship pulls in. So Julie, now that it's almost over, how bad has it been?
JULIE HAIR: Bad. It's been very bad. The conditions in the rooms are just horrible. There's no bathrooms, so you can imagine the smell. But the crew has been unbelievable. They've been very helpful, I mean, coming down the hallways and picking up people's restroom belongings in the hallway (INAUDIBLE) and you walk down the hall, and there are just red bags laying all down the hallway. It's just miserable.
And then the food, they've done their very best, but it's -- it's just not -- it's not what we're used to eating. People are wanting McDonald's. That's what we want, McDonald's. That's our first stop. And a big -- a big diet Coke with lots of ice, is what I want.
VAN SUSTEREN: Well, I hope your husband -- can you hear that, Jon, what she wants? She wants a big diet Coke and McDonald's. Can you take care of that.
JON HAIR: I've got it. We'll be right on the way, yes, ma'am.
JULIE HAIR: Just ice, ice -- we want three glasses of ice. All of us want three glasses of ice. There's been no ice on the ship since Sunday.
JON HAIR: Coming right up.
VAN SUSTEREN: Jace, before I let you go, what are you going to say to your mother when you see her?
JACE HAIR: I love you, and happy Valentine's. And I'll hug her and do everything and make her feel welcome.
JULIE HAIR: I love you, Jace! And I love you, honey. Happy Valentine's Day. I can't wait to see you.
VAN SUSTEREN: All right, well, it's very exciting...
JON HAIR: Thank you, and thanks to all of our church families.
JULIE HAIR: Yes, I'm ready to see them.
VAN SUSTEREN: All right, well, that ship...
JON HAIR: Because Greta, we've been showered with love.
VAN SUSTEREN: That ship will be there soon. I don't know if you guys were warned, but it may take a couple hours for people to get off. But it'll be there soon. Thank you to all of you.


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Choc orange swirl fudge is a smooth scrumptious Jaffa tasting delight.
Gluten free.
Posted by Nic on 11th Jul 2013
This is my favourite spotted dog fudge, you get both the chocolate and orange flavours coming through so well together, sometime I bite one at a time. I could eat it all day!
Posted by Eloise on 27th Apr 2013
So far this is my favourite spotted dog fudge flavour, soo yummy and just melts in your mouth!


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*Courtesy of Richard Beckman Realty Group
4580 E State Route 106
Union, WA 98592
Vacant Land
0 Beds
0.00 Baths
0 SqFt
1.35 acres of Hood Canal Waterfront with a sweeping view of Hood Canal, Olympic Mountains & the Skokomish Valley. The lot has a cleared building site & is ready to build. All the preliminary work has been complete, power, phone and water are to the property. Includes septic drainfield. Prime location near marina, cafe, store, Alderbrook golf course, Robinhood restaurant and Alderbrook Resort and Spa. 100' of waterfront on Hood Canal. Owner Terms available 20% Down, 7% interest, 5 year call.
Listing Number: 803667
Lot Details
- Lot Size: 1.35 acres
- Dead End Street
- Topography: Sloped
- Road: Paved
- Electricity: On Property
- Water: Available
- Water: On Property
- Gas: Not Available
- Sewer: Not Available
- District: Hood Canal #404
- Elem: Hood Canal Elem& Jnr
- Middle: Hood Canal Elem& Jnr
- High: Shelton High
Call or Email:
Pat Lord
(206) 395-4584
What's Near 4580 E State Route 106, Union, WA 98592?
More Homes Near 4580 E State Route 106, Union, WA 98592
Information is based on data available to the associate, including county records. The information has not been verified by the associate and all information presented should be verified by the buyer. Listings marked with the "Three Trees" logo are provided by Northwest Multiple Listing Service. The associate represented on this web site is not a multiple listing service but is a member of a local MLS. DMCA Notice


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LinkedIn Taps Nye as Chief Executive
Networking Firm Makes Strong Push Toward Expansion
LinkedIn Corp. has recruited former Advent Software Inc. executive Dan Nye to become chief executive, as the closely held online professional-networking company prepares for expansion.
Mr. Nye, 40 years old, was executive vice president and general manager for Advent's Investment Management unit, whose software is used by financial professionals. He assumes his new position effective tomorrow.


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Does anyone know this story? Bella was attacked and raped in the woods by one of the wolves not knowing which one it was, she leaves town and becomes a cop I believe in NYC and she has a deal with the Volturi to be changed when her kid is grown. Sam comes and tells her that Charlie was shot in his house, she doesn't want to go back but her daughter runs off to Forks so she comes back to protect her kid and look into Charlie's case. The shooter and Bella's attacker turn out to be Sorry but you are not allowed to view spoiler contents.Thanks for your help. Mod edit: please be considerate of those who have not read the story.
Love this thread! Seeing a lot of new stories that i'm gonna have to read now Maybe someone can help me out? Someone know this Wolf pack story:It's a story about Jacob as Alpha, but the whole pack is scared of him. He lives alone, with long hair despite being a wolf. Bella and Paul have imprinted, but Paul cheats and is not how an imprint is supposed to be. Despite being somewhat intimidated by Jacob's demeanor, Bella and he form a slow bond, ultimately breaking the imprint with Paul. Jacob and Bella have a son in the end, and wolf pack learns to deal with Jacob ultimately making Jacob's house the pack house they all meet.Does this ring a bell? I've read it once, absolutely loved it, but can't remember the author or the title Thanks a lot!
This sounds like this story but it a Sam/Bella story.The Alpha's PrerogativeBy: taoist elf Imprinting, marriage and mating. Duty, choice and need. What do these things have to do with love? In the midst of a failing marriage and strained imprint, Bella is about to find out. It's complicated, when is it ever not? Bella/Sam some Paul. No poly anything.Rated: Fiction M - English - Angst/Romance - Bella, Sam - Chapters: 7 - Words: 77,384 - Reviews: 1,239 - Favs: 1,743 - Follows: 727 - Updated: Oct 8, 2013 - Published: Sep 12, 2013 - Status: Complete - id: 9680711
Hey, a long long time ago, there was a website dedicated to Wolfpack stories only and I can not think of the website. Can anyone think of the website? It's actually driving me crazy. Sent from my iPhone using Tapatalk
To the reader looking for a pregnancy fic by Jusobele, I am sure you are referring to a story titled "Lifelines" by taoist elf. It is short and sweet and Jacob is amazing. Here is the link from fanfiction.net :You are not allowed to view links.
Register or LoginTaoist elf is tremendous and wonderful. Jusobele too, though those stories were pulled from fanfiction.net a long time ago.I hope this is what you thought it was!
Hi! I'm not sure if this is the right place to ask but, I've been looking for a story for awhile now and was hoping someone would be able to assist. I'm not sure which site I read it on but it was most likely fanfiction.net.Details: Paul imprinted on Bella after Edward left in New Moon. Due to her heartbreak they aren't like a normal imprint couple. The do live together and sleep in the same bed but don't have sex. At some point they started sleeping naked. I do remember Paul telling Bella, when she asks, that he is just waiting for her to be ready before they become a real couple.I think it was a completed story and was a one-shot but could be wrong. I don't recall the name of the story or the author.Thank you for your help!
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Kentucky Senator and Republican presidential candidate Rand Paul said he will vote against the Iran nuclear deal, but it's "absurd" to tear it up immediately at Wednesday's primetime debate on CNN.
Rand was asked about fellow candidate Wisconsin Governor Scott Walker arguing the White House should cancel the state dinner for Chinese president Xi Jinping. He answered, "I think this goes back to essentially what we've been saying for the last two or three questions. Carly Fiorina also said we're not going to talk with Putin. Well, think if Reagan had said that during the Cold War. We continued to talk with the Russians throughout the Cold War, which is much more significant than where we are now. Should we continue to talk with Iran? yes. Should we cut up the agreement immediately? That's absurd. Wouldn't you want to know if they compiled? I'm going to vote against the agreement, because I don't think there's significant leverage, but it doesn't mean that I would immediately not look at the agreement and cut it up without looking to see whether Iran is compiling. The same goes with China. I don't think we need to be rash. I don't think we need to be reckless. And I think we need to leave lines of communication open. Often we talk about whether we should be engaged in the world, or disengaged in the world, and I think this is an example of some who want to isolate us, actually, and not be engaged. We do need to be engaged with Russia. It doesn't mean we give them a free pass, or China a free pass, but to be engaged means to continue to talk. We did throughout the Cold War and it would be a big mistake not to do it again."
Follow Ian Hanchett on Twitter @IanHanchett


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Steven Green is a contemporary fine art and travel photographer based in El Paso, Texas.
Purchase original fine art photography in a variety of themes for your home or business art space by Steven Green of El Paso, Texas.
Other works and additional information available at the official website and blog.
Steven Green Photography
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How Do You Create More Happiness?
How Do You Create More Happiness?- In this video I talk about something that all human beings are chasing- more happiness!
How To Overcome Depression
How To Overcome Depression- Depression effects every person in one way or another, find out how you can bring yourself out of depression when it hits!
Improving Negative Moods
Improving Negative Moods- Is this video I guide you through techniques for improving your moods & creating more happiness in your life!
How To Stop Negative Thoughts
How to stop negative thoughts- In this video I give you techniques for stopping negative thoughts & replacing them with more positive ones!
Taking Responsibility
In this video I talk about the empowement that comes from taking responsibility in your life!
Human Needs
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Physical Health
In this video I will be discussing Physical health. How to improve your Physical health through exercise, nutrition and by looking after your spiritual, emotional & mental health. LINK TO PHYSICAL HEALTH PDF https://twitter.com/PotentialChange https://www.facebook.com/PotentialForChange
Mental Health
In this video I will be discussing mental health. What is mental health & how you can improve your mental health. https://twitter.com/PotentialChange https://www.facebook.com/PotentialForChange
Emotional Health
In this video I will be discussing emotional health. What emotional health is & how you can improve your emotional health.


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Hello Truck Drivers! Welcome to this week's edition of Tuesday Tunes. We hope you enjoy the entertainment we have selected for you this week from Leland Martin. I've got to admit the beginning of this video makes me feel a bit like I'm stuck in a horror movie waiting for something to jump out, but the song rings true for so many of our highway heroes, driving truck for the long haul.
So tell us, truck drivers, how was your week on the road? We want to hear from you! There is always a lot of talk about the work / life balance for truck drivers. Do you feel like you are getting that from your current trucking job? Do you earn the salary you want and get the home time you need? If you are in search of something different than what you now get from your current trucking company employer, take a moment while you are here to review our trucking company profiles. There are plenty of trucking companies who are hiring truck drivers with your qualifications on CDLjobs.com.
During your week on the road, truck drivers can connect with CDLjobs.com using any of the social media links at the top of the page. We will keep you informed about items of interest within the trucking industry, as well as notify you of breaking news or new truck driver job openings at some of America's top carriers. Thank you for your continued interest and support of CDLjobs.com. We hope we are helpful to you finding a new job within the trucking industry. Let us know how your search for a trucking job works out! We want to hear from you.
Until next week, thank you for visiting Tuesday Tunes and have a safe week!


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Costa Rica: Caution if Placing your Yacht in Bond
Published: 2012-05-09 21:51:57
Countries: Costa Rica
Posted 11 January, 2012
We arrived at the Costa Rica Yacht Club (CRYC), Puntarenas, on July 29th 2010 and left our catamaran there for 6 months.
As stated in their web site, the CRYC had agreed that while we were away, they would proceed to renewing the customs formalities.
To that purpose, we paid Carlos Chinchilla, the manager, for 6 months moorings fees in advance.
We left the CRYC on August 10th 2010. During our stay in France we sent several mails to check if everything was fine, but never received any answer. Eventually on January 13th 2011, Lisseth GUZMAN, in charge of Public Relations for the CRYC, notified us that the manager was no longer on the payroll of the CRYC.
When we came back to the CRYC on February 21st 2011, we realized that nothing had been done concerning the customs formalities.
On February 28th 2011 we wrote to President Calderon to ask him what arrangements he intended to make to sort out our situation regarding the customs regulations. No answer has been received yet.
We went to the CRYC Annual General Meeting in order to meet President Calderon before or after the meeting, but our attempts to see him were not successful.
We then decided to settle our balance, close our account and leave Costa Rica illegally. We did so on March 12th 2011 with a boat that was not really prepared to complete the long strenuous crossing of the Pacific Ocean.
We have been sailing round the world for over thirty years, visiting more than twenty countries. We have never been confronted to such a situation.
Jean-Luc Avignon
SY Woulib
(Editors Note: The Costa Rica Yacht Club were asked to comment on this incident prior to publishing, but no reply was received. Noonsite however were told that Carlos Chinchilla was dismissed along with some others who worked for him following complaints that had been going on for some years. On 8 May, 2012, noonsite received an e-mail from the CRYC with an apology and explantion of their side of the story).
Posted 9 May, 2012
Response from the Costa Rica Yacht Club
On behalf of the Board of Directors of the Costa Rica Yacht Club, I would like to apologize for the difficulties encountered by Mr. Jean-Luc Avignon when leaving his catamaran in-bond at the Club for six months starting August 2010.
Mr. Avignon´s comments are correct. The unacceptable situation that he describes in his noonsite.com note was unfortunately caused by inefficiencies and irregularities directly attributable to the Administration in charge of the Club at that time. Nevertheless, the General Manager was removed over one year ago (the Club proceeded to take legal action against him) and the management structure was satisfactorily modified.
Also, as of the end of year 2011, the Board composition changed, being now headed by Mr. Humberto di Palma, a seasoned yachtsman and a highly respected Costa Rican businessman. Mr. di Palma´s enthusiastic work and plans are now being supported by a group of Board members and administrative personnel who are highly capable and willing to help our visitors in all of their needs.
The Costa Rica Yacht Club has existed for decades and it is a Pacific Coast icon. Many visitors and sailors -some now retired or long gone- have cherished and shared the memorable and pleasant experiences they lived at the Club... we invite you to visit us and be part of that heritage.
Gonzalo J. Gonzalez
Vice-President, Costa Rica Yacht Club


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|This is a "sponsored post." The company who sponsored it compensated me via a cash payment, gift, or something else of value to write it. Regardless, I only recommend products or services I use personally and believe will be good for my readers. I am disclosing this in accordance with the Federal Trade Commission's 16 CFR, Part 255: "Guides Concerning the Use of Endorsements and Testimonials in Advertising."
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Shark Shack
one of our favorites! Two corn tortillas stuffed with your choice of cheese, chicken, or beef and then topped with red or green sauce, jack & cheddar cheese, and sour cream
fresh dungeness crab stuffed inside a flour tortilla and finished off with our green sauce, jack & cheddar cheeses, and sour cream
rice, refried beans, salsa, and choice of meat
rice, refried beans, sour cream, guacamole, fresh salsa, jack & cheddar cheeses, your choice of chicken or steak, and finally topped off with our delicious red enchilada sauce, and melted jack & cheddar cheeses
large flour tortilla filled with Spanish rice, whole pinto beans, cheese, lettuce, guacamole, sour cream and fresh salsa.
a flour tortilla with melted jack & cheddar cheeses served with sour cream, guacamole, and fresh salsa
rice, refried beans, cheese, sour cream, guacamole, salsa & choice of chicken or steak
hot fudge brownie topped with vanilla ice-cream
cheese cake rolled up in a flour tortilla, deep fried, and topped with raspberry sauce and whipped cream it's to die for!
a slice of the best cheesecake on this side of town
don't do dairy? Then try our sorbet! Raspberry or mango.
back by popular demand
lettuce, red cabbage, shredded carrots, tomatoes, and of course croutons. Ranch, bleu cheese, thousand Island, or Italian
hearts of romaine lettuce, tomatoes, shredded parmesan cheese, lemon, and fresh dungeness crab. Ranch, bleu cheese, thousand Island, or Italian
premium hearts or romaine lettuce tossed in our delicious caesar dressing and topped with crunchy croutons and freshly grated parmesan cheese
large salad with a grilled mahi-mahi or salmon, it's a meal in itself it's so tasty, your taste buds won't believe it
a caesar topped with strips of grilled steak
caesar salad topped with grilled chicken
a crispy flour bowl filled with pinto beans, lettuce, fresh guacamole, sour cream, fresh salsa, and cheese
delicious shredded beef or chicken wrapped in corn tortillas and deep fried to a perfect crisp. Topped with pico-de gallo, guacamole & sour cream (6 pieces)
chicken wings cooked in delicious spicy BBQ sauce (served w/ranch)
this is not your average guacamole. Freshly made to order with avocados, diced tomatoes, cilantro, and a hint of lime. It takes the tortilla chip to a whole new level
the regular stuff plus chicken or ground beef
the regular stuff plus chicken or ground beef
not'yo average nacho. A mountain of flavor! tortilla chips smothered with jack & cheddar cheeses, refried beans, fresh salsa, guacamole, and sour cream (jalapenos available upon request)
succulent shrimp sauteed in butter garlic sauce & pine-nuts, and then topped with onions, cilantro, red cabbage, and diced tomatoes.
tender salmon grilled with butter, lemon & our famous "wipe-out" sauce. Topped with onions, cilantro, red cabbage, & diced tomatoes
the meanest taco in the seal blackened shark with chipotle sauce, onions, cilantro, red cabbage, and chopped tomatoes.
yeah, yeah, yeah, we know ground beef, shredded lettuce, onions, tomatoes, jack & cheddar cheeses, and an incredible sauce all served inside of a seasoned crispy shell so gringo but ooooh soooo good!
steak grilled to perfection with the freshest pico-de-gallo in town (we don't open the can until you order it), it's also topped with cilantro, onions, diced tomatoes, and cheese.
perfectly cooked (blackened) mahi-mahi served with our wipe out sauce, onions, cilantro, red cabbage, and diced tomatoes.
tasty shredded beef, shredded lettuce, chopped tomatoes, onions, cilantro, and jack & cheddar cheeses all inside of a crispy shell.
shredded chicken, whole pinto beans, guacamole, sour cream, cheese, and fresh pico-de-gallo.
shredded pork Carnitas, whole pinto beans, guacamole, sour cream, fresh pico-de-gallo and cheese you've gotta try it!
sauteed red snapper served with our famous "wipe-out" sauce, onions, cilantro, red cabbage, and diced tomatoes.
Menu for Shark Shack provided by Allmenus.com
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Exploring the Pathway: The RAS/RAF/MEK/ERK Pathway in Cancer: Combination Therapies and Overcoming Feedback
Targeting of signaling pathways has come of age in cancer research, with sustained effort in understanding signaling identifying a number of therapeutic targets that are beginning to improve clinical outcomes for patients with cancer. Leading the way has been one of the most important pathways in cancer—the RAS/RAF/MEK/ERK pathway. Signaling is typically complex, with many pathways showing multiple points of divergence to intersect with other molecules and signaling pathways. One of the best-understood and most simple pathways is the RAS/RAF/MEK pathway, summarized in Figure 1. In this pathway multiple, signals are funneled into MEK and ERK kinases, allowing a nodal point for therapeutic targeting.
A wide range of cell-surface molecules activate RAS (KRAS, NRAS, and HRAS), a family of GTPases that act as a molecular switch, turning on downstream RAF protein kinases (BRAF, CRAF, and ARAF). The dominant substrates of RAF kinases are the MAPK/ERK kinases, MEK1, and MEK2. Intriguingly, MEK kinases appear to have only one main substrate extracellular signal–regulated kinase (ERK). This is unusual for protein kinases that are often relatively promiscuous but has led to the use of phosphorylation of ERK to identify small molecules capable of inhibiting signaling of the RAS/RAF/MEK/ERK pathway.
Downstream of ERK, the pathway becomes more complex due to ERK's many substrates.1 Activation of ERK generates extensive changes in gene expression mediated by transcription factors that control cell cycle progression, differentiation, protein synthesis, metabolism, cell survival, cell migration, and invasion and senescence.1 Indeed, activation of ERK leads to cells acquiring many of the hallmarks of cancer. Moreover, ERK directly regulates by phosphorylation pro-apoptotic molecules such as BAD.2 As such, targeting the pathway is an extremely attractive option to overcome the malignant phenotype, and it is not surprising that upstream components of the pathway, such as the RAS GTPases and RAF kinases, are potent oncogenes.
RAS Mutations in Cancer
RAS proteins containing activating mutations that prevent cycling between GTP and GDP and lead to constitutive activation of RAF kinases in cells are the most common oncogenes in human cancer.3 It is estimated that approximately 30% of human cancers contain such mutations, resulting in a staggering 3 million new cancers diagnosed worldwide each year with RAS mutations. Importantly, mutated RAS proteins are also the most potent of human oncogenes, leading to profound changes in cells that in cooperation with other events can transform normal cells into fully malignant cancer cells.4 It is no wonder that targeting RAS has attracted the interest of the pharmaceutical industry and remains a holy grail of the therapeutic targeting of oncogenes.
RAS mutations have been described in both hematologic and solid-tumor malignancies. Different cancers based on cell type of origin show a propensity to mutate different RAS isoforms. For example, NRAS mutations dominate in hematologic malignancies and melanoma, whereas KRAS is the dominantly mutated isoform in colorectal and lung cancers.5 The reason for this is not clear but may relate to levels of expression of the isoforms in different cell types or differences in the capacity of each isoform to activate downstream signaling in a cell type–dependent manner. So despite the fact that RAS mutations have been described in the vast majority of types of cancer, the cellular context remains important with respect to which isoform is mutated.
Cancers with the most frequent RAS mutations are pancreatic cancer (90%), colorectal cancer (40%), non-small cell lung cancer (30%), bladder cancer (30%), peritoneal cancer (30%), cholangiocarcinoma (25%), and melanoma (15%). In contrast, lymphomas, acute lymphoblastic leukemia, hepatocellular carcinoma, osteosarcoma, and prostate cancer less commonly contain RAS mutations.5
One critical area of study involved with improved understanding of signaling in RAS-mutated cancers and more efficient exploitation of this knowledge therapeutically is the dependence of RAS signaling on RAF, MEK, and ERK kinases. Understanding this is essential because RAS can activate other signaling pathways, and attempts to target RAF, MEK, or ERK downstream of RAS would be futile if these kinases were not critical components of RAS signaling. Elegant studies from Dr. Barbacid and colleagues5 on using sophisticated gene-targeting techniques to generate RAS-less cells have been very informative. Strikingly, the proliferative defects in RAS-less cells can be completely restored with activated MEK, telling us that MEK, and by inference ERK, are indeed critical components of RAS signaling. Similar studies have also implicated cyclin-dependent kinases, critical regulators of cell cycle progression, downstream of ERK in RAS signaling6; therefore, inhibition of MEK has shown activity in RAS-mutated cancers7,8 and preclinical studies implicate inhibition of CDK4 as one approach to target cancers with RAS mutations.9 Early clinical data is promising, with the MEK inhibitors trametinib, cobimetinib, pimasertib, and MEK-162 all showing some activity in RAS-mutated cancers.10,11 Although escalation of the dose of MEK inhibitors is limited by cutaneous and gastrointestinal toxicity,10 these clinical studies support the importance of MEK as a key downstream mediator of the cellular effects of mutant RAS in cancer cells.
BRAF Mutations in Cancer
The pioneering work of Drs. Stratton, Futreal, and colleagues12 in identifying mutations in BRAF in human cancer has opened up profound new therapeutic opportunities for the management of cancer. Overall, 6% of human cancers contain activating mutations in BRAF13 that result in more than 500,000 new cases of BRAF-mutated cancer diagnosed worldwide each year.5 Similar to RAS mutations, BRAF mutations are profoundly oncogenic in cooperation with other genetic events and are capable of fully transforming normal cells. In contrast to RAS, a GTPase that has not been successfully targeted directly with small molecules, the BRAF protein kinase has been successfully directly targeted with a number of BRAF inhibitors that have striking clinical results including vemurafenib,14 dabrafenib,15 and LGX818.
Intriguingly, despite expression of the CRAF isoform in most cells, mutations in CRAF are extremely rare.5 One possible explanation for this observation might relate to structural differences in BRAF and CRAF with respect to the ability of these kinases to function as monomers or dimers, with mutated BRAF able to strongly activate downstream signaling as a monomer, a property not shared by CRAF. However, CRAF is an important component of the signaling pathway and is particularly important in mediating signaling through RAS and upstream cell-surface molecules.
BRAF is activated most commonly by single amino acid substitutions but can also be involved in translocations with other proteins resulting in active fusion proteins. Fusion proteins have been described in pilocytic astrocytomas16 and spitzoid melanocytic neoplasms.17 The various point mutations lead to variable biochemical activation of BRAF with amino acid substitutions at and around valine 600, potently activating the kinase activity as assessed biochemically in vitro and, most importantly, generating a kinase resistance to feedback inhibition that typically occurs when the pathway is activated upstream in cells with wild-type BRAF (feedback inhibition is described in greater detail further in this editorial).18 The most common mutation in BRAF by far is the substitution of valine 600 by glutamic acid (V600E), which accounts for more than 85% of the BRAF mutations in melanoma, more than 50% of the mutations in non-small cell lung cancer, and more than 95% of mutations in colorectal cancer, cholangiocarcinoma, and hairy-cell leukemia.5 Lower-activity mutations have been described in a variety of malignancies including melanoma, lung cancer, and prostate cancer, but whether these mutated proteins activate signaling of the MEK/ERK pathway sufficient to induce dependence on MEK and ERK remains untested.19
Just as RAS-mutated cells are dependent on MEK, it is clear that cells harboring the common- and high-activity BRAF mutation, V600E, are dependent on MEK and, by inference, ERK signaling for cell survival and proliferation. This is clearly validated in the landmark METRIC clinical trial that randomly assigned patients with melanoma who harbored BRAF V600E mutations to the MEK inhibitor trametinib or to dacarbazine.20 Not only did patients in the trametinib arm show tumor regressions, proving the dependence of BRAF V600E on MEK for cell survival, but there was an overall survival advantage for these patients as well. There is no doubt that melanomas with V600E mutations are dependent on MEK. However, response rates for trametinib (22%) are clearly lower than those observed for BRAF inhibitors vemurafenib, dabrafenib, or LGX818 (approximately 40%-60%).20,21 The reasons for this most likely relate to the inability to escalate the doses of MEK inhibitors to sufficiently inhibit MEK because of adverse events, whereas BRAF inhibitors can be escalated to a dose that inhibits BRAF, as well as downstream MEK and ERK signaling in the tumor, more potently.
Targeting the RAS/RAF/MEK pathway
Both BRAF (vemurafenib and dabrafenib) and MEK inhibitors (trametinib) are now approved for the treatment of BRAF-mutated melanoma, clinically validating the ability of inhibiting the RAS/RAF/MEK pathway to achieve meaningful benefit for patients. Yet a number of key questions and challenges remain. First and foremost is whether the pathway can be targeted to achieve clinically meaningful outcomes in patients with RAS mutations. The response rates to the first-generation of MEK inhibitors in RAS-mutated cancer is modest7,8 (< 10%) and may be insufficient to achieve clinically meaningful results. The first RAF inhibitor sorafenib, a type 2 inhibitor, does not have significant activity in RAS-mutated cancer. Like the newer type I RAF inhibitors, sorafenib may in fact promote signaling in RAS-mutated cells22; therefore, it is clearly not sufficient to inhibit the pathway in RAS-mutant cells. ERK inhibitors are in clinical development, but whether ERK inhibitors can be escalated to a dose to sufficiently inhibit ERK activity without significant toxicity in patients with RAS-mutated cancers is likely to be a challenge, given the relationship between MEK and ERK in signaling. As discussed further, combination therapy may be the best approach to adequately inhibit the pathway in cells and tumors with RAS mutations.
Another key question is whether the pathway can be inhibited when other upstream components of signaling are activated, most prominently cell-surface receptors including receptor tyrosine kinases and G-protein–coupled receptor (GPCR) complexes. Here the same challenges as with RAS emerge as limiting factors. These challenges are made greater by the ability of these receptors to activate other signaling pathways, most prominently the PI3K/AKT/mTOR pathway23 but also protein kinase C-signaling in the case of GPCRs.24 In these cases, dual or multiple pathway inhibition may be required. This is being pursued clinically, although to date it remains uncertain if, once again, toxicity in normal tissue will allow sufficient dose escalation to adequately inhibit the dual or multiple pathways. Early clinical results suggest this might be the case with, for example, the combination of MEK and PI3K inhibitors due to significant toxicity without impressive clinical efficacy.25
Paradoxical Activation of the RAS/RAF/MEK Pathway by BRAF Inhibitors
If targeting the RAS/RAF/MEK pathway is difficult because of toxicity in normal tissues as doses are escalated, then why can type 1 BRAF inhibitors, such as vemurafenib and dabrafenib, be delivered at doses that provide such profound efficacy? The answer was a surprise and relates to the ability of these compounds to potently inhibit activity of mutated BRAF proteins while actually activating RAF-dependent signaling in normal cells.26,27 Therefore, these compounds display an ideal property for a drug that inhibits signaling: potent inhibition of signaling in cancer with no significant inhibition of signaling in normal cells.
Type I inhibitors bind to the kinase in its active conformation (type 2 inhibitors bind to the inactive conformation) and result in the formation of active heterodimers with unbound wild-type BRAF or unbound CRAF.26,27 These heterodimeric complexes between an inhibited molecule and an active molecule will result in enhanced activation of the active molecule when upstream signaling is activated by mutation in RAS or by activation of cell-surface receptors (Fig. 2). As normal cells use ligand-dependent activation of receptors to regulate cell proliferation of normal tissues (e.g., EGFR in the skin), type I BRAF inhibitors can activate MEK and ERK signaling in normal cells, resulting not only in the absence of hypoproliferative toxicities but actual promotion of hyperproliferative toxicities.14,28
Fig. 2
Fig. 2
This phenomenon of "paradoxical activation" reaches the point of clinical importance when considering the ability of type I BRAF inhibitors to promote proliferation of RAS-mutated– cutaneous cancer and possible other RAS-mutated cancers.14,28,29
Feedback Control of the Output of the RAS/RAF/MEK Pathway—Implications for Treatment
A increasingly studied concept in the understanding of signaling in normal and malignant cells is the ability of pathways to regulate their own output through feedback mechanisms. This phenomenon may be critical to allow cells to achieve the fine balance between dysregulated signaling and uncontrolled cell proliferation (a hallmark of cancer) as well as the capacity to switch pathways on or off when needed for physiologic purposes.
Seminal work from Dr. Rosen and colleagues18 has identified a profound difference in signaling through RAF -kinases, in particular BRAF, when it is activated by mutations compared to activation by more physiologic upstream processes. Mutated BRAF phosphorylates MEK and activates ERK, with notably different downstream molecular consequences when compared with activation of BRAF or other RAF kinases by upstream processes such as engagement of receptor tyrosine kinases by their ligands.18,30 These differences can be quantitatively assessed by examination of gene expression at the mRNA level. Why is there such a fundamental difference? It appears to be related to feedback control by a series of downstream molecules that inactivate upstream components of the pathway. In particular ERK itself and the ERK-regulated phosphatases DUSPs and SPRYs can affect upstream kinases to regulate their activity (Fig. 3). However, these molecules have limited capacity to do this when BRAF is activated by mutation.18 This creates a signaling cascade profoundly different between normal and malignant cells and has contributed the exciting outcome of selectivity of BRAF inhibitors for mutant versus wild-type kinases allowing inhibition of signaling in melanoma, colorectal cancer, thyroid cancer, lung cancer, and other malignancies harboring activation mutations in BRAF at position V600 with relatively limited effects on signaling in normal cells. Other mechanisms may also be involved including inhibition of ERK, which increases expression of ligands for receptor tyrosine kinases and provides a further feedback mechanism that may reduce some of the consequences of ERK inhibition.18
What do we know about feedback control of the cells with RAS mutations? Mutations of RAS lock it in the GTP-bound form and prevent the cycling of GDP and GTP that normally occurs with wild-type RAS. This constitutively activates the RAF/MEK/ERK pathway and drives proliferation, survival, and other changes in cells that contribute to the malignant phenotype. RAS also activates other pathways, such as the PI3K/AKT and RAC1 pathways.31 However, the effects on the RAF/MEK/ERK pathway are important for transformation. Interestingly, the model presented above (Fig. 3) would suggest that activation of the RAF/MEK/ERK pathway by mutant RAS would result in feedback inhibition of RAF kinases, and indeed this appears to occur with significantly lower output of the pathway in RAS-mutated compared with BRAF-mutated cells.8 However this lower activation of ERK appears to be sufficient to mediate the consequences of enhanced signaling induced by mutant RAS because inhibition of MEK and ERK can reverse the malignant phenotypes of some RAS-mutated cells lines.
Fig. 3
Fig. 3
Future Prospects for Achieving Cancer's Holy Grail: Targeting RAS
The most common mechanism of acquired resistance to BRAF inhibitors in BRAF-mutant melanoma is the acquisition of new genomic events that reactivate MEK and ERK signaling though the emergence of activating mutations in NRAS, amplification of BRAF, increased expression of a truncated form of BRAF, and in some instances new mutations in MEK. This has led to the idea that resistance may be overcome, or indeed prevented, by more effective targeting of the pathway. The leading approach to achieve better inhibition of the pathway has been the combination of type 1 BRAF inhibitors with MEK inhibitors such as dabrafefenib plus tranetinib, vemurafenib plus cobimetinib, and LGX818 plus MEK162. Both the combinations of dabrafefenib plus tranetinib and vemurafenib plus cobimetinib show activity in patients acquiring resistance to single-agent BRAF inhibition, and dabrafefenib plus tranetinib has been shown to be superior to single-agent dabrafenib in delaying the emergence of resistance with improvement in median progression-free survival from 5.8 to 9.4 months32 that has led to recent U.S. Food and Drug Administration approval of this combination.
It is worth reflecting on why this combination is successful. The ability of inhibiting the same pathway at two points may not only lead to greater inhibition of the pathway though addictive effects but may also affect feedback mechanisms in a favorable way, allowing more sustained inhibition of output of the pathway. Strikingly, the toxicity of the combination of dabrafenib and trametinib appears to be associated with less toxicity than single-agent dabrafenib,32 suggesting that the downstream inhibition of MEK activated by paradoxical activation allows for normalization of signaling in normal cells and less toxicity.
The most common mutation associated with reactivation of the pathway in patients who develop acquired resistance to BRAF inhibitors is acquisition of mutations in NRAS that activate ERK by signaling through CRAF.33-35 The addition of a MEK inhibitor in this scenario, therefore, can reduce this reactivation of MEK and ERK through direct inhibition of MEK and can also potentially affect feedback pathways to reduce signaling. As such, the combination of RAF and MEK inhibitors may have activity in RAS-mutated cancers.
Given all of this information, it has been postulated that MEK inhibitors may have activity in RAS-mutated cancers. However, results have been disappointing, with low response rates. Recently, data have emerged suggesting that feedback activation of MEK may limit activity of MEK inhibitors in RAS-mutated cancers.36 The allosteric MEK inhibitor GDC-0623 inhibits feedback phosphorylation of MEK and, therefore, appears to be more active in RAS-mutated cells. If this observation is broadly applicable in RAS-mutated cancers, it could lead to the development of the first effective targeted approach for the treatment of RAS-driven malignancy.
The other approach to target mutant RAS aims to inhibit multiple pathways activated by RAS, such as the combination of MEK inhibitors and PI3K inhibitors.37,38 However, this approach is challenging because toxicity from this combined-pathway approach is significant and contrasts to the combination of BRAF and MEK inhibitors, in which toxicity of the combination was reduced compared with BRAF inhibitors alone. The paradoxical activation phenomenon as seen with BRAF inhibitors—with direct targeting of the consequences of paradoxical activation by immediate downstream inhibition of MEK—contrasts to the diverse roles of both MEK and PI3K pathways in normal cells, with limited cross talk between the PI3K and MEK pathways. Nonetheless, RAS-mutated cells might be more sensitive to the combined inhibition of these pathways when compared with normal cells, so the combination approach continues to be worthy of further attention.
The rapid advancement in strategies to target signaling in cancer cells led by small molecules targeting the RAF/MEK/ERK pathway is fundamentally changing the approach to treating cancer. With major advances in targeting cancers with BRAF mutations now achieved, it remains pertinent to not only more effectively target this pathway to reduce toxicity and improve efficacy but also to turn our gaze to the role of this pathway in RAS-mutated cancers.


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SITC Hosts 2nd Annual Little Me Spring Event
Last year, children's clothing designers Little Me opened their first ever shop within shop, at Lord & Taylor. To celebrate that launch, I hosted an event, in the luxury department store. The event was such a success, that we arranged a similar gathering around Christmas time. And now, this past weekend, I hosted the…Read More


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Portugal is one of the countries in Europe that I would like to visit someday. It is the best place for romance, adventure and family vacations. I want to see Lisbon, the city of Seven Hills, which is prized for its mixture of tradition and modernity and stayed in one of its best hote's like the Pestana Palace. I also like to visit Fatima, a place known for the famous apparitions that took place there in 1917. Fatima is 80 miles North of Lisbon but transportation is not a problem. You can board a bus that has good view of the landscape through its large windows or if you want private vehicles there are cheap cars for hire. Sometimes finding cheap cars for hire can be tiring but not with 121 Car Hire Portugal. Their car rental comparison search is completely free to use, and whether you are after a 4×4 or a family car, you will definitely find what you need and you'll enjoy a hassle free vacation.
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We asked our Newcastle United writers to pick three things Steve McClaren must do this weekend to ensure the Magpies don't slip back after their encouraging draw against Chelsea.
1, Pick up where they left off against Chelsea - at the 60 minute mark that is
The Magpies were fantastic for the first hour last weekend but then it was almost like they forgot what to do.
If they start the game how they finished against Chelsea they could be in for a long afternoon. They must focus on the things they got right last weekend.
2, Stop conceding ridiculous free-kicks
Newcastle were in the driving seat when Moussa Sissoko started doing his own thing. He conceded two cheap free-kicks and one of them cost Newcastle the win last weekend.
You don't need me to tell you how many players Man City have with Toure, Navas and De Bruyne all ready to have a crack.
3, Make sure Mitrovic and Perez get the right service
There was a great moment in the game against Chelsea when Vurnon Anita pinged a fine ball across the park for Perez to fire home. But there's still plenty of room for improvement for more service from out wide.
Sissoko isn't doing it at the moment and Florian Thauvin has been disappointing. Gini Wijnaldum, though, performed well last weekend and the time could now come for Sylvain Marveaux again if others don't deliver.
Should Moussa Sissoko keep his place for the Manchester City match?
1, Remain positive and have a go
By this I do not mean suddenly go all gung-ho, because then Manchester City will have a field day and Newcastle fans will have just be forced to endure the latest in a long line of depressing days at The Etihad.
However, it is essential that the Magpies show the same positivity and attacking intent they displayed against Chelsea last week. They must counter-attack with pace, purpose and be direct - just as they were last weekend. In defence they must remain solid, but if they go to just shut up shop they will be beaten heavily because they are not good enough defensively. It is about being smart and attacking at the right moments.
Man City are vulnerable too right now and played in midweek. It's worth having a bit of a go at them.
2, Field an unchanged team
The XI who played (bar possibly Sissoko) against Chelsea were magnificent for 75 minutes - they deserve another chance to impress.
Steve McClaren must hold his nerve and persist with the same side in the hope that they can build on last week's performance. Manchester City have struggled in recent weeks when teams have really gotten after them and shown an intent going forward. Should Newcastle do that, they could yet get a positive result from this match.
The players who played last weekend will have bolstered confidence too, despite conceding two late goals, and that could see them grow as the game progresses - should they make Man City nervous.
McClaren needs consistency in selection for once, starting with this match.
3, Finish the game stronger
As good as United were for 75 minutes last weekend, in the final 15 they began to wilt. They cannot afford a repeat this weekend or they will be picked off mercilessly by Man City and their superstars.
Fitness levels should not be a problem at this stage of the season, even if United will likely be running around the field for the majority of this one without possession, so it's essential the players maintain their concentration for 90-plus minutes this time.
Against both Southampton and Chelsea Newcastle have come unstuck late on in games. They must ensure they do not repeat that against The Citizens - because hopefully they will still be fighting for at least a point by that stage of the game.
1, Play Perez
Ayoze Perez simply has to play. His work-rate and endeavour against Chelsea set the tone, and there is the beginning of a really good partnership with Aleksandar Mitrovic, who has – perhaps – been slightly too built up this week.
Mitrovic was great, a talisman if you will, but Perez was the grease in the wheels of a far more fluent performance. If he's off the team sheet – or even moved from the central role he got against Chelsea – it sends the wrong message.
2, Don't abandon Florian Thauvin
Thauvin was a new sort of dreadful against Sheffield Wednesday. The Daily Mail gave him 1/10 and he could have very few complaints about that mark given his wastefulness in possession and lack of ideas or intent.
But we know how this one goes at Newcastle. A bad performance, momentum turns against the player, he loses confidence, the manager writes him off and then a talented player's United career is over.
Thauvin needs to be kept involved and you know what, Saturday might not be the worst time to give him his head. Manchester City looked dreadfully exposed when players ran at them on Wednesday. Maybe this is the kick-start Thauvin needs.
3, Don't let Moussa Sissoko coast
One week until the international break. Last time out it was suggested that Sissoko sat out the Manchester United game to protect himself for France – a claim the club denied.
He'll play in this one, no doubt. But if he doesn't step up then his place is a legitimate issue to debate during the long international fortnight.


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Wednesday, January 19, 2011
Ulcerate – The Destroyers Of All
Label: music
hanya untuk review saja belilah Ulcerate – The Destroyers Of All atau pasang sebagai nada sambung pribadi di handphone kamu, agar musisi Indonesia terus tetap berkarya. link download Motorhead – The World is Yours by | 4shared | ziddu | mediafire | indowebester | rapidshare | FreeFastUpload | UserShare | Hotfile |
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Mediocre Bad Guys: A Short Story
- Ten Thousand Words or Less, Book 11
- Narrated by: Tom Jordan
- Length: 44 mins
- Unabridged Audiobook
- Release date: 24-08-17
- Language: English
- Publisher: CCS Publishing
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Regular price: £3.79
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Customer ReviewsMost Helpful
By Aimee on 31-08-17
Thoroughly enjoyed this modern tale.
Would you recommend this audiobook to a friend? If so, why?
Yes. Because the book deals with shades of grey when it comes to assessing human behaviour, as opposed to narrow black and white thinking that so dominates our society at this time.
What was one of the most memorable moments of Mediocre Bad Guys: A Short Story?
Without leaving a spoiler, I'll just say I didn't see what happened right before the end coming.
What about Tom Jordan's performance did you like?
Tom's narration added just the right amount of nuisance combined with a super smooth delivery that really made the story engaging.
Did you have an emotional reaction to this book? Did it make you laugh or cry?
Yes. I laughed at the line, 'the hardest thing she was going to have to do for dinner was to run the microwave.'
Customer ReviewsMost Helpful
By R. MCRACKAN on 25-08-17
Morally complex tale of medical care
Any additional comments?
The first third of the story sets up a heart wrenching sober situation that we all hope we never have to face. What follows are a few dull trudging scenes where we follow the main character through some mundane life choices, until she turns on the television. Once she sees the protests on TV, the story jolts into an intense emotional space from which it never returns.
I'm not sure there are any heroes or villains here. At moments, the story flirts with vilifying religion. But then the hospital operating officer isn't exactly lionized either. The final minutes were difficult and unsatisfying. No heroes, no villains, and no satisfying resolution. Grimly appropriate for the subject matter.
The narration somehow does a good job of keeping this world detailed, visual, and immersive while balancing the focus on story and characters.
This book was given to me for free at my request and I provided this voluntary review.
2 of 2 people found this review helpful
By Janice Deane on 07-09-17
Insightful and Inciteful
Mediocre Bad Guys is an insightful, and even an inciteful work about the healthcare industry. This richly provocative short story was skillfully narrated by Tom Jordan, who did a great job making the characters deeply emotive and relatable. A profound story with a twist that I won't soon forget.
1 of 1 people found this review helpful


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OK this is a slighty off-topic post so I apologise in advance and promise to resume craft blogging soon. I've just come home from mothers group and one of those shopping trips that ends with upset children and an embarrassed and frazzled Mummy. As we were heading for the exit after grabbing a few groceries my almost 2yo decides to bolt for the door that leads directly onto the road. The millisecond I go to run after her, my 4yo pulls my arm and everything in my hand or hanging on it crashes to the ground, including a drink I was holding. I am momentarily halted before I can go chasing after the mischievous one, catching her a few metres from the door. I then race the 20m or so back with her under my arm to the 4yo and the mess all over the floor. Meanwhile quite a crowd had stopped to watch all of this as I was yelling at my naughty girl to stop repeatedly as I was chasing after her. A really nice older man helped me get everything back together. I thanked him and then hurried out to the car, glad to be going home.
I get home and about to post a comment on facebook, as you do these days, when I started to read this article along with all the comments posted by other readers. Suddenly I don't feel as angry at my kids or embarrassed. Just glad they are both OK and that we are free to live another day.


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Winning Metaphors
At Office Retreats, Tales of Adversity Fire Up the Staff
Tiring of CEOs' Triumphs, Bosses Book Speakers Who Beat Blindness, Paralysis
CORONADO, Calif. -- At their annual retreat last month, 300 finance managers for Cisco Systems Inc. began the week with strategy meetings, followed by team sand-castle building and water-balloon launching. Then came the visit from a blind man.
He was Erik Weihenmayer, a slim, athletic 38-year-old. In an after-lunch speech, he recounted his bitterness as a teenager over losing his sight. He explained how he channeled his anger into rock climbing and dreamed of climbing Mount Everest. "People said I'd kill myself or my team...


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Information about the company tested and proven on-site.
Company-supplier verification services: China Credit Information Service (P.R.C.) Ltd. [CCIS (PRC)]
Business license (registration number): 04844404
Date of issue of the license: 1986-12-05
The registered capital of the company: NTD 6,000,000
Company Name: HERDSMAN ENTERPRISES CO., LTD.
Country / Territory: Taiwan
Registered address: 6F., No.166, Sec. 5, Roosevelt Rd., Taiwan
Year of Incorporation: 1986
Issuing Authority: Taipei City Government
Operational Address: 6/F, No. 166, Sec. 5, Roosevelt Road, Taiwan
Full Name of Applicant: Mr. Kea Ming Cheng
Department of the Company: Management Dept.
Position in company: Vice General Manager
You have worked with the company HERDSMAN ENTERPRISES CO., LTD.? Do you think this company scams?
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