text:
nate <nate(at)desert-solutions(dot)com> writes: > I have a table that has only about 6000 rows in it, takes up 44941312 > bytes (in the data/base dir), ? Not in just one file, I hope. It should be divided into 1-Gb-sized segments named resume_user, resume_user.1, etc. If it really is one file then the problem likely has something to do with file offset overflow. If there are multiple files, how big are they exactly? > I can 'vacuum' the big table, but it won't 'vacuum analyze'. Here's what > I get when I do a vacuum: > DEBUG: --Relation resume_user-- > DEBUG: Pages 1145: Changed 0, Reapped 740, Empty 0, New 0; Tup 7150: Vac > 0, Keep/VTL 0/0, Crash 0, UnUsed 4349, MinLen 56, MaxLen 6148; Re-using: > Free/Avail. Space 166708/160508; EndEmpty/Avail. Pages 0/449. Elapsed 0/0 > sec. > DEBUG: Rel resume_user: Pages: 1145 --> 1145; Tuple(s) moved: 0. Elapsed > 4/0 sec. That's even more interesting, because it says "vacuum" thinks there's only 1145 disk blocks (about 9Mb, assuming you stuck to the standard 8K block size) in the table. Which is fairly reasonable for a table with 6000 rows in it, whereas 4 gig is right out. Why isn't vacuum noticing all the remaining space? I hope you had a backup, because I'm afraid that table is hosed. But we should try to figure out how it got that way, so we can prevent it from happening again. regards, tom lane
Next: From: Bastian Kleineidam Date: 1999-11-23 12:54:34 Subject: Installation glitches Previous: From: nate Date: 1999-11-23 04:05:41 Subject: postmaster crashing on semi large tabl


text:
Boston Marathon Bombing Suspect in Police Custody
Boston Police and city officials are celebrating after the second Boston Marathon bombing suspect was apprehended.
"We got him" #oneboston twitter.com/mayortommenino…
— Mayor Tom Menino (@mayortommenino) April 20, 2013
WATERTOWN, Mass. (AP) — Boston Police say a 19-year-old college student wanted in the Boston Marathon bombings is in custody after a manhunt that left the city virtually paralyzed and his older brother and accomplice dead.
Police announced via Twitter that Dzhokhar Tsarnaev (JOH'-kahr tsahr-NY'-ev) was in custody. His brother, 26-year-old Tamerlan, was killed Friday in a furious attempt to escape police.
The brothers are suspects in Monday's marathon bombings, which killed three people and wounded more than 180 others. The men are also suspected of killing a Massachusetts Institute of Technology police officer in his vehicle late Thursday.
Authorities in Boston had suspended all mass transit and warned close to 1 million people in the entire city and some of its suburbs to stay indoors as the hunt for the remaining suspect went on.
Information from the Associated Press used in this report

subset: commoncrawl


text:
Oakland, Calif. Cost Plus World Market reported that the electronic-funds transfer devices (more commonly known as PIN pads) at eight of its southern California-based stores may have been tampered with by unauthorized third parties.
To date, there is no evidence of any credit-card fraud associated with the incident.
Cost Plus is working closely with its financial-institution partners and law-enforcement officials to ensure that any customers impacted by this incident are identified. The company is also working with its merchant bank and the payment-card issuers to ensure that any affected cards are blocked and reissued.
To augment the chainwide changes in its point-of-sale procedures earlier, Cost Plus began replacing the PIN pad devices throughout all of its stores nationwide and expects to complete the transition by the end of August. The chain also has engaged Verizon Business/Cybertrust, a national data-security firm, to review its overall data-security program.


text:
Stratagem International's unique offering is based on experience and understanding – those who have lived, worked, and succeeded in highly volatile, insecure, complex, and divided political environments can best assist clients in understanding and navigating these particular environments. We have conducted field research, assisted movements in their shift from violent to political means of influence, brought conflicting parties together in a safe environment, and helped actors engage, develop their profile and advance their interests in the foreign affairs / development arena.
What we do
Providing independent advice, research, analysis, facilitation, campaigning and expertise gained on the ground, we offer sound evidence-based approaches, integrity, and a deep understanding of the particular dynamics and challenges facing actors in complex political environments. Our values are rooted in the promotion of participative, democratic models and theories of change.
How we help
With a network of reliable contacts across the globe, we can source accurate information, analysis and expertise directly from the field. Combined with political analysis and a deep appreciation of how organisations benefit from, (or are damaged by ineffective) strategic positioning, we provide tangible and practical communications recommendations and strategies, helping you understand the challenges, harness your resources and advance your interests.
Stratagem International is a sister company of Stratagem NI. Providing services for organisations with international interests, Stratagem International focuses on and operates in political environments outside the UK & Ireland, specialising in those which are seen as particularly complex.


text:
The Prime Minister, Kevin Rudd, and the Opposition Leader, Tony Abbott, appeared from either side of the stage just before the cameras turned on - like Shakespearean actors springing out of the wings.
One wore a red tie, the other blue. Each man came with a posse - Mr Abbott's wife Margie sat with two of his daughters, Frances and Bridget, in the front row. His sister Christine Forster was also present, as was his father. Rudd's people walked in with him, rolling like a tight crew - wife Terese, daughter Jessica, son Nicholas, and senior adviser Bruce Hawker, who has become a sort of mustachioed honorary Rudd, so omnipresent is he in the Prime Minister's campaign.
The two men shook hands and posed for awkward photos before settling into their podiums. Even the Press Club, normally so affable and loud, seemed hushed by the gravity of the choice in front of it. A magenta background added an eerie '80s disco air to proceedings.
There would be no disco-ing but this was a special night and both men had so much at stake. Rudd needs his re-assumption to the leadership to end in a perfect narrative arc - the Prime Ministership returned to where he knows it rightly belongs. He risks, instead, a revenge tragedy in which everyone ends up necked and bleeding out on the floor.
And Abbott - who had flung himself over the line of the nation's most gruelling fun-run Sunday morning - he needs to win this race more than any of the gazillions of competitions he has urged himself towards before.
He came so close last time. Defeat is not an option this time. As they stood waiting for the cameras to switch on, Rudd stared straight into the middle distance, his mouth a thin hard line, and jiggled his legs. Abbott looked distracted.
Rudd spoke first, having won the coin toss earlier in the day which decides these things. And they were off - the economy, productivity, tax reform, aged care, second Sydney airports and broadband were all wrangled.
The men shook hands again when the debate finished, and each fled to the embrace of his family.
Mr Abbott, who had more parliamentary colleagues present than Mr Rudd, received longer-lasting applause.
At least inside the room.


text:
Economic sanctions not forcing Iran to change
Economic sanctions against Iran aren't working, officials have said.
Follow >
Click here to add Barack Obama as an alert
Disable alert for Barack Obama,
Click here to add Tehran as an alert
Disable alert for Tehran,
Click here to add the Washington Post as an alert
Disable alert for the Washington Post,
Click here to add U.S. administration as an alert
Disable alert for U.S. administration,
Click here to add U.S. embassy in Tehran as an alert
Disable alert for U.S. embassy in Tehran
Tough economic sanctions against Iran has taken a serious toll against its economy, but has not yet produced the kind of public unrest that could force Iranian leaders to change their nuclear policies, U.S. and European officials have acknowledged.
Western diplomats and analysts said that nine months after Iran was hit with the toughest restrictions in its history, the nation's economy appears to have become slow, with no jobs and hard currency, but does not appear to be in no immediate danger of collapse.
According to the Washington Post, at the same time, the hardships have not triggered significant domestic protests or produced a single concession by Iran on its nuclear programme.
Analysts said that although weakened, Iran has resisted Western pressure through a combination of clever tactics, political repression and old-fashioned stubbornness.
The mixed results from the sanctions complicate the West's bargaining position ahead of the next round of nuclear talks with Iran, in early April.
According to the report, at the last round, in February, the United States and five other world powers offered significant new concessions to Iran in exchange for curtailment of its uranium-enrichment programme, but Iran has neither accepted the proposal nor offered concessions of its own.
Iran's continuing resistance will also make it tougher for President Barack Obama to reassure Israeli and Arab allies when he arrives in the region mid-week.
The Iranian regime is showing no sign of giving in. On Thursday, a powerful cleric taunted the U.S. administration, vowing that economic pressure could never force Iran to abandon its nuclear programme.
Although Iran has been under U.S. sanctions since the 1979 takeover of the U.S. Embassy in Tehran, the restrictions imposed last summer were the most significant attempt to hit its oil sector and central bank.
The impact has been hardest on the middle and working classes, which have seen savings evaporate and purchasing power dry up.
According to the report, Iran has also found legal ways to soften the bite of sanctions, using currency reserves of euros in foreign banks and arranging complex financial deals that evade the U.S. banking system.
Iran has used the imported goods - such as cars and air conditioners - to counteract high inflation in the country, a congressional staffer who tracks sanctions on Iran and who spoke on the condition of anonymity to discuss sensitive intelligence on Tehran's economic policies, said.
The imports help Iran conserve cash, which it uses to pay salaries and subsidize consumer prices to keep popular unrest at bay, the staffer added.
Top Headlines
- Al Tayer bucks the US department store trend with Bloomingdale's Kuwait opening
- Gulf Islamic banks set to outperform conventional banks for second year: Moody's
- Jordan secures EU finance for socioeconomic and environmental programs
- Same-day service deliveries in GCC an untapped market: Wing CEO
- Will terror attacks damper Arabs' appetite for European holidays?
- Kicking the wrong 'derrière': Iran's economic sanctions need to be placed on Israel
- Currency crisis in Iran as sanctions start to bite
- White House intensifies political campaign for Iran deal
- Iran's nuclear deal: separating political dreams from economic realities
- Islamic State is Forced to Change Tactics as Pressure Mounts


text:
Family Law
Family Law Questions? Ask a Family Lawyer Online.
Hello and thanks for choosing Just Answer®. I am a licensed Florida family attorney, and I will be glad to try and assist you.
To provide you with accurate information, could you please clarify these points so I can best address your inquiry:
Once I hear back from you, I will be glad to let you know my answer. There may be some delay as I am assisting other customers or am away from my computer. Please rest assured, however, that I will get back to you as soon as possible.
Thank you.
How old is your daughter?
Do you know what her wishes are in this matter?
Do either of you have attorneys?
When did the most recent litigation occur?
I apologize, I should have asked this already....
What exactly does the temporary state as far as custody and visitation?
Where is your daughter now?
As to attorneys and fees, what is the approximate income for each of you?
The "proper" way to handle this is through the court system. Unfortunately, the judge is not giving you a hearing date for four months. Meaning, the "proper" method requires you to wait four long months.
As your child is a bit older, you might consider simply picking her up one day. If she is in school, church or whatever, you have the right to simply pick her up. If the father calls the police, he would likely rely on the "temporary" order. If so, simply point out to the officers that the order expired. In that event, my speculation is that the officers would tell you both that it is a civil matter and that you should contact your attorneys.
Another option would be trying his attorney again. I know you have stated that you have had no success thus far but it might be worth the effort. If you can contact the attorney and share your perspective on the temporary order, he might enlighten you as to their perspective. It would be interesting to know whether he supports your husband's actions. While you may expect that he would support his conduct, I can tell you from experience that clients often do things contrary to their attorneys expressed instructions. If that is the case here, the attorney may be able to help you out.
Due to the complexities of the issues, I would urge you to look into retaining an attorney to assist. First, you should begin with your state bar association. The Florida State Bar has a website, it is located at www.floridabar.org.
I do not know your county of residence but your county bar association likely has a similar site that will be more specific to your location. For example, you could search "Broward County clerk of court".
Additionally, Martindale Hubbell is a national organization that rates attorneys across the country. Their website is located at http://www.martindale.com/.
Another nationwide website is located at http://www.avvo.com/. This site lists attorneys by geographic location and area of practice.
Each of these resources will have a wealth of information as to attorneys in your area that handle such cases. I would suggest you check each site out and you will surely find a great number of attorneys that meet your needs. Pick a few to meet with in person so that you can thoroughly explain your situation and then retain the one that you feel can best represent your interests.
As to fees, you may be able to get some assistance. In Florida, if one party makes substantially more than the other, you can file a motion with the court asking for the other party to pay your fees. So, I would urge you to look into getting the judge to sign an order requiring the father to pay or contribute to your attorneys fees.
I hope you found my answer helpful. If so, please click on the green ACCEPT for my answer. This is necessary for me to be paid for my work and so that I can get credit for assisting you. Even if you are a subscription member, you will need to click ACCEPT. Your question will not close, and you will still have the opportunity to follow-up if needed. Leaving a bonus and positive feedback is not required, but doing so is certainly appreciated! Thank you and good luck!
Also, several customers have asked how they may direct a question to me in particular. If you specifically want me to assist you in your legal matter, just put "FOR JOSEPH" in the subject line and I will gladly pick up the question as soon as I am on-line.


text:
Android Users - Coming Soon! - Migrating from aCar 4.8 to 5.0
Real Name: Mactravisfrench Joined: August 2016
No vehicles yet.
Lower your wind resistance.
Modern cars have folding outside mirrors. When my car is un... ...
by Littlecars
Read more tips
© 2017 Fuelly.com - All Rights Reserved. Sep 20, 2017 11:06 PM CDT
A simple & effecive way to track fuel consumption
Easy to understand the real cost of your vehicle


text:
CLEARWATER — City leaders are talking tough about budget cuts, but one thing that didn't make the chopping block: expenses for a baseball trip to Philadelphia.
Four City Council members, two city managers and the head of parks and recreation will meet with Phillies owners this month, when Vice Mayor George Cretekos will throw out the first pitch of a game.
It's an annual ritual since the Phillies made Clearwater its spring training home 64 years ago, and some of the council members say they're going to pay their own way. But taxpayers are still expected to pick up at least $2,800 for the trip at a time when officials are bemoaning the city's fiscal future.
State lawmakers last year and voters earlier this year successfully approved measures that limit the amount of property taxes local governments can collect. And already Clearwater has reduced hours at recreation centers and libraries and cut jobs and a number of services.
Clearwater leaders are defending the trip, saying it makes good fiscal sense in the long run.
"The (Phillies) are one of our most important taxpayers and these guys have other choices in terms of where to put their operations, but they pour so much money into the city, we think it's a good idea (to go)," said council member Paul Gibson, who's picking up his own tab.
Gibson said the council will probably take a look at further belt-tightening and future trips could be cut. But, he said, he didn't have a problem with taxpayers paying for the trip because "it's a city function."
Three of the City Council members said they're going to pay their own way, but the majority of the tab for the vice mayor and three staffers will be picked up by taxpayers.
Clearwater officials say the trip is worth the expense to nurture a relationship with a business that spends $7-million in the city each year and has an estimated economic impact of $35-million a year.
Most officials plan to attend games June 20, 21 and 22, and meet with team owners to find ways to get the business community to further embrace the Phillies.
Traveling at taxpayer expense will be Cretekos, City Manager Bill Horne, Assistant City Manager Rod Irwin, and parks director Kevin Dunbar. Several city officials' spouses, along with a contingent from the Clearwater Regional Chamber of Commerce, are also on the trip, but are paying their own way. Along with Gibson, council members Carlen Petersen and John Doran are also paying for themselves.
The city's costs: roughly $860 for airfare on Southwest Airlines; a little over $1,600 to stay at the Ritz-Carlton Hotel and Hampton Inn; a combined $330 daily food allowance for officials, per city policy for the trip. (Cretekos said he will pay for his own food.)
Officials say the public shouldn't bash them because the trip will pay for itself. This is no junket, they add, rather a business trip mixed with a little pleasure.
Members plan to attend — for free — the three-game series against the Los Angeles Angels at Citizens Bank Park, where Cretekos will throw out the ceremonial pitch June 21. But they will also spend June 20 with team owners to exchange ideas about better marketing spring training.
In recent years, public outcry has caused officials in local baseball cities, including Tampa, St. Petersburg and Dunedin, to curb the trips, cancel them or cut back on the number of officials who attend.
Dunedin, for example, hasn't sent anyone to Toronto for the past few years to meet with the Blue Jays owners because officials said they were concerned about budget cuts.
"We decided not to do it in general recognition of the tight budget and it's probably not an appropriate expenditure given the changes we have to deal with," Dunedin Mayor Bob Hackworth said.
But, Clearwater's Petersen said "people have to remember the amount of revenue the Phillies bring to the city — it's huge and important — and people tend to forget."
When asked why the city doesn't send only one or two representatives, Horne said each person plays a key role in the relationship with the Phillies. For example, Dunbar is the city's team liaison and Irwin oversees economic development.
He added that in his budget proposal for the upcoming year he recommends cutting travel and training expenses 20 percent for each department — a savings of $146,560 from the city's $123-million general operating fund.
"We're fine this (current) budget year, but next year is a completely different story," Horne said.
The city has been the spring training home of the Philadelphia Phillies for 64 years. The club's Single-A team, the Threshers, also plays at Bright House Networks Field.
The mayor at least once a year gets a chance to throw out the ceremonial first pitch during a Phillies game. But this year Frank Hibbard said family commitments will keep him home. That means Cretekos gets the honor.
"I may end up rolling it in," Cretekos said. "No seriously, I'm not even thinking about the pitch, but I will try to make Clearwater proud."


text:
Isaac Toussie, Brooklyn real estate developer, is Long Island's largest landowner in association with his father and committed to many business focuses. Isaac Toussie is involved with developments, holdings and various ventures when it comes to business, but for this entrepreneur the latest project focus is to continue to help support children with serious illnesses. Isaac also shares a strong commitment to quality charitable causes and currently is involved in giving support to "Ronald McDonald House Charities."
This cause continues to help many seriously ill children in need offering strength and hope to them and their families. This noteworthy cause helps more than 7 million families each year, Ronald McDonald House Charity programs can now be found in 78% of the world's best children's hospitals, with more than $200 million collected through Ronald McDonald House Charity Donation Boxes and Isaac's commitment to helping this cause is strong.
The Toussie family has a long tradition of involvement with New York University, and the philanthropic spirit is a Toussie family affair. Isaac Toussie, who received magna cum laude honors from the NYU Stern School of Business, and received his Master's in Business Administration from the NYU Business School at the young age of 21, kept him busy. Isaac nonetheless is continuing in the path of his father, Robert Toussie, and his charitable mission. For more than a decade Robert and Isaac Toussie and family find the time to continue to commitment to make a difference in the lives of others.
For many the Ronald McDonald House is about helping a sick child fight their illness. They provide stability and support with resources for families everywhere it takes an immense emotional toll on a family when a child is sick and suffering. "When families are," going through emotional strain and financial burden for a sick child it is often too difficult to bear. Ronald McDonald House Charities steps to the plate to address these areas. Whether it involves housing near a hospitalized child, or the expense of staying together in another town or city or helping with basics of medical and dental care in a vulnerable community.
Ronald McDonald House Programs can be found in more than 290 local chapters in 58 countries and regions, currently 326 Ronald McDonald Houses exist today, 184 Ronald McDonald Family Rooms, and 49 Ronald McDonald Care Mobiles scurry about the country.
The Ronald McDonald House is involved with non-profit organizations that focus on the needs of children with Grants, and Scholarships are available to students across the United States. Each of the many Chapters around the world is busy with country-specific programs. Since 1974, Ronald McDonald House Charities has helped address these needs every day, with more than 30,000 volunteers and staff members, with specific connections with medical communities around the world, partnerships with respected companies and our generous donors.
Ronald McDonald House charities exist because of it donors contributions to making a difference to the lives of sick children.Isaac Toussie brings to the forefront awareness and commitment to help those who are suffering and struggling from serious illness.


text:
Checklist for PLA
The following checklist may assist you in determining if you are a candidate for PLA credit. Do any of these statements apply to you? If so, you may be a candidate for PLA credit.
- I am over the age of 24.
- I have a minimum of 5 years' work experience.
- My work experience includes leadership, management, or supervisory responsibilities.
- I have certifications and/or memberships with professional organizations.
- I have participated in corporate training programs.
- I have completed non-credit college courses.
- I have hobbies, personal interests, or have completed an informal independent study.
- I have been involved with extensive volunteer or community work.
- I am or was a member of the armed forces.
- I have lived in a foreign country and/or traveled extensively.


text: Youth Service Bureau (YSB), which provides support services for families, children and teens in the community presented a program Wednesday night at their offices in the historic courthouse. An individual who had gone through the program shared his success story. Those in attendance included members of the community and the leadership of YSB pictured from left: Clinical Program Director Mike Huntley, board member Craig Woolery, Executive Director Mary Planten-Krell and Executive Director of the Youth Intervention Program Association Scott Beaty.


text:
Attention hikers, snowmobilers and other outdoor enthusiasts!
A meeting to discuss a possible long-distance Quabbin-to-Cardigan hiking trail in western New Hampshire will be held at Colby-Sawyer College, Ivey Science Center, in New London, April 12 from 6 to 8 p.m. All are welcome.
Hiking groups and land conservation organizations are evaluating whether it is possible to create a long, inter-connected trail from the Massachusetts / Hampshire border to Mt. Cardigan and beyond to the White Mountains.
The idea came out of the Quabbin-to-Cardigan (Q2c) Partnership, an initiative to protect the region's unfragmented forest blocks for ecological and recreational purposes, said Lelia Mellen with the National Park Service.
This meeting is one of three and is a key part of a trail study managed by the Forest Society and the Appalachian Mountain Club with help from the NPS's Rivers, Trails & Conservation Assistance program. Two weeks ago, the first outreach session was held in Canaan; in early May, the third session will be held in Keene.
The region's existing trail networks, such as the Monadnock-Sunapee Greenway and Sunapee-Ragged-Kearsarge Greenway, could perhaps connect with other hiking trails to the north and with trails where they do not know exist. Meeting participants will be able to look at maps and share their ideas and questions.
For more information, contact Lelia Mellen, NPS, by email or phone 802-457-3368, ext. 14.
Filed under: Announcements, Energy & Environment, Health & Wellness, Land Use, Nature & Outdoors, New Hampshire, Recreation | Tagged: Appalachian Mountain Club, Hiking, Hiking trails, New London New Hampshire, Quabbin to Cardigan, White Mountains |


text:
Ulrich, H;
Abbracchio, MP;
Burnstock, G;
Extrinsic purinergic regulation of neural stem/progenitor cells: implications for CNS development and repair.
Stem Cell Rev
, 8
pp. 755-767.
There has been tremendous progress in understanding neural stem cell (NSC) biology, with genetic and cell biological methods identifying sequential gene expression and molecular interactions guiding NSC specification into distinct neuronal and glial populations during development. Data has emerged on the possible exploitation of NSC-based strategies to repair adult diseased brain. However, despite increased information on lineage specific transcription factors, cell-cycle regulators and epigenetic factors involved in the fate and plasticity of NSCs, understanding of extracellular cues driving the behavior of embryonic and adult NSCs is still very limited. Knowledge of factors regulating brain development is crucial in understanding the pathogenetic mechanisms of brain dysfunction. Since injury-activated repair mechanisms in adult brain often recapitulate ontogenetic events, the identification of these players will also reveal novel regenerative strategies. Here, we highlight the purinergic system as a key emerging player in the endogenous control of NSCs. Purinergic signalling molecules (ATP, UTP and adenosine) act with growth factors in regulating the synchronized proliferation, migration, differentiation and death of NSCs during brain and spinal cord development. At early stages of development, transient and time-specific release of ATP is critical for initiating eye formation; once anatomical CNS structures are defined, purinergic molecules participate in calcium-dependent neuron-glia communication controlling NSC behaviour. When development is complete, some purinergic mechanisms are silenced, but can be re-activated in adult brain after injury, suggesting a role in regeneration and self-repair. Targeting the purinergic system to develop new strategies for neurodevelopmental disorders and neurodegenerative diseases will be also discussed.
|Extrinsic purinergic regulation of neural stem/progenitor cells: implications for CNS development and repair.
|United States
|Animals, Apoptosis, Calcium Signaling, Cell Differentiation, Cell Movement, Cell Proliferation, Central Nervous System, Humans, Nerve Regeneration, Neural Stem Cells, Neurodegenerative Diseases, Purinergic Agonists
|UCL classification:
|UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
Archive Staff Only
|View Item


text:
In World War II, U boats would send up wreckage to the surface to make pursuers think they had been sunk. The GOP presidential campaign is at that stage now.
Huckabee, Trump, Barbour, (gulp) Gingrich…the flotsam and jetsam keep coming, but down below in the engine room, are real missiles being loaded? (Apologies to Sarah Palin for the war image.)
A Gallup poll shows name recognition is still the game with only Romney reaching 20 percent as the preferred candidate. Most GOP voters seem to want something, but they won't know what it is until they see it.
"Top Republicans," reports Politico, "are increasingly convinced that President Barack Obama will be easily reelected if stronger GOP contenders do not emerge, and some are virtually begging Indiana Gov. Mitch Daniels to add some excitement…
"It's a sign of the GOP's straits that the party is depending on the bland, wonkish Daniels for an adrenaline boost."
There is talk of New Jersey Gov. Chris Christie, who has declined, as well as any other Republican governor or senator untainted by scandal or blatant stupidity.
Is John M. Huntsman Jr. the man? Who?
Copyright 2011 The Moderate Voice


text:
Presidents and Their Debt: From FDR To Obama
With the National debt of large concern recently and the debt ceiling debates continuing, many want to see the figures as to what President Barack Obama has done toward the US National Debt. Last year it was reported that Obama added more to National Debt in his first 19 months than all U.S. presidents through Ronald Reagan combined with an increase of $2.5260 trillion. That is more than the cumulative total of the national debt held by the public that was amassed by all U.S presidents from George Washington through Reagan. From CNSnews.com,
"At the end of fiscal 1980, four months before Reagan was inaugurated, the federal debt held by the public was $711.9 billion, according to CBO. At the end of fiscal 1989, eight months after Reagan left office, the federal debt held by the public was $2.1907 trillion. That means that in the nine-fiscal-year period of 1980-89--which included all of Reagan's eight years in office--the federal debt held by the public increased $1.4788 trillion. That is in excess of a trillion dollars less than the $2.5260 increase in the debt held by the public during Obama's first 19 months."
As of June, once the national debt passed $13 trillion mark the Obama administration had increased the debt by $3.398 trillion in just 710 days. The fiscally conservative community is calling for Obama's head as unemployment and inflation continue to hammer the current economy. But lest we not learn from our past presidents and see that debt is practically ingrained in our history. As famed author H.W. Brands said, "Since George Washington, presidents have embraced public debt as an investment in America's future."
Ronald Reagan:
Start of presidency 1981: US National Debt $997.8 billion
End of presidency 1989: US National Debt $2.1 trillion
Reagan began his presidency with a federal deficit of 2.5% of national economy and ended his two terms with that number doubling to 5%. Just four months into his presidency, Reagan told Congress that high taxes and big spending made the present economic mess and that doing the same won't get the U.S. out of their struggle. That moment cemented Reaganomics and our current economics woes. The Democrats that fell at Reagan's feet has to take their "spend and tax" methods and jump on board the "spend and borrow" Republicanism. To defeat former Vice President Walter Mondale in the 1984 election, Reagan's chief of staff passed him a note. On the note read "Taxes are a big picture issue. If we want to win – and win big – the exigencies of the election force us to solemnly swear that Mondale is the tax increase candidate and Reagan is the no-tax-increase candidate." The note ended by saying after Reagan get re-elected, he could do whatever he pleased with the generalizations like the deficit. Interestingly enough previous Vice President Dick Cheney said that politically Reagan showed that deficits don't actually matter. Reagan proved that by running up more debt than any prior president and easily won re-election.
Franklin D. Roosevelt:
Start of presidency 1933: US National Debt $22.5 billion
End of presidency 1945: US National Debt $258.5 billion
Our only president elected to more than two terms and the man behind the New Deal many conservatives consider the "tax and spend" policies that lead to incredible fiscal misery. As David Kennedy says, "Yes, Roosevelt was a bold and visionary innovator who substantially rewrote the American social contract [with his signing of Social Security into law in 1935]. But the Beelzebub of the Budget he was not." Roosevelt was a stubborn fiscal conservative yet was always compared to former president Herbert Hoover's deficit, which he exceeded twice (1934, '36) after the New Deal. In 1936, Roosevelt had the largest absolute deficit of $4.4 billion, or 5.3% of Gross National Product (with help from a overlooked Roosevelt veto from Congress for Bonus Bill $2 billion for World War II vets.) The Roosevelt Recession followed as he produced an austerity budget which drastically reduced government spending and the economy crumbled; unemployment ballooned to 19% from 14% and generated deficits reached nearly 30% of G.N.P.
Lyndon Johnson:
Start of presidency 1963: US National Debt $306 billion
End of presidency 1969: US National Debt $353 billion
LBJ had a lot of issues to deal with in his time in office, particularly in 1968. Fiscally Johnson had to find a way to fund the Vietnam conflict and his Great Society reforms all while anti-war demonstrations, inner city riots and violence in Chicago during the Democratic convention stood in his way. Americans did not want tax increases but an economic collapse was destined if Johnson's plea for a 10% tax surcharge was enacted. Congressional conservatives wanted cuts to domestic spending instead of the surcharge but Johnson said failure to pass a tax surcharge would mean "a major world political defeat for the United States," and LBJ got what he wanted against 79% of Americans wishes. US National Debt grew by $21 billion in 1968 alone, closing out Johnson's presidency on a very sour note.
Richard Nixon:
Start of presidency 1969: US National Debt $353 billion
End of presidency 1974: US National Debt $475 billion
The proudly proclaimed conservative Keynesian, President Nixon focused much of his early presidency on foreign and domestic economics as he took the reigns from Johnson's dwindling US economy and faced inflation within his first eight months in Washington. He didn't take a high priority on balancing the budget and by 1970, the economy looked to be heading to a recession. Joan Hoff explains,
"Nixon became the first president to submit a budget based on "the high-employment standard," which meant the country would spend as if it were at full employment to bring about full employment, thus justifying an "acceptable" amount of deficit spending. Second, he dramatically announced in August 1971 what he called the New Economic Policy. The N.E.P. attempted to balance U.S. domestic concerns with wage and price controls and international ones devaluing the dollar."
He failed to obtain more revenue through tax reform in 1969. With that, unemployment rose to 4.9% in parallel with inflation jumping to 5.7% which set off the federal budget deficit totaling $23.03 billion. But there was positives his N.E.P. as unemployment fell and output rose and he became the only president since World War II to bring an economic upturn in a presidential election year and he was re-elected.
Harry Truman:
Start of presidency 1945: US National Debt $258 billion
End of presidency 1953: US National Debt $266 billion
Truman was the first president since 1930 to reduce the nation debt and according to the numbers, the only president to truly make an effort to cut the debt significantly. His first year in office Truman was preceded by Franklin Roosevelt's big spending to dig the country out of Depression with astronomical year-to-year national debt change. In 1942, FDR's national debt went up by $23 billion, then up $64 billion the next year, another $64 billion the following year, and to close out his presidency in 1945 with another large increase in debt by $57 billion, totally over $200 billion in increased debt in his last term. The numbers drastically dropped once Truman came to office, and within his 18 months in office, he reduced the debt by $11 billion and by the time he left office in 1953, he is the only president of the 1900s to exist the Oval Office with a reduced year-to-year national debt total.
Dwight Eisenhower:
Start of presidency 1953: US National Debt $266 billion
End of presidency 1961: US National Debt $288 billion
Preceding Harry Truman in terms of fiscal resolve was a difficult task, but some could say Eisenhower lived up to the role fairly well. He continued all of the major New Deal programs and focused much of his attention toward nuclear weapons over conventional arms which was more of a fiscal policy than anything else. Eisenhower feared that the costlier conventional forces would unbalance the federal budget and thereby undermine American freedoms. His plans proved successful as he is the last president to reduced the year-to-year national debt (1955: $1.6 billion reduced, 1956: $2.2 billion reduced).+9
More like this...Unemployment: From Disappointing to Dismal
Economy only picked up 54,000 jobs in May...much lower than anticipated. Employment is now at 9.1%.
Marc Faber Says Beware the National Debt
Guest contributor Brianna Panzica summarizes an interview with Marc Faber and his severe warnings against the government.
The Real Budget Picture
As the debt debate heats up, Obama requests a grand bargain. Check out this startling graph comparing government spending & revenue from taxes.
Greece is a Lost Cause: Entire EU Given 5 Years to Survive If Italy and Spain's Debt Crisis Is Not Resolved
Former Prime Minister predicts the 'decline of the West' if reconstruction plan is not found soon. Greece is out, Italy and Spain hold the key to the EU.
Will Debt Ceiling Increase By $2.4 Trillion?
House Republicans will vote on the issue next week. Obama seems optimistic towards reaching a "big deal" in this video...


text:
When the .mobi domain launched in September 2006, people quickly understood it was a Top-Level Domain (TLD) designed to locate mobile content in the same way — for example — that .se locates Swedish content or .museum helps users recognize genuine museum activity. In short, think "mobile phone" when you think ".mobi".
Now, the .tel domain is launching ... and people are asking, "Won't .tel help me locate content that will work on a phone — mobile or not? Do I still need a .mobi domain?"
The purpose of these two domains is very different. There is no overlap except in that they can easily work together to make content creation a bit easier.
To better understand, think of ".tel" as being shorthand for "telephone directory." The .tel domain allows users to put personal or corporate contact information directly in the Internet's Domain Name System (DNS), which then makes that contact information universally accessible. In other words, you update your information in one place and it then populates across every single place where you reference that .tel domain.
This is a unique application for a Top-Level Domain. Definitely, .tel does not act at all like other Top-Level Domains, where the DNS provides a mapping between domain names (like dotMobi.mobi) and IP addresses (184.108.40.206), so that users can more easily find content instead of worrying about the numeric sequence of the IP address.
In practical terms, this means you would likely use "MyCompanyName.tel" to create a simple "address book" style entry that would be repurposed across a wide range of digital media and traditional media as "See MyCompanyName.tel for ways you can reach us."
You use "MyCompanyName.mobi" as a way to tell your customers and prospects, "I have a site designed for your needs when you're on the go. This is where you come when you need information that meets your mobile needs." For example, "Where's the closest ATM?" or "What's on the 'to go' menu so I can order now and get it as I walk by?" On .mobi pages such as these, you might insert a link to MyCompanyName.tel so that your customer will always have the correct contact information.
Adding to the confusion ...
... is that the team behind .tel have issued collateral that indicates that they believe .tel is a good mobile solution because (1) it uses DNS lookups rather than pulling traditional HTML content and (2) that traffic generated by a .tel lookup is small, so that it's fast for consumers to access.
Given many of the things we've learned over the past three years, I can say that there may be some interesting mobile applications that can be done with direct DNS look-ups but it's not going to be related to a true mobile web presence unless there's a mobile web site involved. And more to the point, what business or brand wants its mobile web presence limited to its contact information instead of a robust, loyalty-building site offering the full interactivity and capabilities of the mobile web?
Will .tel be easy and fast for contact information? Absolutely. Is .tel available for rich content beyond contact information? No.
So, despite a second or two of confusion, I think it's easy to see how a .mobi(le phone) can easily work with a .tel(ephone directory) — and also see that there's really no overlap between the two domains.
About Afilias Mobile & Web Services – Afilias Technologies Limited, a wholly owned subsidiary of Afilias plc, is an expert provider of mobile and web technologies that help companies to reach their customers, regardless of device, content, or context. Products include the DeviceAtlas device intelligence solution, the goMobi mobile website publishing solution and Developer tools such as mobiReady. Learn More
Related topics: Domain Names, Mobile Internet, Registry Services, Top-Level Domains, Wireless
|Access Providers
|Cloud Computing
|Net Neutrality
|Data Center
|Policy & Regulation
|DNS Security
|Regional Registries
|Domain Names
|Registry Services
|Intellectual Property
|Top-Level Domains
|Internet Governance
|Internet of Things
|Internet Protocol
|White Space
|IP Addressing
IP AddressingSponsored by Avenue4 LLC
CybersecuritySponsored by Verisign
Mobile InternetSponsored by Afilias Mobile & Web Services
DNS SecuritySponsored by Afilias
ACCELR/8 is a transformative IPv4 market solution developed by industry veterans Marc Lindsey and Janine Goodman that enables organizations buying or selling blocks as small as /20s to keep pace with the evolving demands of the market by applying processes that have delivered value for many of the largest market participants. more»


text:
As a parent, your expectations for your child are simple, really – for the child to feel loved and accepted, to have the opportunity to participate in childhood activities, and to interact with family, friends, classmates and others in meaningful ways. Above all, to find ways to enable them to fully realize their individual potential. At Amy Zier & Associates, you will find that everything about our pediatric therapy practice revolves around this idea.
The clinic's uniquely homey spaces help to relieve the anxiety associated with therapy, and programs promote progress through innovative thinking and activities. What's more, our individualized approach goes beyond the diagnosis to take into account all the people and places that are associated with your child's life.
Welcome to Amy Zier & Associates Pediatric Therapy – where you'll discover potential realized.
Powered by Waitt Interactive


text:
As careful as we try to be during pregnancy, occassionally accidents do happen.
Frequent falling can sometimes be a result of plain old clumsiness, but most times it is related to your changing center of gravity. As your belly and breasts grow, it can become increasingly difficult to handle situations that require balance.
Another factor that can cause you to be less than graceful is the pregnancy hormone relaxin. Relaxin loosens joints and connective tissue—allowing for the extra room that Junior is taking up. This loosening of the joints can also lead to a feeling of unsteadiness.
But don't worry, your baby is well protected by your abdominal muscles; fat, thick uterine wall; and amniotic fluid, which surrounds the baby.
If you've fallen or received a blow to your belly, it's a good idea to call and check in with your doctor right away—just to be safe. And be sure to keep the following warning signs in mind:
- vaginal bleeding
- dizziness or feeling faint
- shortness of breath
- uterine contractions
- decreased fetal movement
- fluid leaking from the vagina
Just to make sure that everything is OK, you doctor may order an ultrasound after speaking with you. If you are in your second or
third trimester, and you're feeling cramping or contractions after receiving a blow to the belly, your doctor will most likely monitor you and your baby by EFM (external fetal monitoring) to make sure you're not going into labor prematurely and to asses the baby's well-being.
As your pregnancy progresses, be mindful of your wobbly status and take care when exercising or playing with your busy toddler! Be careful, know the warning signs, and don't hesitate to call your doctor with questions or concerns.


text: ×Close Product Image 1 of 1 The Last Banner The Story of the 1985-86 Celtics and the NBA's Greatest Team of All Time See image The Last Banner The Story of the 1985-86 Celtics and the NBA's Greatest Team of All Time By Peter May × Added to Cart List Price $20.95 Your Cart ( items) Cart total Continue Shopping CHECKOUT NOW Choose a format: Trade Paperback Format: Trade Paperback Simon & Schuster | 304 pages | ISBN 9781416552123 | February 2007 Add to Cart Buy Simon & Schuster Add to Cart Amazon Barnes & Noble Books-a-Million IndieBound List Price $20.95 In Stock: Usually ships within 1 business day Browse Related Books Sports & Recreation > General Buy from another retailer Amazon Barnes & Noble Books-a-Million IndieBound Get a FREE eBook when you join our mailing list. Plus, receive updates on new releases, recommended reads and more from Simon & Schuster. Email Address Free eBook available to NEW subscribers only. Offer redeemable at Simon & Schuster's ebook fulfillment partner.Offer expires in three months, unless otherwise indicated.See full terms and conditions and this month's choices. More Books from this Author The Big Three The Big Three By Peter MayBy Peter May About the Author Peter May BECOME A FAN BOOKS


text:
Cravin 20" Wide End Table in Walnut - TDERC2020Item#: I92-7713 | Model#: TDERC2020
Currently Out Of Stock!
Cravin 20" Wide End Table in Walnut Product Details
Manufactured by: Cravin Furniture
Warranty provided by: Cravin Furniture
UPC No: 623788007414
Mfg Part No: TDERC2020
Box Size:
( Length:24, Width:23, Depth:7)
Shipping Weight: 21.0000 pound(s)
Click here for full warranty and support information
- Cravin Furniture logos are registered trademarks of Cravin Furniture. All others trademarks and copyrights mentioned herein are the property of their respective owners.


text:
Pacers hold free pep rally Thursday
The Indiana Pacers will hold a free and open to the public pep rally ahead of Thursday night's NBA playoffs Game 6 between the Pacers and the Miami Heat.
The rally takes place in the parking lot north of Bankers Life Fieldhouse on Pennsylvania St.
The pep rally will run from 5:30 p.m. to 7:30 p.m. Game time is slated for 8:00 p.m. and the team announced doors will open one half hour earlier than usual at 6:30 p.m.
There will be a children-friendly section for kids and an adult section with beer being served.
Fans will have the opportunity to enjoy live music and entertainment, participate in games to win Pacers prizes and surprises. The Pacemates will be on hand as well as special Pacers celebrities.
Fans will have a chance to sign a huge "I Love the Pacers" banner that will later be hung outside the team's locker room.
A very limited number of tickets for Game 6 are being held for NBA Playoffs requirements. If those tickets are not utilized by the league and/or league partners, they will be released for sale to the general public as they become available. Fans should visit Pacers.com to check on ticket availability.


text:
Chronic inflammation is involved in the pathogenesis of most common cancers. The aetiology of the inflammation is varied and includes microbial, chemical and physical agents. The chronically inflamed milieu is awash with pro-inflammatory cytokines and is characterized by the activation of signalling pathways that cross-talk between inflammation and carcinogenesis. Many of the factors involved in chronic inflammation play a dual role in the process, promoting neoplastic progression but also facilitating cancer prevention. A comprehensive understanding of the molecular and cellular inflammatory mechanisms involved is vital for developing preventive and therapeutic strategies against cancer. The purpose of the present review is to evaluate the mechanistic pathways that underlie chronic inflammation and cancer with particular emphasis on the role of host genetic factors that increase the risk of carcinogenesis.
- cancer
- chronic infection
- genetic polymorphism
- inflammation
There is a significant body of epidemiological evidence showing a clear association between chronic inflammatory diseases and subsequent malignant transformation. Microbially induced inflammation is estimated to be associated with approx. 15% of the global cancer burden [1]. Moreover, strong evidence is also available to support long-term use of non-steroidal anti-inflammatory drugs as a means of reducing risk of several cancers [2]. Attempts aimed at defining the role of inflammation in carcinogenesis initially identified that inflammation can activate and induce a variety of oxidant-generating enzymes including NADPH oxidase and iNOS (inducible nitric oxide synthase), which can cause DNA damage and ultimately result in tumour initiation. More recently, however, it has been recognized that cancer development on the back of inflammation may be driven by inflammatory cells and a variety of mediators which together establish an inflammatory micro-environment.
Chronic inflammation may progress from acute inflammation if the injurious agent persists, but more often than not, the inflammatory response is chronic from the outset. The most compelling examples of chronic-inflammation-induced carcinogenesis are seen within the gastrointestinal tract including inflammatory-bowel-disease-induced colon carcinogenesis and also Helicobacter-pylori-induced gastric cancer [3]. However, there are numerous other examples throughout the body (Table 1). In contrast with the largely vascular changes of acute inflammation, chronic inflammation is characterized by infiltration of damaged tissue by leucocytes. Initially neutrophils and tissue mast cells are recruited as part of a multifactorial mechanism which co-ordinates inflammatory cell involvement. Mast cells especially play an important role in releasing preformed stored inflammatory mediators that attract migratory inflammatory cells to the site. Next, monocytes migrate to the area, differentiate into macrophages and become activated in response to local chemokine and cytokine interactions. Macrophages in turn secrete a number of potent bioactive inflammatory mediators which promote tissue healing at the site of injury. When considering the inflammatory environment within a neoplastic site, TAMs (tumour-associated macrophages) make up the largest proportion of the inflammatory cell infiltrate and their presence has a profound impact on the local micro-environment [4,5]. However, the downside is that persistent macrophage activation can result in continued tissue damage through the stimulation of local tissue remodelling, cellular proliferation and angiogenesis, which helps to potentiate neoplastic progression [6].
It is well-established that free-radical-mediated DNA damage occurs in cancer tissue, with overexpression of iNOS, an enzyme catalysing nitric oxide production, found in several cancers with known inflammatory involvement [7–11]. Leucocytes including neutrophils, dendritic cells, mast cells and lymphocytes are all capable of producing a variety of ROS including nitric oxide, superoxide anions and hydrogen peroxide. In addition to ROS, RNS (reactive nitrogen species), such as peroxynitrites and nitrogen oxides, are also formed and can react to generate mutagenic adducts [12–15]. To date, more than 100 products have been identified which cause oxidation of DNA. Nitric oxide and its products may exert oncogenic effects via several mechanisms including direct DNA (single- or double-stranded DNA breaks, deoxynucleotide or deoxyribose modifications and DNA cross-links) and also protein damage. This can result in altered transcription or signal transduction induction, genomic instability and also replication errors [16,17]. Other mechanisms include inhibition of apoptosis, mutation of DNA and cellular repair functions such as p53 and also via promotion of angiogenesis [9,11]. There is also evidence of mitochondrial oxidative DNA damage within the carcinogenic process, with mutations and altered expression in mitochondrial genes encoding complexes I, III, IV and V having been identified in several human cancers [17a].
Most of the DNA-damaging effects of ROS are non-specific; however, studies have revealed that, in addition to inducing these actions, ROS can specifically activate certain intracellular signalling cascades and thus contribute to tumour development and metastasis through the regulation of cellular functions such as proliferation, death and motility. Growing evidence suggests that ROS production is tightly regulated and their downstream targets are quite specific [18]. It is also known that different cellular responses are affected by specific ROS. ROS are divided into free oxygen radicals and non-radical ROS. Free radicals contain one or more unpaired electrons and include superoxide and nitric oxide. Non-radical ROS include hydrogen peroxide. Hydrogen peroxide, which is generated by numerous intracellular reactions, exerts most of its mutagenic effects via hydroxyl ions which can activate oncogenes including K-ras [19]. In contrast, nitric oxide production is more specifically involved with tumour-cell killing and activation of the proto-oncogene p21 and the tumour-suppressor gene p53. These effects are thought to be caused as a consequence of overproduction of nitric oxide [20]. Nitric oxide is also associated with the generation of carcinogenic p53 mutations which have been shown to occur in approx. 50% of cancers [21–26].
ROS, tumour survival and metastasis
It has been suggested that when subjected to oxidative stress such as the effects of ROS, certain cancer cells exhibit decreased attachment to the basal lamina meaning that they are more likely to detach and possibly metastasize. ROS can regulate cellular adhesion by modulating integrin expression, they have also been shown to suppress anoikis [apoptosis which is induced by anchorage-dependent cells detaching from their surrounding ECM (extracellular matrix)]. The degradation of the ECM involves MMPs (matrix metalloproteinases), with ROS including hydrogen peroxide, nitric oxide and iNOS implicated in the increased expression of several MMPs and also inactivation of tissue inhibitors of metalloproteinases [27–30]. It is possible that this effect on MMP expression may be due to activation of Ras, or direct action by MAPK (mitogen-activated protein kinase) family members including ERK1/2 (extracellular-signal-regulated kinase 1/2), p38 or JNK (c-Jun N-terminal kinase). In vitro experiments have shown that induction of various MMPs occurs in response to expression of the Ras oncogene [31]. Ras can be activated by ROS via oxidative modification, which leads to the inhibition of GDP/GTP exchange [32]. Other redox-sensitive transcription factors such as NF-κB (nuclear factor κB) have also been implicated in MMP gene regulation [27].
Aside from elevated ROS, the reduction in physiological tissue oxygen tension (hypoxia), which occurs during tumour initiation, can also regulate cancer cell proliferation. Since angiogenesis within a tumour can be both erratic and also sub-optimal once established, tumours often become hypoxic. HIF-1, a heterodimeric transcription factor comprising HIF-1α and HIF-1β, is a mediator of oxygen homoeostasis which, under hypoxic conditions, binds to the promoter of hypoxia-regulated genes and activates a range of hypoxia-responsive molecules including iNOS and VEGF (vascular endothelial growth factor), a potent angiogenic factor that is important in tumour growth and metastasis [14,33,34]. As such it is considered that the presence of HIF-1α plays an important role, in particular in early tumorigenesis in endocrine cancers [35]. Hypoxia-induced NF-κB activation is dependent on the presence of HIF-1α, the oxygen-sensitive component of the HIF-1 molecule [36,37]. HIF-1α is also activated by pro-inflammatory cytokines, including TNF-α (tumour necrosis factor α) and IL (interleukin)-1β, in an NF-κB dependent manner [38,39]. COX-2 (cyclo-oxygenase-2) also mediates IL-1β-induced HIF-1α expression through production of PGE2 (prostaglandin E2) [38]. Cancer cells have adapted these pathways effectively, allowing tumours to survive and even grow under adverse hypoxic conditions. This adaptation of tumour cells to hypoxia contributes to the malignant phenotype and to aggressive tumour progression, with the presence of tumour hypoxia resulting in poorer prognosis at diagnosis [40,41].
Another inducible enzyme with carcinogenic properties that is active within inflamed and malignant tissues is COX-2. COX-2 is overexpressed in various cancers and, as COX-2 protein accumulates, it catalyses the formation of prostaglandins (most notably PGE2 within the tumour environment) and reactive by-products which in turn accelerate neoplastic progression [42]. This includes inhibition of apoptosis, modulation of cellular adhesion and motility, promotion of angiogenesis and metastasis, and immunosuppression [43–47]. Other by-products of the COX-2 pathway, such as malondialdehyde production, are known to form DNA adducts which result in mutations that also play a role in neoplastic initiation [47]. Upon binding to cell-surface receptors, PGE2 not only activates downstream G-coupled proteins but also indirectly activates other pathways which are becoming increasingly implicated in cancer progression, including the Wnt and PPAR (peroxisome-proliferator-activated receptor) signalling pathways [47–49]. In particular it has been demonstrated that PGE2 increases phosphorylation of glycogen synthase kinase-3β which prevents β-catenin degradation and results in increased β-catenin/T-cell-factor-mediated transcription which activates various Wnt target genes involved in early neoplasia including c-myc, c-jun, cyclin D1 and PPARδ [50].
There is strong epidemiological evidence implicating COX-2 in the pathogenesis of a number of epithelial malignancies. Inhibitors of the enzyme are associated with a reduction in risk of several cancers including gastric, cervical, lung, colon and prostate [51–53], with a reduction of up to 50% in the morbidity and mortality of colorectal cancer [2,44,54–56]. Among the most potent inducers of COX-2 are the key pro-inflammatory cytokines IL-1α, IL-1β and TNF-α, as well as LPS (lipopolysaccharide), growth factors and oncogenes [57]. It has been reported that human gastric tumours with p53 missense mutations exhibit higher levels of COX-2 expression compared with tumours without p53 mutations suggesting that p53 mutations may down-regulate COX-2 expression [58].
Until recently the role of COX in tumorigenesis has focused almost exclusively on the inducible form COX-2. However, there is now emerging evidence that COX-1, the constitutively expressed form of COX, is also important, with increased COX-1 expression shown in cancers of the female reproductive tract including ovarian and cervical cancers. Up-regulation of COX-1, but not COX-2, has been demonstrated in ovarian cancer, with COX-1-derived PGE2 promoting angiogenesis through production of VEGF [59,60].
INFECTION, INFLAMMATION AND CANCER: ROLE OF NF-κB
Chronic inflammation caused by persistent infection with a micro-organism is a major driving force in tumour development. Classic examples among others include H.-pylori-associated gastritis and gastric cancer, inflammatory bowel disease-associated colorectal cancer, Epstein–Barr virus and nasopharyngeal carcinoma (Table 1). Unless micro-organisms carry their own oncogenes, toxins or growth factors, they affect the host and trigger inflammation through activation of receptors that recognize PAMPs (pathogen-associated molecular patterns), which include LPS, peptidoglycan and also viruses and nucleic acids. The best described of these PRRs (pattern-recognition receptors) are TLRs (Toll-like receptors). TLRs play a key role in the inflammatory response against invading micro-organisms. TLRs are membrane-bound receptors that are expressed on a large number of cell types and recognize highly conserved components of bacteria, viruses and parasites (Table 2). TLRs also recognize various endogenous ligands, several of which are present within the inflammatory environment (Table 2). The engagement of PRRs activates numerous signal transduction pathways that target several transcription factors which regulate innate and adaptive immune responses [61,62]. These responses in turn activate other receptors that hone and amplify the inflammatory response, with the central role in this process being played by the NF- κB pathway (Figure 1). However, depending on the cell type in which it acts, NF-κB can either facilitate or inhibit cancer progression [63].
The NF-κB transcription factor family was discovered in 1986 by Baltimore and co-workers and has since been shown to be ubiquitously expressed in all human cell types [64,65]. NF-κB is a hetero- or homo-dimer consisting of five subunits of the Rel family of polypeptides comprising RelA (p65), C-Rel, RelB, p50/p105/NF-κB1 and p52/p100/NF-κB2; however, NF-κB mainly exists in the form of the heterodimer p65/p50. Prior to activation, most NF-κB molecules are retained in the cytoplasm, bound to one of the IκB (inhibitor of NF-κB) proteins. Upon stimulation, the IKK (IκB kinase) complex is activated which phosphorylates NF-κB-bound IκB and targets them for polyubiquitination and ultimately degradation. This allows NF-κB to enter the nucleus and bind to κB-regulatory elements and co-ordinate the transcriptional activation of many immune response genes [66–68]. This is known as the classical NF-κB signalling pathway and is triggered in response to pro-inflammatory cytokines and micro-organisms. Once activated, NF-κB regulates expression of over 200 genes, including genes encoding cell adhesion molecules and immune response genes including cytokines, and cell proliferation. NF-κB also regulates expression of NF-κB members and also the IκB proteins.
There are other pathways of NF-κB activation which are less well described. These 'alternative' pathways are not directly activated as part of an innate immune response, and are triggered by only a limited number of stimuli. These other pathways are involved in generation of secondary lymphoid organs as well as B-cell maturation and survival and are thought to be important in B-cell lymphoma and skin carcinogenesis [69–71].
Evidence supporting the role of NF-κB in the initiation and promotion of malignancy comes from the fact that constitutive expression of NF-κB has been identified in a number of malignancies including hepatocellular carcinoma and breast and colorectal cancer [72–85]. NF-κB activation in at least two cell types is crucial for cancer development and progression. First, cells that are recruited to the tumour environment and produce cytokines, growth factors and proteases which support cancer development and progression. Production of several pro-inflammatory cytokines, including TNF-α, IL-1 and IL-6, chemokines such as IL-8, growth factors including VEGF and GRO-α (growth-related oncogene α), MMPs, adhesion molecules and also anti-apoptotic proteins including c-FLIP [cellular FLICE (Fas-associated death domain-like IL-1β-converting enzyme) inhibitory protein], Bcl-2 and p53, by these recruited cells are known to be dependent on NF-κB activation via the classical pathway [57,86,87]. However, once activated, these cells can also promote ROS production which induces DNA damage in a second cell type, cells that are programmed to undergo malignant transformation [88]. NF-κB also activates COX-2 expression, which is responsible for the induction of HIF-1α, which ultimately controls VEGF gene expression [57,89,90]. The up-regulated expression of cytokines and growth factors promotes cancer cell proliferation both directly and indirectly by increasing NF-κB-mediated angiogenesis, tumour invasion and metastasis, with anti-apoptotic proteins protecting against apoptosis and immune attack [91]. NF-κB activation also leads to a suppression of autophagy which is an alternative cell death pathway that is called in to play when apoptosis is inactivated. The role of autophagy in cancer will be discussed below. Furthermore, NF-κB contributes to drug resistance through multi-drug resistance-1 expression in cancer cells which is the basis for resistance to anti-cancer chemotherapy [92].
Defects in apoptosis which promote tumour growth and treatment resistance are common during tumorigenesis and have been well defined over the years. However, the importance of other forms of cell death such as autophagy and necrosis has been less well-understood and has only recently been linked with the carcinogenic process. Various cancers including breast, ovarian and prostate cancers have all been shown to display allelic loss of an essential autophagy gene beclin 1, which suggests that autophagy may well play a role in tumour suppression [93–95]. Autophagy, or type II programmed cell death is a highly regulated catabolic process in which organelles and cytoplasm are engulfed and targeted to lysosomes for degradation [96,97]. This is in contrast with apoptosis, which is termed type I programmed cell death. Autophagy is an adaptive response to nutrient deprivation, allowing cells to persist for prolonged periods under suboptimal nutrient conditions including during carcinogenesis where tumour growth frequently outstrips nutrient and oxygen supply, with autophagy known to localize to hypoxic tumour regions [97,98]. However, there is also evidence that autophagy, when allowed to proceed to completion, is a means of achieving cell death [98,99]. Autophagy also plays a crucial role in removal of damaged or surplus organelles. This removal limits exposure of cellular DNA to free radical damage which ultimately decreases basal DNA mutation rates, inflammation and suppresses oncogenesis [100,101]. These two mechanisms of the role of autophagy in carcinogenic development would appear to be paradoxical. However, it is thought that during carcinogenesis, where normal apoptotic function is decreased, abrogation of autophagy creates reduced metabolic stress tolerance and cell viability which ultimately activates necrotic cell death and increases the inflammatory load of the tumour [96] (Figure 2). Moreover several oncoproteins including c-Myc, PI3K (phosphoinositide 3-kinase) and Ras are potent inhibitors of autophagy, whereas certain tumour suppressors including p53 actually activate autophagy [102–105]. Consistent with the observation that autophagy is reduced in tumour progression; it has been clearly demonstrated to be induced by several anti-cancer drugs and is therefore a target for cancer therapy. The growing evidence identifying the role of autophagy within carcinogenic progression cannot now be ignored; however, several important questions remain to be answered. These include defining what benefits a tumour derives from suppressing autophagy and also identifying the mechanisms by which cancer treatments induce autophagy.
It is known that cancer cells are capable of attracting different cell types into the tumour micro-environment through secretion of extracellular proteases, pro-angiogenic factors and cytokines. Cytokines are small molecules that can either inhibit or propagate inflammation and activate or deactivate cancer genes and their pathways. Several examples exist to show how important cytokines are in the inflammatory neoplastic environment, with various animal knockout models showing predisposition of knockout animals to cancer development and also a growing body of evidence showing that numerous cytokine polymorphisms are associated with increased risk of inflammatory diseases and cancer [106–110]. Production of cytokines is induced via the classical NF-κB pathway; with many cytokines directly affecting signalling pathways including induction of iNOS and also COX-2. Cytokines also induce pro-cancerous pathways and directly influence tumour-suppressor function and oncogene induction. Therefore cytokine signalling is thought to contribute to the tumour environment via two mechanisms: first, stimulation of cell growth and differentiation, and, secondly, inhibition of apoptosis of damaged cells [111]. Key pro-inflammatory cytokines include IL-1, -6, -12 and -18, TNF-α and macrophage MIF (migration inhibitory factor) [23]. Anti-inflammatory cytokines include IL-4 and -10, IFN (interferon)-α and -β. MIF and IL-6 are both known to ameliorate p53 function which favours cell survival. IL-6 also induces other anti-apoptotic genes including Bcl-2 and Bcl-XL, with the role of IL-6 becoming increasingly apparent within colon carcinoma progression [112–115]. Cytokines also affect cell death and cell cycle pathways, with IL-2 and TNF-α able to induce apoptosis in colon cancer cells [116]. IL-10 is secreted by tumour cells as well as macrophages, and among other effects, it inhibits cytotoxic T-cells and thus aids in suppressing the immune response against the tumour [5]. Quite often it is the profile of cytokines existing at an inflammatory site which is pivotal to defining outcome. For example, TNF-α, which is produced mainly by macrophages but also by tumour cells, is associated with tissue destruction and plays a role in destroying tumour blood supply. However, when chronically produced, it can act as a tumour promoter by contributing to tissue remodelling and stromal development [4,117].
Chemokines, which comprise the largest family of cytokines, are characterized by their ability to induce migration and activation of leucocytes to specific sites. This includes tumour stroma and the CC chemokine MCP (macrophage chemotactic protein)-1, which has been shown to be a major determinant of monocyte/macrophage infiltration in tumours. Tumour epithelial areas have also been found to express MCP-1, whereas additional chemokines such as MIP (macrophage inflammatory protein)-1β and RANTES (regulated upon activation, normal T-cell expressed and secreted) may be detected in the stroma and regulate the infiltrate of other inflammatory cells including T-cells. Furthermore, chemokines may stimulate cells to release proteolytic enzymes, aiding the digestion of the ECM and providing a path for further inflammatory cell migration, tumour growth and metastasis. However, it is important to appreciate that in many preneoplastic conditions an inflammatory cell infiltrate is already well-established and drives pro-tumour effects.
Genetic polymorphisms have emerged in recent years as important determinants of disease susceptibility and severity [118]. The completion of the human genome project has opened up the opportunity to dissect complex human diseases including cancers and to identify and understand the role of genetic polymorphisms. Although linkage analysis studies are suitable for pursuing rare high-risk alleles in conditions that have a hereditary basis, population-based association studies are much more useful for examining genes with a role in more common multifactorial diseases that have a strong environmental component [119]. These association studies often estimate the risk of developing a certain disease in carriers and non-carriers of a particular genetic polymorphism. The overwhelming majority of polymorphisms studied are SNPs (single nucleotide polymorphisms) that occur with a frequency of >1% in the normal population (in contrast with mutations that occur with a frequency of <1%). It is estimated that up to 10 million SNPs are probably present in the human genome although not all have thus far been identified. Naturally, most of these SNPs do not occur in coding sequences and even those that do are not associated with any alteration in the amino acid sequence and are therefore of no functional consequence. A more useful definition of the variability of these SNPs involves haplotype analysis. Haplotypes are a combination of alleles at different markers along the same chromosome that are inherited as a unit. The HapMap project was set up to address this (http://www.hapmap.org) and is a valuable tool that will facilitate the study of genetic polymorphisms relevant to human health and disease. Other types of genetic variation include deletion and insertion polymorphisms and microsatellite-repeat polymorphisms.
Genetic polymorphisms directly influence inter-individual variation in the magnitude of an inflammatory response, and this clearly contributes to the ultimate clinical outcome of an individual. An excellent example of this from our own work [120] is the role of genetic polymorphisms in the pathogenesis of H.-pylori-induced gastric cancer. H. pylori infection elicits a powerful humoral and cell-mediated immune response that causes inflammation in the gastric mucosa. The mediators of this inflammatory response belong to the two main arms of the immune system, namely adaptive and innate immunity. We speculated that the most relevant candidate genes would be ones whose products were involved in handling the H. pylori attack and ones that mediated the resulting inflammation. Because such a list of candidate genes would be prohibitively extensive, our initial search focused on genes that were most relevant to gastric physiology and, in particular, gastric acid secretion. H.-pylori-induced gastritis is associated with three main phenotypes that correlate closely with clinical outcome: duodenal ulcer phenotype, benign phenotype and gastric cancer phenotype [120]. Studies have shown that inhibition of gastric acid pharmacologically can lead to a shift from an antrum-predominant pattern (duodenal ulcer phenotype) to a corpus-predominant one with onset of gastric atrophy (gastric cancer phenotype) [121]. Thus it was clear that an endogenous agent that was up-regulated in the presence of H. pylori, has a profound pro-inflammatory effect and was also an acid inhibitor would be the most relevant host genetic factor to be studied. IL-1β fitted this profile perfectly, for not only is it one of the earliest and most important pro-inflammatory cytokines in the context of H. pylori infection, but also it is the most powerful acid inhibitor known [122]. We have shown that pro-inflammatory IL-1 gene cluster polymorphisms (IL-1B encoding IL-1β and IL-1RN encoding its naturally occurring receptor antagonist) increase the risk of gastric cancer and its precursors in the presence of H. pylori [108]. Individuals with the IL-1B−31*C (rs1143627) or −511*T (rs16944) and IL-1RN*2/*2 genotypes are at increased risk of developing hypochlorhydria and gastric atrophy in response to H. pylori infection. This risk also extends to gastric cancer itself with a 2–3-fold increased risk of malignancy compared with subjects who have the less pro-inflammatory genotypes [108,109].
Furthermore, the pro-inflammatory IL-1 genotypes increased the risk of both intestinal and diffuse types of gastric cancer but the risk was restricted to the non-cardia subsite. Indeed, the IL-1 markers had no effect on the risk of cardia gastric adenocarcinoma, oesophageal adenocarcinoma or oesophageal squamous cell carcinoma [109]. The latter findings are entirely in keeping with the proposed mechanism for the effect of these polymorphisms in gastric cancer, namely reduction of gastric acid secretion. Thus a high IL-1β genotype increases the risk of non-cardia gastric cancer, a disease characterized by hypochlorhydria, whereas it has no effect on cancers associated with high acid exposure such as oesophageal adenocarcinoma and some cardia cancers.
The association between IL-1 gene cluster polymorphisms and gastric cancer and its precursors has been confirmed independently by other groups covering Caucasian, Asian and Hispanic populations [123–129]. Machado et al. [125] were the first to confirm the association between IL-1 markers and gastric cancer in Caucasians and reported similar ORs (odds ratios) to those reported by our group [108]. Furthermore, the same group subsequently reported on the combined effects of pro-inflammatory IL-1 genotypes and H. pylori bacterial virulence factors (cagA positive, VacA s1 and VacA m1) [123]. They showed that for each combination of bacterial/host genotype, the odds of having gastric carcinoma were greatest in those with both bacterial and host high-risk genotypes. This highlights the important interaction between host and bacterium in the pathogenesis of gastric cancer. The role of IL-1 polymorphisms has also been investigated in other cancers, with associations shown with hepatitis-C-induced hepatocellular carcinoma, colorectal and also breast cancer [130–133].
Soon after the IL-1 gene cluster polymorphisms were identified as risk factors for gastric cancer, the pro-inflammatory genotypes of TNF-A and IL-10 were reported as independent additional risk factors for non-cardia gastric cancer [109]. TNF-α is another powerful pro-inflammatory cytokine that is produced in the gastric mucosa in response to H. pylori infection. Like IL-1β, it has an acid inhibitory effect, albeit much weaker [134]. The TNF-A−308 G>A (rs1800629) polymorphism is known to be involved in a number of inflammatory conditions. Carriage of the pro-inflammatory A allele increased the OR for non-cardia gastric cancer to 2.2 [95% CI (confidence intervals), 1.4–3.7]. The role of the TNF-A−308 G>A polymorphism in gastric cancer was independently confirmed by a study from Machado et al. [124], with its role in other cancers also now confirmed [135,136]. IL-10 is an anti-inflammatory cytokine that down-regulates IL-1β, TNF-α, IFN-γ and other pro-inflammatory cytokines. Relative deficiency of IL-10 may result in a Th-1 (T helper-1)-driven hyperinflammatory response to H. pylori with greater damage to the gastric mucosa. We have reported that homozygosity for the low-IL-10 ATA haplotype [based on three promoter polymorphisms at positions −592 (rs1800872), −819 (rs1800871) and −1082 (rs1800896)] increased the risk of non-cardia gastric cancer with an OR of 2.5 (95% CI, 1.1–5.7), with the importance of the IL-10 haplotype confirmed now in other cancers ([137] and extensively reviewed in [138]). We have studied the effect of having an increasing number of pro-inflammatory genotypes (IL-1B−511*T, IL-1RN*2*2, TNF-A−308*A and IL-10 ATA/ATA) on the risk of non-cardia gastric cancer [109]. The risk increased progressively so that by the time three or four of these polymorphisms were present, the OR for gastric cancer was increased to 27-fold [109]. The fact that H. pylori is a pre-requisite for the association of these polymorphisms with malignancy demonstrates that in this situation, inflammation is indeed driving carcinogenesis. Another important cytokine that is key in the pathogenesis of H.-pylori-induced diseases is IL-8. This chemokine belongs to the CXC family and is a potent chemoattractant for neutrophils and lymphocytes. It also has effects on cell proliferation, migration and tumour angiogenesis. The gene has a well-established promoter polymorphism at position −251 [IL-8−251 A>T (rs4073)]. The A allele is associated with increased production of IL-8 in H.-pylori-infected gastric mucosa [139]. It was also found to increase the risk of severe inflammation and precancerous gastric abnormalities in Caucasian and Asian populations [140]. However, the same polymorphism was found to increase risk of gastric cancer only in some Asian populations [141–143] with no apparent effect in Caucasians. It is probable that other pro-inflammatory cytokine gene polymorphisms will be relevant to cancer initiation and progression. This exciting field has expanded greatly over the last few years and the search is now on for the full complement of risk genotypes that dictate the likelihood of an individual developing cancer.
Genetic polymorphisms of cytokines of the adaptive immune response clearly play an important role in the risk of microbially induced carcinomas. However, micro-organisms are initially handled by the innate immune response and it is conceivable that functionally relevant polymorphisms in genes of this arm of the immune system could affect the magnitude and subsequent direction of the response of the host against the infection. In the case of H.-pylori-induced gastric carcinoma, the majority of H. pylori cells do not invade the gastric mucosa but the inflammatory response against it is triggered through attachment of H. pylori to the gastric epithelia, with TLR4 playing an important role in recognition [144]. Arbour et al. [145] described a functional polymorphism in the TLR4 gene (rs4986790). This A>G transition results in replacement of a conserved aspartic acid residue with a glycine residue at amino acid 299 (D299G) and alteration in the extracellular domain of the TLR4 receptor. This renders carriers hyporesponsive to LPS challenge by either disrupting transport of TLR4 to the cell membrane or by impairing ligand binding or protein interactions [145]. The mutation has been associated with a variety of inflammatory and infectious conditions including atherosclerosis, myocardial infarction, inflammatory bowel disease and septic shock [146–149]. Recent work demonstrates that defective signalling through the TLR4 receptor ultimately leads to an exaggerated inflammatory response with severe tissue destruction, even though the initial immune response may be blunted [150]. This is due to inadequate production of IL-10-secreting type 1 regulatory cells [150].
We hypothesized that the TLR4+896A>G polymorphism would be associated with an exaggerated and destructive chronic inflammatory phenotype in H. pylori-infected subjects. This phenotype would be characterized by gastric atrophy and hypochlorhydria, the hallmarks of a subsequent increased risk of gastric cancer. We further hypothesized that the same polymorphism might increase the risk of gastric cancer itself. We proceeded to test the effect of this polymorphism on the H.-pylori-induced gastric phenotype and the risk of developing pre-malignant and malignant outcomes. We assessed associations with pre-malignant gastric changes in relatives of gastric cancer patients, including those with hypochlorhydria and gastric atrophy. We also genotyped two independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer. TLR4+896G carriers had a 7.7-fold (95% CI, 1.6–37.6) increased OR for hypochlorhydria; the polymorphism was not associated with gastric acid output in the absence of H. pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation [151]. Also 16% of gastric cancer patients in the initial study and 15% of the non-cardia gastric cancer patients in the replication study had one or two TLR4 variant alleles compared with 8% of both control populations (combined OR, 2.4; 95% CI, 1.6–3.4) [151]. In contrast, the prevalence of TLR4+896G was not significantly increased in oesophageal squamous cell (2%; OR, 0.4) or adenocarcinoma (9%; OR, 0.8) or gastric cardia cancer (11%; OR, 1.2).
The association of the TLR4+896A>G polymorphism with both gastric cancer and its precursor lesions implies that it is relevant to the entire multistage process of gastric carcinogenesis, which starts with H. pylori colonization of the gastric mucosa. Subjects with this polymorphism have an increased risk of severe inflammation and, subsequently, development of hypochlorhydria and gastric atrophy, which are regarded as the most important precancerous abnormalities. This severe inflammation is initiated by H. pylori infection but it is entirely feasible that subsequent co-colonization of an achlorhydric stomach by a variety of other bacteria may sustain and enhance the microbial inflammatory stimulus and continue to drive the carcinogenic process. Evidence supporting this concept comes from the work of Sanduleanu et al. [152] who showed that pharmacological inhibition of acid secretion was associated with a higher prevalence of non-H. pylori bacteria. Furthermore, the simultaneous presence of H. pylori and non-H. pylori bacteria was associated with a markedly increased risk of atrophic gastritis, and with higher circulating levels of IL-1β and IL-8. Supporting evidence also comes from animal studies where hypochlorhydria was induced in mice either genetically (G−/G− gastrin-deficient mice) or pharmacologically (administration of omeprazole). Zavros et al. [153] found that genetic or chemical hypochlorhydria predisposes the stomach to bacterial overgrowth resulting in inflammation, which was not present in the wild-type mice or those not treated with an acid inhibitor.
The potential mechanism by which the TLR4 polymorphism increases the risk of gastric cancer and its precursors is intriguing and may lie in the nature of the overall response of the host to the H. pylori LPS attack. Failure to handle the invasion by appropriately recognizing and activating the necessary pathways may lead to an imbalance of pro- and anti-inflammatory mediators. The findings emphasize, for the first time, the importance of innate immune response gene polymorphisms in outcome to neoplastic progression.
This field of host genetic polymorphisms has expanded greatly over the last few years, and the search is now on for the full complement of risk genotypes that dictate the likelihood of an individual of developing cancer. This approach has now been adopted for many other cancers as described below. In Japanese patients with chronic HCV (hepatitis C virus) infection, the IL-1B−511 T/T genotype has been associated with an increased risk of progression to hepatocellular carcinoma [131]. Because the T/T pro-inflammatory genotype is related to greater IL-1 production, it is feasible that the risk of malignant transformation is higher. IL-1 leads to the production of PGE2 and hepatocyte growth factor and has angiogenic influence via iNOS and COX-2 expression. Furthermore, the degree of HCV-induced liver inflammation and fibrosis has been correlated with hepatic expression of Th-1 cytokines. At present, there is relatively little information on the relationship between other gastrointestinal malignancies and innate immune and cytokine polymorphisms. Some studies have addressed the influence of polymorphisms on cancer outcome. Barber et al. [154] found that possession of a genotype resulting in increased IL-1 production was associated with shortened survival in pancreatic cancer. Park et al. [155] investigated TNF-A and -B polymorphisms in 136 colorectal cancer patients and 325 healthy controls in an Asian population. Their results indicated that TNF-B*1/TNF-B*1 genotypes showed an increased risk for colorectal cancer. De Jong et al. [156] performed pooled analyses on 30 polymorphisms in 20 low-penetrance genes and identified an additional three studies investigating TNF-A polymorphisms and colorectal cancer. Associations were detected for the a2, a5 and a13 TNF alleles and colorectal cancer.
There is now substantial evidence that chronic inflammation and malignant development are causally linked. However, further studies are required to fully understand the complex relationship. The situation is further complicated by the recent acceptance of the role of chronic infection and also the contribution of host genetic polymorphisms to the risk of an individual of developing malignancy. Chronic inflammation, whether caused by microbes, chemical or physical trauma, within a pre-malignant environment favours neoplastic progression. However, once present, cancer cells can 'educate' the immune infiltrate to produce the necessary cytokine composition to facilitate tumour growth and metastasis as well as acquiring immune tolerance. Understanding this feedback loop is fundamental to resolving the complex interplay between the causes of chronic inflammation and the genetic disposition of the host to neoplastic progression, which will aid the development of new and more effective anti-inflammatory cancer prevention strategies in the future.
Abbreviations: CI, confidence interval; COX, cyclo-oxygenase; ECM, extracellular matrix; HCV, hepatitis C virus; HIF-1, hypoxia-inducible factor-1; IFN, interferon; IκB, inhibitor of nuclear factor κB; IL, interleukin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MCP, macrophage chemotactic protein; MIF, migration inhibitory factor; MMP, matrix metalloproteinase; NF-κB, nuclear factor κB; OR, odds ratio; PGE2, prostaglandin E2; PPAR, peroxisome-proliferator-activated receptor; PRR, pattern-recognition receptor; ROS, reactive oxygen species; SNP, single nucleotide polymorphism; Th-1, T helper-1; TLR, Toll-like receptor; TNF-α, tumour necrosis factor α; VEGF, vascular endothelial growth factor
- © The Authors Journal compilation © 2008 Biochemical Society
- 1.↵
- 2.↵
- 3.↵
- 4.↵
- 5.↵
- 6.↵
- 7.↵
- 8.
- 9.↵
- 10.
- 11.↵
- 12.↵
- 13.
- 14.↵
- 15.↵
- 16.↵
- 17.↵
- 17a.↵
- 18.↵
- 19.↵
- 20.↵
- 21.↵
- 22.
- 23.↵
- 24.
- 25.
- 26.↵
- 27.↵
- 28.
- 29.
- 30.↵
- 31.↵
- 32.↵
- 33.↵
- 34.↵
- 35.↵
- 36.↵
- 37.↵
- 38.↵
- 39.↵
- 40.↵
- 41.↵
- 42.↵
- 43.↵
- 44.↵
- 45.
- 46.
- 47.↵
- 48.
- 49.↵
- 50.↵
- 51.↵
- 52.
- 53.↵
- 54.↵
- 55.
- 56.↵
- 57.↵
- 58.↵
- 59.↵
- 60.↵
- 61.↵
- 62.↵
- 63.↵
- 64.↵
- 65.↵
- 66.↵
- 67.
- 68.↵
- 69.↵
- 70.
- 71.↵
- 72.↵
- 73.
- 74.
- 75.
- 76.
- 77.
- 78.
- 79.
- 80.
- 81.
- 82.
- 83.
- 84.
- 85.↵
- 86.↵
- 87.↵
- 88.↵
- 89.↵
- 90.↵
- 91.↵
- 92.↵
- 93.↵
- 94.
- 95.↵
- 96.↵
- 97.↵
- 98.↵
- 99.↵
- 100.↵
- 101.↵
- 102.↵
- 103.
- 104.
- 105.↵
- 106.↵
- 107.
- 108.↵
- 109.↵
- 110.↵
- 111.↵
- 112.↵
- 113.
- 114.
- 115.↵
- 116.↵
- 117.↵
- 118.↵
- 119.↵
- 120.↵
- 121.↵
- 122.↵
- 123.↵
- 124.↵
- 125.↵
- 126.
- 127.
- 128.
- 129.↵
- 130.↵
- 131.↵
- 132.
- 133.↵
- 134.↵
- 135.↵
- 136.↵
- 137.↵
- 138.↵
- 139.↵
- 140.↵
- 141.↵
- 142.
- 143.↵
- 144.↵
- 145.↵
- 146.↵
- 147.
- 148.
- 149.↵
- 150.↵
- 151.↵
- 152.↵
- 153.↵
- 154.↵
- 155.↵
- 156.↵


text:
2011 NISSAN Xterra S Sport Utility 4D
Use the SHIFT key to zoom in.
Use the CTRL key to zoom out.
Similar Vehicles
2016 DODGE Journey SXT Sport Utility 4D46K $16,499 View Details
2015 HONDA Pilot LX Sport Utility 4D46K $22,943 View Details
2017 HYUNDAI Santa Fe SE Sport Utility 4D36K $23,499 View Details
2011 NISSAN Xterra S Sport Utility 4D
No-Haggle Price
Estimated payment:2 Adjust Pmt. Terms
Call Us
Visit Us
Woodbridge, VA 22191-3414
- Running Boards
- Power Door Locks
- Cruise Control
- Head Curtain Air Bags
- Side Air Bags
- CD (Single Disc)
- Power Windows
- Custom Bumper
- Roof Rack
- AM/FM Stereo
- Power Steering
- Privacy Glass
- Traction Control
- Keyless Entry
- Air Conditioning
- Dual Air Bags
- Vchl Dynamic Control
- ABS (4-Wheel)
- Tilt Wheel
- Manual tilt steering column
- Pwr door locks w/selective unlock feature
- Glove box w/lower lock light & damper
- Rear HVAC vents under front seats
- In-cabin microfilter
- Manual day/night rearview mirror
- Remote keyless entry system
- Dual front door pockets & bottle holders
- (3) 12-volt pwr outlets
- Steering wheel cruise controls
- Front air conditioning
- Storage compartment under cargo area
- Dual front/rear cup holders
- Rear window defroster
- Dual sunvisors
- Accessory pwr delay
- Engine immobilizer system
- Cloth seating surfaces
- Easy clean cargo area w/C-channel system
- Pwr windows w/driver auto-down
- Security alarm system
- Cargo area hooks on ceiling
- Black door handles
- Full size spare tire w/steel wheel
- Body side molding
- Rear intermittent wiper w/washer
- Variable intermittent windshield wipers w/washer
- Rear bumper w/steps
- Splash guards
- Angled strut style front grille
- Black folding pwr outside mirrors
- P265/70R16 all-season Long Trail OWL tires
- Roof rack rails w/cross bars gear basket & air dam
- Dark tinted rear privacy glass
- Electronic brake force distribution (EBD)
- Rear outboard 3-point seat belts
- Driver & front passenger advanced dual stage airbags w/occupant sensor
- Front/rear crumple zones
- Child safety rear door locks
- Front active head restraints
- 4-wheel anti-lock braking system (ABS)
- Front seat-mounted side-impact airbags
- Lower Anchors & Tethers for Children (LATCH)
- Front 3-point seat belts w/height adjusters pretensioners & load limiters
- Dual note horn
- Side door guard beams
- Energy absorbing steering column
- Vehicle dynamic control system (VDC) -inc: 4-wheel brake limited slip (ABLS)
- 4-wheel drive
- Continuous valve timing control system
- 4-wheel vented disc brakes
- Double wishbone independent front suspension
- Stainless steel exhaust system
- Engine speed-sensitive pwr rack & pinion steering
- 4.0L DOHC 24-valve V6 engine w/continuous variable valve timing
- Lower radiator skid plate
- Front tow hook
- Rigid leaf rear suspension w/solid axle
Similar Vehicles
2016 DODGE Journey SXT Sport Utility 4D45,619 $16,499 View Details
2015 HONDA Pilot LX Sport Utility 4D45,329 $22,943 View Details
2017 HYUNDAI Santa Fe SE Sport Utility 4D35,474 $23,499 View Details