text:
Latest Titles With Fran Kranz
- Job Types
- Movies or TV
- Genres
- Keywords
- IMDb Rating
- Instant Watch Options
- In Theaters
- On TV
- Release Year
Dating Rules from My Future Self (2012– )
Chapter Five: Be YR Own Wingwoman
7 min | Comedy
One way to get over your loser ex is to hook up with a "sorbet": one night only-then he melts! Meet Lucy's tasty love-life palate cleanser on chapter 5 of Dating Rules From My Future Self, starring Shiri Appleby
Writer: Wendy Weiner | Director: Elizabeth Allen Rosenbaum | Stars: Alison Becker, Mircea Monroe, Fran Kranz, Shiri Appleby
Dating Rules from My Future Self (2012– )
Chapter Six: Open Yr Eyes
7 min | Comedy
The twelve-step program to get over dating a jerk includes hook-ups and house parties-but does flirting with your ex's roommate take things a step too far?
Writer: Wendy Weiner | Director: Elizabeth Allen Rosenbaum | Stars: Shiri Appleby, Alison Becker, Mircea Monroe, Taylor Kinney
3. The Dark Tower (2017)
Adventure, Fantasy, Sci-Fi | Post-production
Gunslinger Roland Deschain roams an Old West-like landscape in search of the dark tower, in the hopes that reaching it will preserve his dying world.
Writers: Nikolaj Arcel, Akiva Goldsman, Anders Thomas Jensen, Stephen King, Jeff Pinkner | Director: Nikolaj Arcel | Stars: Idris Elba, Katheryn Winnick, Matthew McConaughey, Jackie Earle Haley
4. Rebirth (I) (2016)
100 min | Thriller
A white-collar suburban father Kyle (Fran Kranz) who is surprised at his office by long-lost college buddy Zack (Adam Goldberg). Zack is as wild and crazy as ever, brimming with excitement ... See full summary »
Writer: Karl Mueller | Director: Karl Mueller | Stars: Fran Kranz, Adam Goldberg, Nicky Whelan, Kat Foster
Votes: 826
5. A Midsummer Night's Dream (2016)
Comedy | Post-production
Creator: William Shakespeare | Director: Casey Wilder Mott | Stars: Finn Wittrock, Paz de la Huerta, Ted Levine, Rachael Leigh Cook
6. The Truth About Lies (2016)
94 min | Comedy, Romance | Post-production
Gilby finds himself in a tangled web of lies when the truth proves to be too much to admit and even harder to accept.
Writer: Phil Allocco | Director: Phil Allocco | Stars: Odette Annable, Chris Diamantopoulos, Colleen Camp, Mary Elizabeth Ellis
7. Bloodloss (2016)
Thriller | Announced
BLOODLOSS is the story of a reporter who infiltrates a secret society of people who worship the vampire myths.
Writer: Jason Dolan | Director: Jason Dolan | Stars: Fran Kranz, Alex Essoe, Jordan Blair Mangold Brown, Ian Collins
TripTank (2014– )
TV-MA | 21 min | Animation, Comedy
Roy had a bad memory and steve has to go inside him and destroy it.
Creators: Sean Donnelly, Matt Ferrucci, Daniel Katz, Matt Mariska, Alessandro Minoli, Thomas O'Donnell, Joe Plichter, Andrew Sipes, Dana Snyder, Zach Stafford | Directors: Sean Donnelly, Daniel Katz, Aaron Long, Alessandro Minoli, Joel Moser, Mike Roberts, Christopher Romano, Ben Bjelajac, David de Rooij, Niall Madden, Chris Osbrink, Skyler Page | Stars: Pamela Adlon, Jason Alexander, Eric Bauza, Alison Becker
TripTank (2014– )
TripTank 2025
TV-MA | 21 min | Animation, Comedy
Stand-Up Dad's family is unhappy with his "Rocko" character, Bootf**ker McGillicutty hosts another edition of "Pills, Pills, Pills," and the noble Sir Ian fights a warlock.
Creators: William Brasington, Sean Donnelly, Ryan Hudson, Jeroom, Michael Mcalister, Alessandro Minoli, Kyle S. More, Peter Nelson, Chris Osbrink, Rohitash Rao, Jared Tweedie, Greg White | Directors: Ben Bjelajac, Sean Donnelly, Eric Hoff, Aaron Long, Alessandro Minoli, Mike Roberts, Crystal Stromer, Chris Weller, Joe Corrao, Sean Lee, Chris Osbrink, Nathan Palm | Stars: Carlos Alazraqui, Jason Alexander, Diedrich Bader, Dan Bakkedahl
10. Mojave (2015)
R | 93 min | Thriller
A suicidal artist goes into the desert, where he finds his doppelgänger, a homicidal drifter.
Writer: William Monahan | Director: William Monahan | Stars: Oscar Isaac, Garrett Hedlund, Louise Bourgoin, Cletus Young
Votes: 1,889
11. Bloodsucking Bastards (2015)
Not Rated | 86 min | Comedy, Horror
An action-packed horror comedy, BLOODSUCKING BASTARDS stars Fran Kranz as Evan, a dutiful and overworked employee stuck at a soul-killing corporation with his beautiful co-worker and ... See full summary »
Writers: Dr. God, Ryan Mitts | Director: Brian James O'Connell | Stars: Fran Kranz, Pedro Pascal, Joey Kern, Joel Murray
Votes: 3,233
12. Exposed (2015 TV Movie)
An investigative journalist relies on questionable methods in order to expose the truth.
Writer: Charles Randolph | Director: Patty Jenkins | Stars: Mary Elizabeth Winstead, Pedro Pascal, Ben Barnes, Sandrine Holt
Votes: 7
13. TripTank (2014– )
TV-MA | Animation, Comedy
The sickest, most twisted animated shorts ever put on television.
Creators: Matt Mariska, Andrew Sipes, Sean Donnelly, Alessandro Minoli, Dana Snyder, Thomas O'Donnell, Mike Roberts, Josh Mecouch, Chris Osbrink, Daniel Katz, Peter Nelson, Rohitash Rao, Jeroom, Chris Weller, Felix Colgrave, Andy Herd, Will Hettinger, Matt Ferrucci, Andrew Racho, Chris Allison, Jacob Andrews, Kyle S. More, Eoin Ryan, Brian Studler, Abram Makowka, Reza Farazmand, Natalie Hazen, Jesse Nylund, Paul McLalin, Greg White, Wes Citti, Brian Frisk, Bill Oakley, Tony Wilson, William Brasington, James Carr, Ryan Hudson, Joe Plichter, Guy Shelmerdine, Zach Stafford, Scott Swayze, Matthew Vescovo, Tofer Chin, Jed Hathaway, Deirdre Devlin, Ralph Guerra, Douglas Paszkiewicz, Dustin Rhoads, Nick Mouyiaris, Tom Gianas, Tim Saccardo, Jeff Sloniker, Alex Digiacinto, Joel Moser, Ed Salazar, Peter Hoare, Marc Moceri, Seth Cohen, Amy Pocha, Alex Anfanger, Tommy Blacha, Will Carsola, Shane Dering, Kurtis Estes, Nicholas Gurewitch, Evan Keogh, Mike L. Mayfield, Jordan Morris, Bob Odenkirk, Johnny Roque, Dan Schimpf, Jamie Spicer-Lewis, Dave Stewart, Dean Swanton, Zack Bornstein, Ian Camacho, Aaron Chrenen, Bo Crutcher, Kyle Dooley, Jon Ethridge, Ari Grabb, Ben Lepley, Avery Monsen, John Paliferro, Tyler Riggers, Benjamin Smolen, Paul Stanton, Robert Yulfo, Jason Antoon, Mike Clattenburg, Max Crandall, Jonny Cruz, Jc Currais, Mike Hollingsworth, Landon Kirksey, Shaan Kirpalani, Damir Konjicija, Dario Konjicija, Michael Mcalister, Murderfist, Jeff Newman, Mark Raterman, Ray Timmons, Jared Tweedie, J.C. Currais | Stars: Eric Magnussen, Dana Snyder, Jonah Ray, Matt Mariska
Votes: 664
14. Before I Disappear (2014)
93 min | Drama
At the lowest point of his life, Richie gets a call from his estranged sister, asking him to look after his eleven-year old niece, Sophia, for a few hours.
Writer: Shawn Christensen | Director: Shawn Christensen | Stars: Shawn Christensen, Fatima Ptacek, Emmy Rossum, Paul Wesley
Votes: 6,478 | Gross: $0.00M
15. Murder of a Cat (2014)
Not Rated | 101 min | Comedy, Crime, Mystery
A man investigates the murder of his cat.
Writers: Christian Magalhaes, Robert Snow | Director: Gillian Greene | Stars: Fran Kranz, Nikki Reed, J.K. Simmons, Blythe Danner
Votes: 967
16. The Living (2014)
R | 89 min | Crime, Drama, Mystery
A man hires an ex-con to kill his sister's abusive husband, but the desperate act sets into motion a shocking series of events in this intense indie drama.
Writer: Jack Bryan | Director: Jack Bryan | Stars: Fran Kranz, Jocelin Donahue, Kenny Wormald, Chris Mulkey
Votes: 1,731
17. Lust for Love (2014)
Not Rated | 85 min | Comedy, Romance
Astor's happy tenacity spoils his one chance at love with his lifelong crush Mila. Convinced he needs more experience with women to win her back, he engages her ex-best friend Cali to teach... See full summary »
Writer: Anton King | Director: Anton King | Stars: Fran Kranz, Dichen Lachman, Beau Garrett, Caitlin Stasey
Votes: 1,191
18. Last Weekend (2014)
94 min | Comedy, Drama
When an affluent matriarch gathers her dysfunctional family for a holiday at their Northern California lake house, her carefully constructed weekend begins to come apart at the seams, leading her to question her own role in the family.
Writer: Tom Dolby | Directors: Tom Dolby, Tom Williams | Stars: Patricia Clarkson, Zachary Booth, Joseph Cross, Chris Mulkey
Votes: 670 | Gross: $0.01M
19. The Lord of Catan (2014)
13 min | Short, Comedy
A husband and wife find themselves thrust into an apocalyptic rivalry over a game of Settlers of Catan.
Writer: Stuart C. Paul | Director: Stuart C. Paul | Stars: Amy Acker, Fran Kranz
Votes: 44
20. Doc of the Dead (2014)
81 min | Documentary
The definitive zombie culture documentary, brought to the screen by the makers of THE PEOPLE vs. GEORGE LUCAS.
Writers: Chad Herschberger, Alexandre O. Philippe | Director: Alexandre O. Philippe | Stars: Kyle William Bishop, Charlie Adlard, Joanna Angel, Steven Barton
Votes: 1,011
21. Seven Lovers (2014)
108 min | Drama, Romance
A young woman cycles through seven relationships, each one depicted in a distinct cinematic style. As she adapts all-too-seamlessly to the world of each new partner, she begins to ask herself the question: who am I when I'm not in love?
Writer: Keith Boynton | Director: Keith Boynton | Stars: Fran Kranz, Erin Darke, Peter Mark Kendall, Gia Crovatin
22. The GQ Hangover Lab (2014– )
Stars: Fran Kranz, Keller Wortham
The Broadway.com Show (2013– )
Episode #2.29
Writers: Lindsay Champion, Ryan Lee Gilbert, Imogen Lloyd Webber, Beth Stevens, Paul Wontorek | Stars: Annaleigh Ashford, Elizabeth Ashley, Will Brill, Rose Byrne
Dallas (2012–2014)
Like Father, Like Son
43 min | Drama
On the heels of Bobby's appointment as Railroad Commissioner, John Ross scrambles to find the funds to keep the Arctic lease deal alive, even if it means betraying those who love him most. ... See full summary »
Creators: David Jacobs, Cynthia Cidre | Director: Steve Robin | Stars: Josh Henderson, Jesse Metcalfe, Jordana Brewster, Julie Gonzalo
Votes: 73
Dallas (2012–2014)
Like a Bad Penny
43 min | Drama
As Bobby and Ann work to get Sue Ellen released, John Ross pushes ahead on his plans for control of Ewing Global, enlisting the help of one of J.R.'s last business partners. Meanwhile, ... See full summary »
Creators: David Jacobs, Cynthia Cidre | Director: Millicent Shelton | Stars: Jesse Metcalfe, Josh Henderson, Jordana Brewster, Julie Gonzalo
Votes: 66
Dallas (2012–2014)
Victims of Love
42 min | Drama
As Ewing Global goes public, twists and turns abound while everyone scrambles to claim ownership. Pamela struggles with what to do now that she knows Cliff didn't really kill J.R., and ... See full summary »
Creators: David Jacobs, Cynthia Cidre | Director: Ken Topolsky | Stars: Josh Henderson, Jesse Metcalfe, Jordana Brewster, Julie Gonzalo
Votes: 58
27. The Broadway.com Show (2013– )
Weekly round-up of the hottest news stories on Broadway, written by and starring the Broadway.com editorial staff.
Stars: Lindsay Champion, Beth Stevens, Paul Wontorek, Ryan Lee Gilbert
Votes: 20
28. Seasick Sailor (2013)
23 min | Short, Crime, Drama
A lonely teenager working as a debt collector for an underground gambling ring in Los Angeles tries to fit in with a new group of friends.
Writer: Torre Catalano | Director: Torre Catalano | Stars: Keir Gilchrist, Martha MacIsaac, Al Sapienza, Brandon Jay McLaren
Votes: 10
29. Grow (2013 TV Movie)
26 min | Comedy
Writer: Paul Mastroianni | Director: Jonathan Kesselman | Stars: Matt Ballard, Ashley Bell, Rob Benedict, Adam Busch
30. Bad Sports (2013– )
Stars: Miles Fisher, Dan Gill, David Branson Smith, Amanda Lund
Votes: 8
The Good Wife (2009–2016)
A More Perfect Union
TV-14 | 44 min | Crime, Drama, Mystery
Alicia's case involving at-will employees trying to unionize sparks a possible mutiny at Lockhart Gardner. Meanwhile, Peter gives Alicia an opportunity to renew their wedding vows, but he also needs her help on the campaign.
Creators: Robert King, Michelle King | Director: Michael Zinberg | Stars: Julianna Margulies, Matt Czuchry, Archie Panjabi, Graham Phillips
Votes: 248
Bad Sports (2013– )
Chad Hails the Redskins
Stars: Miles Fisher, Dan Gill, Fran Kranz
Bad Sports (2013– )
Fuck Marry Kill, NBA JAM Edition
Stars: Miles Fisher, Dan Gill, Fran Kranz, Amanda Lund
Bad Sports (2013– )
Movie Night with Chad Whipple
Stars: Miles Fisher, Dan Gill, Fran Kranz, Amanda Lund
35. The Cabin in the Woods (2012)
R | 95 min | Fantasy, Horror, Mystery
Five friends go for a break at a remote cabin in the woods, where they get more than they bargained for. Together, they must discover the truth behind the cabin in the woods.
Writers: Joss Whedon, Drew Goddard | Director: Drew Goddard | Stars: Kristen Connolly, Chris Hemsworth, Anna Hutchison, Fran Kranz
Votes: 275,887 | Gross: $42.04M
36. Dallas (2012–2014)
42 min | Drama
The next generation of the Ewing family - cousins John Ross Ewing and Christopher Ewing - clash over the family's oil business and vast fortune.
Creators: Cynthia Cidre, David Jacobs | Stars: Josh Henderson, Jesse Metcalfe, Jordana Brewster, Julie Gonzalo
Votes: 9,016
37. Much Ado About Nothing (I) (2012)
PG-13 | 109 min | Comedy, Drama, Romance
A modern retelling of Shakespeare's classic comedy about two pairs of lovers with different takes on romance and a way with words.
Writers: Joss Whedon, William Shakespeare | Director: Joss Whedon | Stars: Alexis Denisof, Amy Acker, Fran Kranz, Jillian Morgese
Votes: 13,939 | Gross: $4.33M
38. Dating Rules from My Future Self (2012– )
A girl gets romantic advice from herself ten years in the future via text message.
Stars: Shiri Appleby, Alison Becker, Mircea Monroe, Taylor Kinney
Votes: 750
39. It's Not You It's Me (2012)
12 min | Short, Comedy
A young woman's relationship takes a dark turn when every sound her boyfriend makes starts to annoy her. We don't want to spoil the ending for you, but things get a little messy.
Writers: Eric Spicer, Matt Spicer | Director: Matt Spicer | Stars: Ithamar Enriquez, Rob Huebel, Gillian Jacobs, Fran Kranz
Votes: 140
40. Putzel (2012)
88 min | Comedy, Drama, Romance
For Walter Himmelstein, a young man endearingly known as Putzel, life literally doesn't go beyond his family's fish store on the upper west side of Manhattan. In this heartwarming romantic ... See full summary »
Writers: Rick A. Moore, Jason Chaet | Director: Jason Chaet | Stars: Jack Carpenter, Melanie Lynskey, John Pankow, Susie Essman
Votes: 212
Big Morning Buzz Live (2011– )
Ali Fedotowsky/Fran Kranz/Imagine Dragons
Director: Sarah De Lao | Stars: Carrie Keagan, Ali Fedotowsky, Fran Kranz, Imagine Dragons
JourneyQuest (2010– )
Better Than Sex
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Bob Sapp
Votes: 5
JourneyQuest (2010– )
City of the Dead
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Bob Sapp
Votes: 7
JourneyQuest (2010– )
Fall Into Darkness
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Emilie Rommel Shimkus
Votes: 5
JourneyQuest (2010– )
Gibbering Automatons
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Bob Sapp
Votes: 5
JourneyQuest (2010– )
Mewling Monkey Talk
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Samara Lerman
JourneyQuest (2010– )
Much to Discuss
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Brian Lewis
JourneyQuest (2010– )
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Emilie Rommel Shimkus
Votes: 5
JourneyQuest (2010– )
Spry Little Bugger
Action, Adventure, Comedy
Writer: Matt Vancil | Director: Ben Dobyns | Stars: Christian Doyle, Anne K. Brady, Fran Kranz, Bob Sapp
Votes: 5
50. Diary of a Wimpy Kid: Rodrick Rules (2011)
PG | 99 min | Comedy, Family
Back in middle school after summer vacation, Greg Heffley and his older brother Rodrick must deal with their parents' misguided attempts to have them bond.
Writers: Gabe Sachs, Jeff Judah, Jeff Kinney | Director: David Bowers | Stars: Zachary Gordon, Devon Bostick, Robert Capron, Rachael Harris
Votes: 18,628 | Gross: $52.69M


text: After a huge ratings debut, the Uncle Buck staff has found their way on the unemployment line. ABC pulled the plug on the show. Uncle Buck was a remake of the original series, but with an all Black cast. With the success of Blackish, ABC was hoping to find the same level of success. Although the ratings were not too bad, ABC just decided to cancel the series at one season. The show was good but not great. The actors have voiced their opinions on the decision via twiter.

subset: commoncrawl


text:
Book your room at Hotel Florida
Get an overview of this hotel4-star Lisbon hotel in Marques de Pombal, near Rossio Square
Located in Marques de Pombal, this boutique hotel is within 1 mi (2 km) of Marques de Pombal Square, Rossio Square, and Santa Justa Elevator. Castle of Sao Jorge is 1.9 mi (3 km) away.
Hotel Features
This hotel features a restaurant, a fitness center, and a bar/lounge. WiFi in public areas is free. Other amenities include a 24-hour business center, conference rooms, and dry cleaning.
Room Amenities
All 72 individually decorated rooms feature free WiFi and minibars. Comforts include pillow menus and down comforters, and guests will also find conveniences like refrigerators and coffee makers.Would you like to give us feedback? Share it! Opens in a new window
Hotel FloridaRua Duque De Palmela 34 Lisbon 1250-098
Hotel Amenities
Hotel Amenities
The hotel offers a restaurant. A bar/lounge is on site where guests can unwind with a drink. This 4-star property offers access to a 24-hour business center.
High-speed wireless Internet access is complimentary. 3 meeting rooms are available. This business-friendly hotel also offers a fitness center, tour/ticket assistance, and multilingual staff.
Hotel Florida has designated areas for smoking.
- 24-hour business center
- 24-hour front desk
- Babysitting or childcare
- Bar/lounge
- Breakfast available (surcharge)
- Free newspapers in lobby
- Conference space
- Designated smoking areas
- Dry cleaning/laundry service
- Elevator/lift
- Fitness facilities
- Free WiFi
- Laundry facilities
- Luggage storage
- Multilingual staff
- Number of floors - 9
- Number of meeting rooms - 3
- Restaurant
- Safe-deposit box at front desk
- Television in common areas
- Total number of rooms - 72
- Tours/ticket assistance
Family Friendly Amenities
- Babysitting or childcare
- Free Wi-Fi
- Laundry facilities
- Refrigerator
Available in all rooms: Free WiFi
Available in some public areas: Free WiFi
Room Amenities
- Air conditioning
- Cable TV service
- Coffee/tea maker
- Free bottled water
- Cribs/infant beds available
- Daily housekeeping
- Desk
- Down comforter
- Free WiFi
- Hair dryer
- In-room safe
- Individually decorated
- Minibar
- Pillow menu
- Private bathroom
- Refrigerator
- Room service (limited hours)
- Shower/tub combination
Where to Eat
Buffet breakfasts are available for a surcharge between 7 AM and 10:30 AM.
Great American Disaster - This restaurant serves lunch and dinner.
Room service (during limited hours) is available.
Nearby Things to Do
The recreational activities listed below are available either on site or nearby; fees may apply.
- Golfing nearby
- Scooter/moped rentals nearby
- Ecotours nearby
To make requests for specific accessibility needs, complete the "Special or Accessibility Requests" section of "Trip Preferences" when you book your hotel.
- Accessible bathroom
- In-room accessibility
Hotel Policies
Check-in time starts at 2 PM
Check-out time is noon
Payment types
- Pets not allowed
You need to know
Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
- No onsite parking is available.
- A tax is imposed by the city: EUR 1 per person, per night, up to 7 nights. This tax does not apply to children under 13 years of age.
- Resort fee
Optional extras
- Fee for buffet breakfast: EUR 11 per person (approximately)
Hotel Name
- Florida Lisbon
- Hotel Florida Lisbon
We should mention
A resort fee is included in the total price displayed.
Awards & Affiliations
- The property is a member of Preferred Hotels & Resorts.


text:
Tom Coughlin's Shakedown Artist Gets Nabbed -- But What Are The "Work-Related Issues"?
The Smoking Gun has an FBI affidavit for the arrest of one Herbert Alex Simpson for... well, let Special Agent Todd Berry tell it:
On or about July 30, 2008 Thomas Coughlin, head coach of the New York Giants, a National League Football Team, received a letter via U.S. mail that had been mailed from Philadelphia, purportedly from two females identified as "ND" and "AB" who were claiming to have had sexual relations with Mr. Coughlin when he was in Philadelphia with the team during December 2007. The letter threatened that "ND" and "AB" would share this information will Mr. Coughlin's wife and family unless he paid them $10,000-$15,000 each.
The quasi-legalistic FBI-speak amplifies the humor of the situation: we imagine "ND" and "AB" telling Mr. Coughlin that they want "ten to fifteen thousand dollars," and Coughlin's face puckering as he tries to figure out what their game is.
When Coughlin got a second letter and brought this case to the NFL, they gave it to the FBI, who gave it to Berry, who talked to ND and AB, who said they had never met Coughlin and knew nothing about it, but identified the author as "a former co-worker who had previously written threatening letters" from his handwriting. The perp, Herbert Alex Simpson, told Bell he was just trying to mess with the girls as revenge for "work-related issues," and that he never meant to send the letters to Coughlin, yet somehow did.
So the Feds have Simpson, and for some that would be the end of it. But we ponder and wonder: what was this threesome's line of work? And what were the "work-related issues"? Were they fast-food employees, and one night the girls left Simpson to clean the fryer himself, so he figured he'd show them? Were they high-level corporate types involved in a power struggle? Were they Lindsay and Ali Lohan and a disgruntled personal assistant? It's at least as interesting as wondering whether Coughlin gets laid on the road.
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text:
Introducing the greatest innovation in fly sheets! The Amigo Bug Buster is infused with the Buzz-Blocker insect repellent, proven effective in human clothing against flies, mosquitoes, chiggers, midgies and ants. The repellent-infused Bug Buster is EPA approved and will remain effective through at least 28 washings.
Made for comfort and protection! This Amigo® Fine Mesh Fly Mask with Ears is lightweight and stretchy. It boasts a contoured shape, soft ears and fleece bindings for a great fit against your horse's face.
Protect your horse from irritating insects and harmful UV rays with the Amigo® Fly Mask with Ears from Horseware® Ireland. PVC-coated polyester holds its shape.
The Amigo® Mio Fly Sheet offers your horse complete protection from insects and UV rays. This fly sheet with hood is constructed with Horseware's classic cut for comfort and to prevent slipping. Made of soft polyester knit with nylon-lined shoulders.
The Upland Basic Turnout Fly Sheet is a great value in summer horse clothing. It's made of a soft, fine mesh with a two-buckle front closure and fleece at the withers. Helps protect against coat fading.
Stylish, breathable and effective, this Black Diamond Fly Veil with Lycra® ears keeps insects at bay while your ride or drive. A lightweight cotton mesh fly bonnet with stretch ears that won't bind.
Helps reduce stomping and stress, Cashel® Cool Crusader™ Fly Leg Guards protect your horse's legs against nagging pests. Great for turnout in fly and tick prone fields. Contoured fit limits sagging.
Featuring great colors and glittery detail on the fringe, the Centaur® Bling Crochet Ear Net protects your horse's ears from bugs while you ride. Helps keep ear plugs securely in place as well.
The Cotton Mesh Fly Veil prevents insects from ruining your ride. This fly bonnet is lightweight, breathable and effective and offered in great colors!


text:
Have you ever considered working with a dedicated team of staff providing residential services to adults with developmental disabilities in a small home setting? We are always looking for qualified health care professionals to join our DD Homes team.
Spectrum Brands Holdings, a member of the Russell 2000 Index, is a global and diversified consumer products company and a leading supplier of consumer batteries, residential locksets, residential builders hardware, plumbing and accessories, shaving and grooming products, personal care products, small household appliances, specialty pet supplies, lawn and garden and home pest control products, personal insect repellents, and auto care products.
The Tri-County Opportunities Council (TCOC), Community Action Agency, was organized and incorporated in 1965 by a group of interested citizens from Lee, Ogle, and Whiteside Counties for the purposes of investigating the frequency, location, character and cause of poverty; and coordinating efforts to prevent, alleviate and eliminate poverty through the cooperation of public agencies, private organizations, business, industry and interested individuals.
UPM Raflatac develops and manufactures high-quality, high-performance self adhesive label materials for product and information labeling. Our film and paper label stocks are designed to build brand, provide competitive advantage and streamline operations. And our commitment to sustainability is second to none.
BorgWarner is a global product leader in powertrain solutions. We focus on developing leading powertrain technologies that improve fuel economy, emissions and performance. Our facilities are located across the globe to provide local support for our diverse customer base
FRANTZ Manufacturing Company, located in Sterling, Illinois, is a manufacturer and marketer of conveyor system components and steel ball products used in a variety of applications.
With a firm foundation anchored by family ownership and involvement, Heritage Enterprises strives to be the leader in providing high quality health care services. Our well-trained and compassionate staff work hard to make our residents feel at home, whether it is through the services we provide, the relationships we build, or the time we spend with each individual.
No matter where we are or what we do, there are fundamental beliefs and behaviors that guide our decisions, focus our actions and unite us as a company. ManpowerGroup's vision and values serve to inspire how we interact, create and deliver on our promise to clients, job seekers and ourselves.
Pets are our passion. We advance the world and communities to be better with and for all of our pets. Safety is our promise. We continuously and consistently deliver the highest quality and safety standards in the industry. Progress is our pledge. Never-ending pursuit in breakthrough nutrition and innovation to advance pets lives with a portfolio of best-in-class products for all pets.


text:
Diya Web Development
This project received 55 bids from talented freelancers with an average bid price of $450 USD.Get free quotes for a project like this
Skills Required
Project Budget$250 - $750 USD
Total Bids55
Project Description
I want a good website developer to host my domain and create a very beautiful website for my smal [url removed, login to view] should have logo
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text:
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Date: 1900 ca.
Description: Man harvesting grain with hand cradle in a field. There are many haystacks in the field in the background.
Date: 1920 ca.
Description: A view of the the front facade of the town hall and of the World War I memorial statue. A line of cars are parked in front of the building.
Date: 1945 ca.
Description: Exterior view of McCue's Drugstore. In the window are drawings of drug specimens produced by a local botany class.
Date: 1932 ca.
Description: The Bhend family posing with a Studebaker. John Bhend and Sarah Krueger Bhend sit together on the running board, while their children, Marcel and Irene, st...
Date: 1942
Description: Mrs. John T. Shea, Mary Elma Riddell, and Mrs. John R. Riddell, participants in "Tractorette" class, pose around a Farmall H tractor with J.S. Inman, farm...
Date: 1951-07-22
Description: Outdoor group portrait of Soap Box Derby racers from Mineral Point.
Date: 1953-05-30
Description: Elevated view looking down towards the corner of Carroll and Main Streets at one of the largest marching groups in the parade observing Memorial Day, the...
Date: 1949-02-10
Description: Exterior view of Madison Bible Fellowship Church in the snow, 1704 Roberts Court. (Now Society of Friends, Quaker meeting house.)
Date: 1905 after
Description: Color image of courthouse with a large tree in front. View taken at an angle to the building from across the street. Horse-drawn carriages are on the roa...
Description: Outdoor portrait of the John Bhend family in front of a group of trees. From left to right, Irene, Sarah Krueger, John and Marcel Bhend.
Description: A man and a boy are each driving their own mower. Each mower is pulled by two horses. The young boy is waving his hat. A man on the right is riding in a b...
Date: 1950 ca.
Description: Agricultural exhibit designed by the Wisconsin State Cranberry Growers Association and Eatmor Cranberries. The exhibit shows various types and stages of cr...
Date: 1910 ca.
Description: View of Zambezi River, South Africa, from a boat tour. The railroad bridge is in the far background.
Date: 1916-04-15
Description: Pawling & Harnischfeger concrete breaker on a residential street with a operator in the cab. Men are working in the street, and trees and power lines are l...
Date: 1912 ca.
Description: Frank B. Fargo, wearing a double-breasted duster and cap, is sitting at the wheel of an open automobile. His wife, Louise Mears Fargo, is sitting beside hi...
Description: Full-length portrait of a woman standing and holding a basket full of pottery on her head. There is more pottery in a pile on the ground near a bamboo fenc...
Date: 1936
Description: A level pasture terrace showing water in the channel. These terraces, largely experimental, are built on the level, drainage being provided for by means of...
Date: 1937-12-30
Description: An Arab man plowing sand with a plow harnessed to a camel.
Date: 1953-06-26
Description: David Vilas is shown pinning a carnation corsage on his date, Beth Herman, at the Maple Bluff social party for teens.
Date: 1955
Description: "Cows graze on the William Engman farm south of Theresa. The new water tower, at right, is being constructed."
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This articles reviews the environmental risk factors and predisposing conditions for the two main histological types of esophageal cancer, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA). Tobacco smoking, excessive alcohol consumption, drinking maté, low intake of fresh fruits and vegetables, achalasia, and low socioeconomic status increase the risk of ESCC. Results of investigations on several other potential risk factors, including opium consumption, intake of hot drinks, eating pickled vegetables, poor oral health, and exposure to human papillomavirus, polycyclic aromatic hydrocarbons, N-nitroso compounds, acetaldehyde, and fumonisins are also discussed. Gastroesophageal reflux, obesity, tobacco smoking, hiatal hernia, achalasia, and probably absence of H. pylori in the stomach increase the risk of EA. Results of studies investigating other factors, including low intake of fresh fruits and vegetables, consumption of carbonated soft drink, use of H2 blockers, non-steroidal anti-inflammatory drugs, and drugs that relax the lower esophageal sphincter are also discussed.
Esophageal cancer (EC) is the 8th most common incident cancer in the world and, because of its high fatality rate, ranks 6th among all cancers in mortality [1,2]. It is not surprising, therefore, that the etiology of EC has been investigated for over a century. Based on clinical observations, Craver in 1932 and Watson in 1939 list excessive use of alcohol and tobacco, low socioeconomic status, poor oral health, and consumption of hot drinks as risk factors for EC [3,4]. They also cite papers on EC etiology published decades earlier. For example, Craver cites a 1920 article from Argentina that suggests maté drinking as a risk factor for EC.
Etiology of EC differs by histology. EC can be histologically classified into two main types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA). These two cancer types differ not only histologically, but also with respect to their incidence trends, populations that they affect, and risk factors. One could call EA "an emerging disease". Until the 1970s, ESCC constituted the large majority (over 90%) of all EC cases in all parts of the world. Since then, however, incidence rates of EA have sharply increased in many countries in the Western World [5–9], so that this cancer type now constitutes approximately half of all EC cases in some Western countries. In contrast, ESCC continues to be the dominant type in the rest of the world.
Most etiological studies conducted before the 1980s did not distinguish between ESCC and EA, but their results were mainly relevant to ESCC, because EA was uncommon before then. Also, results of the more recent studies from Asia, South America, or Africa that do not report histology are mainly applicable to ESCC because EA is still relatively uncommon in these areas [10–12]. Extensive investigations into the etiology of EA started only in the 1990s, mainly in Western countries, where larger numbers of this cancer began to be diagnosed.
Some parts of the world have distinct epidemiologic patterns of ESCC. In most parts of the world, incidence rates of ESCC, adjusted to the 1970 World Population, are lower than 15/105 person-years and ESCC is 2–3-fold more common in men than in women [13]. However, in certain areas of China (in the Taihang mountain region) and Iran (in Golestan Province), a completely different pattern is observed: incidence rates above 100/105 person-years have been reported, and men and women have similar incidence rates [13]. As we shall see below, ESCC risk factors in these areas may be different from those seen elsewhere. For example, unlike almost everywhere else, tobacco smoking and alcohol consumption play a minor role [14,15].
ESCC and EA have known precursor lesions, esophageal squamous dysplasia (ESD) and Barrett's esophagus (BE), respectively. Compared to subjects with no ESD, those with mild, moderate and severe ESD have an increased risk of ESCC of approximately 3-, 10- , and 30-fold, respectively [16]. Presence of BE substantially increases EA risk; risk of progression to EA is 0.5 – 1% per year [17,18]. Therefore, ESD and BE have been used as surrogate endpoints for ESCC and EA, respectively.
With this background, we review some factors that increase or decrease EC risk. Where data are available, we discuss the effect of each factor separately for ESCC and EA. Many factors have been investigated in relation to EC, among which we have chosen those that are established risk factors, or those for which there is substantial data, or those for which there is currently strong research interest. These factors include habits (tobacco use, alcohol consumption, opium consumption, maté drinking, consumption of hot drinks, consumption of carbonated soft drinks, eating pickled vegetables), nutritional deficiencies (low intake of fresh fruit and vegetables, vitamin and mineral deficiencies), medications (non-steroidal anti-inflammatory drugs, medications that relax lower esophageal sphincter, H2 receptor antagonists), infections (Helicobacter pylori, Human papillomavirus), chemical carcinogens (polycyclic aromatic hydrocarbons, nitrosamines, acetaldehyde), physiologic or pathologic predisposing conditions (gastroesophageal acid reflux, hiatal hernia, achalasia, gastric atrophy, poor oral health), occupational exposure (to silica and asbestos), and low socioeconomic status (Table 1).
As early as 1979, the Untied States Surgeon General reported that: "Cigarette smoking is significant causal factor in the development of EC. The risk … increases with the amount smoked."[19]. The 1989 Surgeon General report added that: "The proportion of EC deaths attributable to tobacco use in the United States is estimated to be 78 percent for men and 75 percent for women" [20]. Since the publication of these reports, a large number of case-control and cohort studies have confirmed these statements.
Cigarette smoking is more strongly associated with ESCC than with EA. Studies have shown that ESCC risk is increased by approximately 3–7-fold in current smokers [21–25]. Smoking cigars or a pipe confer risks similar to cigarette smoking [26]. The International Agency for Research on Cancer (IARC) has concluded that chewing betel quid that includes tobacco, which is common in South and South-East Asia, can also cause ESCC [27]. There is less data available for other forms of tobacco use, such as using waterpipe (hookah) and chewing nass (a mixture of lime, ash, and tobacco), which are predominantly used in the Middle-East. However, these forms of tobacco also seem to increase ESCC risk [28]. The only exceptions to strong association with tobacco have been reported from the very high-risk regions of China (in the Taihang mountain region) and Iran (in Golestan Province). In these areas, cigarette smoking is minor risk factor for ESCC, with relative risk of approximately 1.5 [12,28,29]. It is unclear why the association is much weaker in these areas than what has been observed in the rest of the world. One hypothesis is that other strong risk factors may exist in these high-risk areas that account for the majority of the cases, and therefore the effect of smoking is diluted [30].
Although smoking is less strongly associated with EA, there is now little doubt that smoking is a risk factor for EA. At least 10 population-based case-control studies [31–40] and a large-scale cohort study [25] have evaluated the association between cigarette smoking and EA, and almost all of these studies have found an increased risk of nearly 2-fold. Several of these studies have also shown a dose-response relationship. The consistency of association and the dose-response relationship both indicate a causal relationship. Further supporting this causal relationship are the effect of smoking in causing cancers in other organs [41,42], and the presence of a large number of carcinogens, such as polycyclic aromatic hydrocarbons, nitrosamines, and acetaldehyde in tobacco smoke [43]. Also, because smoking starts years before tumor formation, there is no doubt about the direction of temporal relationship. Indeed the 2004 report of the Untied States Surgeon General on health consequences of smoking concluded that there is sufficient evidence for a causal relationship between cigarette smoking and EA [41].
Like tobacco use, alcohol consumption has long been known to be a major cause of EC in most areas of the world. Classic ecologic and case-control studies by Tuyns and others in the 1970s and 1980s [44–47] established alcohol as a strong cause of EC in many countries, and showed that alcohol drinking and tobacco smoking interact to increase EC risk in a multiplicative manner. IARC has classified alcohol drinking as a known cause of EC [48].
The increased risk of EC associated with alcohol use is perhaps limited to ESCC. When used in excessive amounts (3 or more drinks per day), alcohol has almost universally been associated with an elevated risk of ESCC; it typically increases risk by 3–5 fold [25,49–51]. In contrast, there is little evidence for an association between alcohol drinking and EA. The majority of the case-control and cohort studies that have investigated this association have found no overall relationship between alcohol consumption and EA, or have found relatively weak associations, both direct and inverse [25,31–33,35,36,38,39,52]. Some studies have suggested that only certain types of alcohol may be associated with EA. For example, one study [32] suggested that drinking straight liquor could increase risk and another one [33] suggested that drinking wine may reduce risk. These results need to be confirmed in other studies.
The exact mechanism of carcinogenicity of alcohol is not known, because alcohol itself does not bind DNA, is not mutagenic, and does not cause cancer in animals [53]. However, several mechanisms for its carcinogenicity have been suggested, including its conversion to acetaldehyde (see below, under acetaldehyde), acting as a solvent for other carcinogens, and causing nutritional deficiency [53].
A role for opium as a potential cause of EC was first suggested when ecologic studies showed very high rates of opium consumption in high risk areas of northeastern Iran. In a study of 1,590 rural individuals, the prevalence of appreciable levels (≥ 1 μg/ml) of urinary morphine metabolites was almost 6-fold higher among residents of high-risk vs. low-risk areas [54]. This study also compared household members of 41 cases and 41 matched control for urinary opium metabolites and found a non-significantly 2-fold increased risk among case household members [54]. The results of a recent case-control study in this same area also showed that opium use was associated with a 2-fold increased risk of EC [28].
Crude opium, itself, is not mutagenic in the Ames test [55,56]. However, smoking opium may produce polycyclic aromatic hydrocarbons or other carcinogenic compounds. Opium dross and smoke condensates from opium and morphine cause mutations in S. typhimorium [55,56], sister chromatid exchanges in human lymphocytes [57], and morphological transformations in cultured Syrian hamster embryo cells [58].
Although the results of the studies conducted thus far suggest that opium use could increase EC risk, the level of evidence for this association is not yet strong enough to be convincing. Data from case-control studies may be subject to recall or observer biases, and associations found in these studies may be due to reverse causation. The results of an ongoing cohort study in northern Iran will provide further evidence to evaluate this potential association [59].
Maté, an infusion of the herb Ilex paraguayensis (also known as yerba maté) is commonly consumed, sometimes in large volumes (1–2 liters/day), in some areas of South America, including southern Brazil, northeastern Argentina, Uruguay, and Paraguay [60,61]. These areas also have the highest risks of EC are seen in South America [62]. Therefore, several case-control studies in these countries have examined the association between drinking maté and EC, and nearly all have found an increased risk [63–69]. A combined analysis of five of these studies showed a dose-response association with amount, duration, and temperature of maté and drinking, with a relative risk of 3 in those who drank over 3 liters of maté per day [61].
Two independent mechanisms may explain the carcinogenicity of maté: repeated thermal injury, resulting from drinking hot maté, and exposure to polycyclic aromatic hydrocarbons (PAHs) that are found in maté [70]. Maté is often consumed hot or very hot, but it also can be consumed warm or cold. In 1991, IARC classified hot maté as a probable (Group 2A) carcinogen to humans [71], implying that repeated thermal injury was the probable mechanism of carcinogenicity. However, several studies have now suggested that contaminants, especially PAHs, may also be involved. Studies have found large amounts of PAHs in processed yerba maté leaves [70,72,73] and high concentrations of urinary markers of PAHs in maté drinkers [74]. Maté has also been shown to have mutagenic effects in bacterial assays and to cause chromosomal aberrations in human peripheral lymphocytes treated ex vivo [75]. These lines of evidence, in addition to finding associations between maté drinking and smoking-related cancers in other organs (lung [76], larynx [77], oral cavity and oropharyx [78], kidney [79], and bladder [80,81]) suggest that PAHs may play an important role. Further evaluation of the role of PAHs in the carcinogenicity of maté is of public health significance [70] because the PAH content of maté can potentially be modified.
The large majority of EC cases in high-risk regions of South America are ESCC; there is no evidence yet with which to evaluate the association between maté drinking and EA.
Although recurrent thermal injury from intake of hot foods and drinks has long been hypothesized as a cause of EC [4], it is still unclear whether this association exists. Some have doubted a causal association because of its biological implausibility. For example, in 1956 Steiner suggested that the temperature of hot foods and drinks fall so rapidly in the upper digestive tract that they cannot cause injury to the esophageal mucosa [82]. However, later De Jong and colleagues showed that intake of hot drinks could substantially increase the intraesophageal temperature, and this increase was a function of the initial drinking temperature and more importantly, the size of the sip [83]. For example, drinking 65 °C coffee increased the intraesophageal temperature by 6–12 °C, depending on the sip size [83].
The results of epidemiologic studies have shown little consistency on the role of hot drinks in esophageal carcinogenesis. Around 50 case-control studies and 2 cohort studies have investigated the association of drinking hot tea (green, black, and other types), coffee, maté, and other hot foods and drinks with EC. Except for maté, for which most studies have shown an increased risk (see above), other hot drinks have been found to be associated with EC only in a minority of studies. There are several problems in establishing or refuting an association between hot drinks and EC: 1) most of the evidence comes from case-control studies, which are prone to several biases, including recall bias and interviewer bias; 2) in some studies, consuming various types of hot drinks have been asked or analyzed together; 3) little has been done to measure sip size or the actual temperature of the drinks -- at best, the study questionnaire has asked whether the study participants drink their tea or coffee hot, warm, or cold, which may not produce reliable results; and 4) these drinks have chemicals that may cause or prevent cancer, which may confound the effect of thermal irritation. To overcome some of these problems, an ongoing cohort study in northern Iran has measured the tea drinking temperature in approximately 50,000 subjects, but the data are not available yet [59].
It has been suggested that carbonated soft drinks may have contributed to the rising incidence of EA, because these drinks are acidic and may increase reflux by causing gastric distension [84]. Also, per capita consumption of these drinks increased approximately 20 years prior to the rise of EA rates [84]. However, case-control studies have found no association [85,86] or even an inverse association [87] between consuming soft drinks and EA risk. Likewise, case-control studies have found no association [87,88] or an inverse association [86] between soft drink consumption and ESCC risk. Therefore, the current data show no evidence that soft drinks increase EA or ESCC risk.
Eating pickled vegetables was once very common in high-risk areas of China and was thought to be a major risk factor for EC in those areas [89]. As reviewed by CS Yang, ecological studies showed higher risk of EC in areas that used higher amounts of pickled vegetables [89]. Fungi and yeasts grow in pickled vegetables and they may release potentially carcinogenic compounds such as N-nitrosamines, Roussin red methyl ester, and mycotoxins [89–91]. Studies have shown that samples of pickled vegetables are mutagenic in the Ames test, can cause sister chromatid exchanges in Syrian hamster, and can also cause cancer when fed to rats [89,92,93]. However, the results of epidemiologic studies have been inconsistent. Whereas some case-control studies have shown an association between pickled vegetable intake and EC [94–99], typically with relative risks of 2–3, other case-control or cohort studies have shown no association [12,100,101]. Lack of a consistent association could partly be due to the fact that in the past the large majority of people in some high-risk areas ate pickled vegetables, which might have resulted in lack of variance. Also, a public health campaign by the government of China, which aimed to reduce pickled vegetable consumption, may have led to reporting bias in high-risk populations subject to the campaign. Therefore, further investigation of this hypothesis may be of interest. It is noteworthy that an IARC evaluation in 1993 concluded that traditional Asian pickled vegetables are possibly carcinogenic to humans (Group 2B) [102].
Low intake of fresh fruit and vegetables has long been considered as a possible risk factor for EC. A review of the evidence by World Cancer Research Fund and American Institute for Cancer Research (WCRF-AICR), published in 2007, identified 4 cohort studies (all from China), 36 case-control studies, and 7 ecological studies of the association of fruit intake and EC. The large majority of these studies found inverse associations between intake of fruits, especially citrus fruits, and EC risk. These protective associations were stronger in the case-control studies. The panel concluded that "the evidence … though mostly from case-control studies, is consistent with a dose-response relationship … Fruits probably protect against esophageal cancer" [103]. The WCRF-AICR panel also identified 5 cohort studies, 37 case-control studies, and 6 ecological studies that had investigated the association of non-starchy vegetables and esophageal cancer. Most case-control studies found inverse associations but cohort studies, which were mostly from China, overall found a weak inverse association. The panel's final comment was: "Non-starchy vegetables probably protect against esophageal cancer" [103].
Since the WCRF-AICR review was conducted, at least three additional cohort studies have published their results on fruit and vegetable intake and risk of EC [104–106]. The results of all three of these cohort studies provided support for a protective association of both fruit and vegetable intake with EC [104–106]. Putting all evidence together, high intake of fruit and vegetables probably decreases EC risk by approximately 20% per 50 gram of fruit or vegetable intake per day [103].
The large majority of data on the association of fruit and vegetable intake with risk of EC comes from studies that have mainly investigated ESCC, so the results of these studies may apply only to ESCC. To our knowledge, only one cohort study has had a large enough number of ESCC and EA cases to study the effect of fruits and vegetables on these tumor types separately [104]. This study found decreased risk of ESCC, but not EA, associated with higher intake of both fruit and vegetables.
By the early 1980s, both epidemiologists and basic scientists had obtained intriguing evidence that vitamin and micronutrient deficiencies may play important roles in the etiology of EC and several other cancers. Low intake of fruit and vegetables, which contain vitamins, were inversely associated with EC risk in most studies conducted until then; in vitro studies had shown that antioxidant effects of some vitamins could prevent tumor formation; and people in some areas with very high risk of EC, such as Linxian (a county in the Taihang mountains region of China), had severe deficiencies in some vitamins and minerals [107]. These findings led to the conduct of two large chemoprevention trials in Linxian. One of these studies, the Linxian Dysplasia Trial, randomized approximately 3,300 subjects cytologically diagnosed with esophageal squamous dysplasia (ESD) to receive a combination of 26 vitamins and mineral or a placebo [108]. The other trial, the Linxian General Population Trial, enrolled approximately 30,000 people from Linxian to test four nutrient factors: Factor A (retinol, zinc), Factor B (riboflavin, niacin), Factor C (ascorbic acid, molybdenum), and Factor D (selenium, α-tocopherol, β-carotene) [109]. There was no risk reduction for EC in either trial using any of these nutritional supplements after 5–6 years of intervention. Longer term follow-up (through 10 years after ending the intervention) in the General Population Trial, however, showed Factor D reduced EC risk in younger subjects by 17% but increased risk in older individuals by 14% [110]. These findings, along with disappointing overall mortality and cancer incidence results from some other vitamin chemoprevention trials [111,112] and the results of some meta-analyses [113,114] have largely discouraged scientists from pursing the micronutrient hypotheses further. However, selenium and zinc deficiency may play a role in the etiology of ESCC.
Selenium deficiency has been shown to be a risk factor for upper gastrointestinal tract cancers. Both observational and experimental studies have shown that higher selenium status reduces the risk of esophageal and gastric cancers in selenium deficient populations [109,115–117]. In the Linxian General Population Trial, Factor D, which included selenium, reduced overall mortality, morality from gastric cancer, and also mortality from EC in younger individuals [110]. And, in another randomized chemoprevention trial in Linxian, selenium increased regression and reduced progression of mild ESD [118].
Zinc deficiency enhances the effects of N-nitrosomethylbenzylamine and certain other nitrosamines in esophageal carcinogenesis in rodents [119,120]. Tissue zinc is perhaps the most relevant measure of zinc in relation to carcinogenesis [121]. The only human study investigating the association between tissue zinc and EC showed that there was a significant dose-response relationship between lower levels of zinc and increased risk of EC [121].
A meta-analysis of 9 studies, published in 2003, concluded that Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduced risk of EC in a dose-response manner. More frequent use was associated with lower risk, with an overall risk reduction of approximately 40% [122]. This meta-analysis also showed that these drugs had similar inverse associations with ESCC and EA. Several other studies published since then, mostly focused on EA, have shown similar results [123–127]. This association may be due to reverse causation; people with a history of upper gastrointestinal symptoms, who are also at higher risk of cancer, may limit their use of Aspirin and other NSAIDs. However, some studies stratified their results by having or not having upper gastrointestinal disorders and did not find a difference in results in these two groups of patients [127]. If the associations are causal, aspirin and NSAIDs may reduce risk by reducing inflammation and affecting the inflammation-metaplasia-cancer sequence at its early stages.[124]
Results of a short-term randomized trial in Linxian showed that celecoxib did not have any effect on regression or progression of ESD [118]. The protective effect of aspirin against the progression of BE to EA is being tested in a large, long-term trial [128].
Reflux of acid from the stomach to the esophagus is usually blocked by the lower esophageal sphincter. Certain medications such as asthma drugs (β-adrenergic agonists and drugs containing theophylline), calcium channel blockers, nitroglycerin, and benzodiazepines relax the lower esophageal sphincter and hence may promote acid reflux and higher risk of BE and EA. The fact that use of many of the aforementioned treatments increased rapidly after the mid-1950s and the plausibility of their relation to reflux and EA led to the hypothesis that these treatments may be responsible for the EA epidemic that started in the mid-1970s [129].
Case-control studies, however, have provided conflicting results. Whereas some studies have found no overall association with LES-relaxing drugs [126,130] others have shown increased overall BE or EA risk [125,131,132]. Among these studies, some showed increased risk with only one or two groups of medications. For examples, although Vaughan and colleagues found no overall association, they found increased EA risk with β-adrenergic agonists [130]. The most consistent association has been seen with asthma medications, but this association may be confounded by acid reflux, which causes both asthma and EA [133]. Other subgroup analyses have suggested that only younger individuals may be susceptible [131]. Overall the results are not entirely consistent and further studies are warranted.
H2 receptor antagonists (H2 blockers), such as cimetidine and ranitidine, are a class of drugs that reduce acid production in the stomach. These drugs were first marketed in 1977 and have been highly prescribed since then. One the one hand, these medications may reduce EA risk by reducing the acid content of gastroesophageal reflux. On the other hand, they may increase EA risk via neutralizing the gastric pH, which allows bacteria to proliferate in the stomach and thus may result in increased production of carcinogens such as nitrosamines and acetaldehyde. In addition, cimetidine can be nitrosated in the stomach to form nitrosocimetidine, which has a chemical structure similar to the potent carcinogen N-methyl-N′-nitro-N-nitrosoguanidine [134]. At least 5 epidemiologic studies have investigated the association of H2 blocker use with EC [135–139] but the results are inconclusive. Two of these studies showed increased risk of EC [136] or EA [139] with H2 blocker use but they did not adjust for acid reflux symptoms, which is an important indication for using these treatments. Two other studies that adjusted for acid reflux symptoms found a statistically non-significant increased risk of EA, but they acknowledged that this non-significant increase might have been due to residual confounding from acid reflux [135,137]. Another study from Sweden classified the results by indication of medication use and found an increased risk of EA in the group that received H2 blockers for "esophageal indications", rather than other indications, suggesting that the increased risk was confounded [138]. Only one of these studies [137] looked for an association between H2 blockers and ESCC, and it did not find an association.
H. pylori is a known cause of noncardia gastric adenocarcinoma and gastric MALT lymphoma [140]. The association of this gram-negative bacterium with other gastrointestinal cancers, most notably EC, has also been evaluated in several studies.
H. pylori has shown a consistent pattern of association with EA. The large majority of epidemiologic studies have found a protective association, and the results of three recently published meta-analyses showed that H. pylori colonization of the stomach is associated with a nearly 50% reduction in risk [141–143]. One of these meta-analyses also tested and showed an inverse association of H. pylori with BE [142]. H. pylori may decrease risk of EA by reducing gastric acid production and hence reducing acid reflux from the stomach to the esophagus [144]. It may also reduce EA risk by decreasing the production of ghrelin, a hormone that is mostly produced in the stomach and stimulates appetite [145]. A reduction in the level of ghrelin may lead to lower rates of obesity, an important risk factor for EA [40].
In the past few decades, advances in sanitation and the widespread use of antibiotics have caused a rapid decline in H. pylori colonization prevalence in human populations [146], especially in Western countries. In the United States, for example, data from the National Health and Nutritional Examination Survey 1999–2000 indicated the presence of H. pylori in only 5% of children who were born in the 1990's [147], which was far lower than that seen in older people of the United States [147] or than children of other countries with lower socioeconomic status [148]. Therefore, it is conceivable that the steep decline in H. pylori colonization rates in the past few decades may be partly responsible for the recent increase in EA incidence in Western countries.
In contrast to its association with EA, H. pylori has not shown a consistent association with ESCC. Whereas some studies have found a 2-fold increased risk of ESCC with H. pylori colonization in the stomach [98,149], others have found no association [150] or even reduced risk [151]. Three recent meta-analyses that summarized the association of H. pylori with ESCC found no overall association, with summary odds ratios very close to unity, but they showed substantial heterogeneity in results of the published studies [141–143].
Oncogenic types of HPV, most notably HPV 16 and HPV 18, are necessary causes of cervical cancer [152,153], and also play an important role in the etiology of the epithelial cancers of the vulva, anus, penis, and oropharyngeal cavity [153,154]. However, despite 25 years of research and well over 100 studies of EC, the role of HPV in the etiology of this cancer remains controversial [153].
HPV was first suspected to have a role in the etiology of EC in 1982, when histological findings suggesting the presence of HPV were observed in benign esophageal epithelia and malignant esophageal tumors [155]. Since then, two major approaches have been used to investigate a possible role of HPV in causing EC: searching for the presence of HPV DNA in tumors using polymerase chain reaction (PCR), and comparing cases and controls in case-control or cohort studies for serum antibodies against HPV. PCR-based methods can detect DNA from the carcinogenic HPV types in nearly all cervical cancers [153]. In contrast, PCR results have been very inconsistent in esophageal cancers [153,156]. While many studies have found no evidence of HPV in esophageal tumors [157–163], others have found HPV in up to 75% of them [164]. This inconsistency may be due to true geographic variation [156] or it may simply reflect contamination during sample preparation or conducting the PCR. The results of case-control or cohort studies that have used serologic assays against HPV virus-like particles have also been inconsistent. Whereas some studies have found very strong (relative risks of 5 or more) [165,166], moderate to strong (relative risks of 2–5) [167], or weak (relative risks of 1–2 ) associations between HPV 16 or HPV 18 and EC, others have found no association [168–170] or even inverse associations. The inconsistency of these results may be due to differences in study design (case-control versus cohort studies), geographic variation (high-risk versus low-risk areas), differences in positivity cutpoints used in different studies, lack of appropriate adjustment for tobacco use or alcohol consumption, or simply chance fluctuation due to the small number of cases in some studies. Efforts to find the source of heterogeneity have so far been inconclusive [170]. Because of these conflicting results, a recent report by IARC concluded that "there is inadequate evidence in humans for carcinogenicity of HPV in the esophagus"[153].
Polycyclic aromatic hydrocarbons (PAHs) are produced during incomplete combustion of organic materials. The major sources of exposure to PAHs are smoking tobacco [43], eating charbroiled meat and other food products [171], air pollution [172], and occupational exposure [173].
PAHs have long been suspected to be human carcinogens. In 1755, Percivall Pott found that exposure to soot, which contains high amounts of PAHs, causes scrotal cancers in chimney sweeps [174]. In 1915, Yamagiwa, a Japanese pathologist, induced cancer for the first time by applying coal to the ears of rabbits [175]. Kennaway and his colleagues at Royal Cancer Hospital in London found dibenz(a, h)anthracene and benzo(a)pyrene, two PAHs, to be the active carcinogenic compounds in coal tar capable of inducing skin cancer in mice [175].
A causal link between PAHs or PAH-containing substances and cancer has been established for cancers of the skin, lung, and bladder [176]. Tobacco smoke, which contains significant amounts of PAHs, is causally linked to EC. However, evidence linking other PAH-containing substances or individual PAHs to EC is based only on ecologic studies and is therefore only circumstantial. Studies in Linxian have shown histopathologic evidence in EC cases consistent with high exposure to PAHs [177], presence of high levels of carcinogenic PAHs in staple foods [178], and high concentrations of urinary markers of PAHs [179]. Studies in Golestan Province of Iran have also shown very high concentrations of urinary markers of PAHs in a majority of the residents [180]. Therefore, further evaluation of this association is of significant interest. Evaluating the association of PAHs with EC or other cancers, however, has proven to be difficult, partly because there are no valid and reliable markers of long-term PAH exposure that can be used in epidemiologic studies. Urinary markers of PAHs reflect exposure only in the 24 – 72 hours prior to urine collection [181]. Using PAH-DNA adducts or PAH-protein adducts as markers of exposure in epidemiologic studies have also been hampered by other limitations [182,183], such as lack of sensitivity to low exposures, non-linearity at high exposures, use of surrogate tissues (such as blood lymphocytes) instead of the target tissue of interest, and high cell turnover rates in many tissues, which make it impossible to measure long-term exposure. Nevertheless, adducts have been useful in establishing causal links between some carcinogens and cancer, such as the causal relationship between tobacco smoking and cervical cancer, and better assays may help future research evaluation of a PAH link to EC.
N-nitroso compounds (NNCs) are strong animal carcinogens and have been shown to cause cancers of the nasal cavity, esophagus, and stomach in several animal models [184–187]. The role of these compounds as human carcinogens is less well established.
The relevance of NNCs to human cancer has been difficult to assess because humans are exposed to these compounds in many different ways and because no valid and long-term integrated biomarker of exposure has been developed. Humans can be exposed to NNCs from tobacco smoking, occupational exposure, and many food sources [188] and also from endogenous synthesis, which contributes to 45–75% of the total exposure [189]. Nitrosamines and nitrosamides, two major subgroups of NNCs, are formed by the endogenous reaction of nitrites with amines or amides, respectively. Nitrites are directly found in sodium nitrite and various foods, and are also formed by reduction of ingested or salivary nitrates [190–192]. Vegetables are the main sources of exogenous nitrates but high levels of nitrates may also be found in water [192]. Reduction of nitrates to nitrites by oral bacteria is a major contributor to the formation of N-nitroso compounds and may be one of the reasons why poor oral health has been associated with higher risk of EC and gastric cancer [193,194]. To date, no NNC-DNA adducts are available that are easily measurable and accurately represent long-term exposure to NNCs.
Despite these challenges, there is some indirect evidence linking NNCs to EC. Jakszyn and Gonzalez recently conducted a systematic review of case-control and cohort studies associating nitrosamine exposure and foods that are direct or indirect sources of these compounds with EC risk [195], and found that eating processed meat, a major source of nitrites and nitrosamines, was consistently associated with higher risk of EC [195].
Humans can be exposed to acetaldehyde in several ways, most notably by drinking alcohol. Ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH) enzymes and then to acetate by acetaldehyde dehydrogenase (ALDH) enzymes [196]. Therefore, higher alcohol consumption and genetic polymorphisms that enhance the activity of ADHs or decrease the activity of ALDHs result in higher acetaldehyde exposure [196]. In addition to alcohol drinking, humans are exposed to acetaldehyde by smoking cigarettes, eating moldy food, burning wood and coal, and also by in vivo metabolism of sugars by oral and colonic bacteria [197,198]. In vitro, acetaldehyde causes point mutations in human lymphocytes, sister chromatic exchanges, cellular proliferation, and inhibits DNA repair. In 1999, IARC classified acetaldehyde as a known carcinogen for animals but only a possible carcinogen for humans [197], mostly because there was little human data at the time this IARC evaluation was done. Since then, genetic polymorphisms in ADH genes and ALDH2 that favor the accumulation of acetaldehyde have been observed to increase ESCC risk [196], thus adding to the evidence of acetaldehyde carcinogenicity in humans. In addition, acetaldehyde may link alcohol drinking, tobacco smoking, eating moldy foods, and poor oral health to ESCC [198]. Therefore, further studies in humans are warranted.
Fumonisins are toxins secreted from Fusarium verticillioides (formerly Fusarium moniliforme), a fungus that grows mostly on maize. Fumonisin B1 is a known animal carcinogen and has been shown to cause tumors of the liver and kidney in mice and rats [199,200]. Evidence for the carcinogenicity of fumonisins in humans, however, is circumstantial, and is mostly limited to ecologic studies. Ecologic studies in China, Iran, and South Africa have shown higher exposure to fumonisins in areas with higher risk of EC [201–203]. The only case-control study that examined fumonisin exposure in relation to EC risk was conducted in Linxian, China, and found no association between exposure and risk [204]. However, the biomarkers of exposure used in this study were of uncertain value and the results were not conclusive. Further epidemiologic studies are needed to establish or refute an association between fumonisins and EC.
Symptomatic gastroesophageal acid reflux is perhaps the strongest known risk factor for EA. In a population-based case-control study from Sweden, Lagergren and colleagues showed a strong dose-response association of both frequency and duration of reflux with EA [205]. In this study, any reflux was associated with approximately 8-fold increased risk, but risk was increased up to 20-fold in those with very frequent and severe reflux [205]. Several other studies published since then have confirmed a dose-response association between reflux and EA [39,40,137,206], but the relative risks have been almost half as strong as those reported in Lagergren's original study (approximately 4-fold overall and 8-fold for those having the highest frequencies).
Consistency of the results across studies, dose-response relationship, and strength of association all implicate a causal relationship between reflux and EA. There is also a strong association between acid reflux and BE [207]. Recurrent acid reflux may cause EA by inducing metaplasia in the mucosa of the lower part of the esophagus and changing the local squamous tissue into BE. Unlike EA, ESCC is not caused by acid reflux.
Two meta-analyses [208,209] have summarized the association of overweight (body mass index from 25 to < 30 Kg/m2) and obesity (body mass index of 30 Kg/m2 or higher) with EA. The more recent of these two [209] identified 14 studies and found that EA risk increased approximately 2–3-fold in overweight and obese individuals. It also observed a dose-response relationship; risk was slightly higher in obese than in overweight people. Since the publication of this meta-analysis, several additional population-based or cohort studies of obesity and EA risk have been published, which have also shown 2–3-fold increased risks and dose-response relationships [39,40,210,211].
Since this association is consistent across a large number of studies, is moderately strong, and has a dose-response pattern, it is highly likely that it is causal. In fact, increasing weight trends in the United States and other Western countries may be partially responsible for increasing incidence rates of EA in these countries. Several mechanisms have been suggested to explain the causal link [212]. Obesity increases intra-abdominal pressure which in turn could increase risk of gastroesophageal reflux and BE. In fact, obesity has been convincingly linked to GERD [208,213], and measures of central obesity, such as waist-to-hip ratio and abdominal circumference, have been linked to BE [214,215]. In addition, adipose tissue is physiologically active and may increase risk via modulation of levels of polypeptides such as ghrelin, leptin, adiponectin, and insulin-like growth factors [212].
Hiatal hernia can increase EA risk by increasing gastroesophageal acid reflux. Many studies have investigated the association of hiatal hernia with EA, and all have found increased risks, with relative risks ranging 2–6-fold [135,137,138,206]. Also, among people with BE, having a large hiatal hernia increases the risk of high grade dysplasia and EA [216,217]. In contrast to EA, the risk of ESCC is not increased by the presence of a hiatal hernia.
Achalasia is a motility disorder of the esophagus characterized by aperistalsis in the distal esophagus and loss of LES relaxation. This lead to stasis and fermentation of food in the esophagus, which may cause increased inflammation and higher EC risk [218].
Most case series have reported EC in 3–7% of achalasia patients [219], which is far higher than the rates seen in normal population. Follow-up studies of achalasia patients have consistently shown substantially increased risk of EC [220–223], but because the size of achalasia cohorts have been small, different magnitudes of relative risks have been reported. One of the largest of these cohorts that has had a long-term follow-up is conducted in Sweden. The latest results from this cohort [223] showed a 10-fold increased risk of both ESCC and EA in achalasia patients compared to the rest of the population.
Substantial increases in risk of EC have also been reported in patients with other benign diseases that cause esophageal obstruction, including patients with esophageal webs and lye stricture [224].
Atrophy of the gastric mucosa has long been known to be a precursor lesion for gastric cancer [225]. However, finding an association between gastric atrophy and ESCC is a relatively recent finding.
A Swedish study showed for the first time that pernicious anemia patients had a 3-fold higher risk of ESCC than the general population [226,227]. Because a main feature of pernicious anemia is gastric atrophy, it was hypothesized that gastric atrophy may also cause ESCC.
Gastric atrophy can be detected either by direct histologic examination of gastric biopsies or by measuring serum pepsinogens, pro-enzymes that are secreted by the gastric epithelial cells; low serum pepsinogen I (PGI) or low serum pepsinogen I/pepsinogen II (PGI/II) ratio indicate atrophy [228,229]. Ye and colleagues published the first case-control evaluation of the association between serum pepsinogens and ESCC risk and found a 4-fold increased risk of ESCC in patients with low serum PGI [230]. These findings were confirmed by a case-control study from Japan that found gastric atrophy, diagnosed serologically or histologically, was associated with a 4-fold or higher increased risk of superficial ESCC [231]. Also, a case-control study from Linxian showed an almost linear association between the lower serum PGI/II and risk of ESD [232]. A recent study from Netherlands found that patients with gastric atrophy had a 2-fold higher risk of ESCC than the general population [233] but ESCC risk did not increase with increasing severity of atrophy, which suggested that the association of gastric atrophy and ESCC may be confounded by other factors such as smoking. There is no evidence for an increased risk of EA associated with atrophy [227,230].
How could gastric atrophy increase the risk of ESCC? Because gastric glands disappear in atrophy, acid secretion is reduced, which results in a proliferation of bacteria in the stomach [234]. These bacteria, in turn, may increase the production of carcinogens such as nitrosamines and acetaldehyde, which may explain association between gastric atrophy and gastric and esophageal neoplasia.
Like several other etiological hypotheses, the hypothesis that poor oral health could potentially be a risk factor for EC dates back at least seven decades [3,89]. American physicians earlier in this century suggested that patients with EC had poorer dental hygiene than the general population [3]. Chinese scientists also found that the prevalence of dental caries was higher in people from high-risk areas than other Chinese people, and oral hygiene was poorer in patients with EC or ESD than other people (reviewed by CS Yang [89]). More recently, a long-term prospective cohort study conducted in Linxian showed that tooth loss was associated with a small but statistically significant increase in ESCC risk (relative risk of 1.3, comparing above versus lower than median) [193,235]. Subsequent case-control studies in South America [236], Central Europe [236], Japan [237], and Iran [238] also showed that tooth loss was associated with a 2–3-fold increased risk of EC. Furthermore, other studies from China and Iran showed a significantly increased risk of ESD associated with poor oral health [239,240].
The associations found between tooth loss or poor oral hygiene with EC could be confounded by smoking, alcohol consumption, low socioeconomic status, or other factors. Some of the aforementioned studies have extensively addressed these issues. For example, Abnet et al. [238] examined the associations in people who never smoked or drank and the results did not change materially. Other issues still exist. In some studies, clear dose-response associations were not observed and, in some, associations were seen with some markers of oral health but not with others. In a small study in Finland, no association was seen between tooth loss and EC risk [194]. Nevertheless, the accumulated data are definitely intriguing.
If these associations are indeed causal, there are several mechanistic hypotheses [194]: (a) changes in oral microbial flora which result in both poor oral health and in increased production of carcinogens such as nitrosamines and acetaldehyde; (b) physical irritation and damage to the esophageal epithelium due to swallowing unchewed food; (c) change in dietary patterns and nutrient intake due to poor dentition; (d) infection of the esophageal mucosa with an oral microorganism; (e) genetic factors that affect both oral health and EC. Among these, the first proposed mechanism seems most intriguing and could be tested in several ways, for example by comparing nitrosamine and acetaldehyde production among people with and without ESD.
Nearly all studies of the association between poor oral health and EC risk have been done in areas that ESCC constitutes the large majority of the cases, so the results are most relevant to ESCC. To date, there have been no studies specifically evaluating an association between poor oral health and EA.
EC is generally not considered an occupational cancer. However, several studies have suggested that occupational exposure to asbestos could increase EC risk between 2-fold and 16-fold [241–245]. Other studies have found increased EC risk in relation to occupational exposure to silica [246–249]. However, other studies have shown no or only very slight increased risk with these occupational exposures. For example, Kang found only 8% increased risk of EC in relation to asbestos exposure [250]. Further research is required in this area.
IARC has classified crystalline silica and asbestos as a carcinogenic to humans (Group 1 carcinogen), mostly because of their effect in causing lung cancer and mesothelioma [251,252].
It has long been known that EC is a disease of the poor and the socially disadvantaged. In his 1939 paper, Watson writes "… it should be noted that a large percentage of the patients in this series [of 771 EC cases] are … of station in life definitely below average, and further, that 9 out of 10 patients with this disease are in the lower middle class socially, and on the whole financially insecure" [4].
Since then, a large number of epidemiologic studies have confirmed that EC risk is higher in populations with lower socioeconomic status (SES) [12,29,31,51,240,253–260]. These studies have had different designs (case-control, cohort, and comparisons of incident cases with the general population), used different SES indicators (e.g., income and education), and were from all parts of the world (North America, Europe, East and South Asia, the Middle East, and Africa). Therefore, the finding that EC is more common in lower SES groups is nearly universal.
It is difficult to assign an approximate relative risk to SES, partly because SES itself is not a well-defined entity, and various SES indicators, such as education and income, may have different meanings in different populations. However, using various indicators, most studies have reported an increased risk of 2–4-fold among those with lower compared to those with higher SES.
Low education and low income are not direct biologic causes of EC. Attempts have been made to identify more direct causal mechanisms, such as higher use of tobacco or alcohol or poorer nutrition among people with lower SES. However, these attempts have not yielded consistent results.
The majority of studies of SES and EC have been conducted in populations with high risk of ESCC, so there is little doubt that ESCC is inversely associated with SES. There is less data available for EA; three recent studies suggested that SES is inversely associated with EA too [31,256,257] but one study did not find an association [261].
Over the past century, a large number of factors have been tested for their potential association with EC risk. Whereas older studies mainly investigated the etiology of ESCC, the newer studies in Western countries have also investigated the causes of EA.
The results of these studies have established excessive use of alcohol, tobacco use, low intake of fresh fruit and vegetables, low socioeconomic status, and drinking maté as risk factors for ESCC. Also, certain physiologic or pathologic conditions, such as gastric atrophy and achalasia, may predispose people to higher risk of ESCC. There are other potential but as yet unsubstantiated risk factors. For example, PAHs and acetaldehyde may play an important role in the etiology of ESCC in high-risk areas of Iran or China, but this remains to be verified in future studies.
Three important risk factors have been identified for EA: gastroesophageal acid reflux, obesity, and smoking. Absence of H. pylori in the stomach is also becoming increasingly recognized as a risk factor. Other factors, such as the use of LES-relaxing medications need to be further studied.
Writing this review article was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Farin Kamangar, Division of Cancer Epidemiology and Genetics, NCI, 6120 Executive Blvd., Room 3034, Bethesda, MD 20892-7232, Phone: (301) 594-2936, Email: vog.hin.liam@fagnamak.
Wong-Ho Chow, Division of Cancer Epidemiology and Genetics, NCI, 6120 Executive Blvd., Room 8100, Bethesda, MD 20892-7240, Phone: (301) 435-4708, Email: vog.hin.liam@wwohc.
Christian Abnet, Division of Cancer Epidemiology and Genetics, NCI, 6120 Executive Blvd., Room 3042, Bethesda, MD 20892-7232, Phone: (301) 594-1511, Email: vog.hin.liam@ctenba.
Sanford Dawsey, Division of Cancer Epidemiology and Genetics, NCI, 6120 Executive Blvd., Room 3024, Bethesda, MD 20892-7232, Phone: (301) 594-2930, Email: vog.hin.liam@syeswad..
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library 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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Best Western Airport Inn
Tastefully decorated in a warm, contemporary style, all the guestrooms of Best Western Airport Inn in Warwick, Rhode Island, provide guests with those special touches that all travelers are looking for like comfortable beds, premium cable television, refrigerators and microwaves upon request. Don't forget to bring Fido along as the Best Western... more
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Providence Marriott Downtown
Providence Marriott Downtown hotel is in downtown Providence, one-quarter mile from the Rhode Island State Capitol Building and within a mile of Waterplace Park and the Rhode Island School of Design. Providence Marriott Downtown features a restaurant, a coffee shop, and room service. A business center is on site, and the hotel includes a... more
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NYLO Providence/Warwick
NYLO Providence/Warwick is beautifully situated along the Pawtuxet River in the heart of New England. The hotel pays tribute to the region's stunning beaches and marinas by blending NYLO's urban, industrial design with a whimsical nautical expression, creating an aesthetic that is unique, comfortable, and inspiring. The hotel attracts business and... more
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Rockwell House Inn
1809 Federal style Inn located in the heart of historic downtown Bristol, one block from the Narraganssett Bay. Four guest rooms furnished with antiques with private baths, terry cloth robes, hair blowers, irons, fireplaces & A/C. Full gourmet breakfast; 5 star hospitality. AAA/Mobil 800-815-0040... more
Jacob Hill Farm
Jacob Hill Farm entertains guests in an Old Fashioned Way. Swim in the beautiful inground pool, tour the local antique shops, pick blueberries, strawberries, pumpkins or just settle back in our wonderful relaxing world and simply enjoy the magnificent sunsets, performing daily over the valley below. If you must wander, all of Rhode Island is close... more
Point Pleasant Inn & Resort
The stunning views and sumptuous rooms of Point Pleasant Inn & Resort create lasting memories! Overlooking Bristol Harbor, the enchanting Point Pleasant Inn & Resort sets the background for any getaway. Start your day with a delicious breakfast before heading out to see the sights of Bristol, from a living history museum to the Newport... more
Rose Farm Inn
The Rose Farm Inn on Block Island is known for its natural setting, romantic rooms and informal hospitality. Ocean and country views, whirlpool tubs for two and queen or king beds, some with canopies. Decks and flower gardens. Light buffet breakfast in our porch dining room. Bicycle rentals. This peaceful sea and country setting is only a few... more
Hearth House
Since 1798, The Parker Borden House, now the home of the Hearth House, has stood at the northern tip of Bristol's Hope Street, only a few short blocks from the center of town. Conveniently located midway between burgeoning Providence 15 minutes to our north, and Newport's Gold Coast, 20 minutes to our south, Hearth House, an authentic example of... more
Bradford-Dimond-Norris House
The Bradford-Diamond Norris House, one of Bristol's best known landmarks, is located in the heart of Bristol's Waterfront National Register Historic District. Built (circa 1792) for Deputy Governor Wm. Bradford, the house retains a Federal-era appearance with mid-1800's renovations by noted architect Russel Warren. Including the elegant foyer with... more
H. L. Johnson House Bed and Breakfast
Warwick, Rhode Island has been called The Crossroads of Southern New England with good reason. It is situated in the heart of the scenic beauty and historic charm that is New England. The H. L. Johnson House, located at historic Pawtuxet Village and beautiful Narragansett Bay, offers several fine restaurants and antique shops. Boating and fishing... more
Old Court
Filled with antique furniture, chandeliers, and memorabilia from the nineteenth century, the Old Court is a reminder of the sophisticated styles of a century past. Built in 1863 as a rectory and Italiante in design, the Old Court is ideally situated for visiting Providence. A three minute walk puts you in the center of downtown Providence or on... more


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Carrie Underwood Hearts Mike Fisher, Marriage
Carrie Underwood hearts being married to Mike Fisher, but keeps her personal life so private there are hardly any pictures of them together in public. Respect.
Opening up about her marriage in a rare interview, she tells People that given their careers, they haven't been together too much since their summer wedding.


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The truck will start up fine runn for a couple of seconds then die. Replaced mass air flow sensor and it did not fix. If you unplug the maf the truck will run with no issue. Put 2 different mafs in it and the problem was not fixed. It is also a 5.0L
Monday, July 2nd, 2012 AT 6:36 PM