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Punta Gorda Condo Rental Photos and Description
2 Bedrooms 2 Baths Sleeps 2-4 Burnt Store Marina #497397
Wifi. Newly renovated and furnished.
Relax in the screened-in lanai and watch the manatees play and the sunset over the harbor.
Fully equipped kitchen, high definition TV, beach towels and chairs.
At Burnt Store Marina, enjoy golfing, biking, walking and boating. If you bring your boat you will see it right in front of you. (Boat dockage fee additional). Take a swim in the Harbor Towers pool or a dip in the jacuzzi.
Come on down to beautiful SW Florida where the living is fine.
- Suitability:
- Long-term Renters Welcome
- children welcome
- non smoking only
- pets not allowed


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Thursday, 21 August 2014 10:07
So much has already been said about Robin Williams' death by suicide that there really isn't much left to say. While shining a light on the serious issues of substance abuse, mental illness and suicide helps to remove the stigma attached, journalists and radio and TV personalities have an obligation to their readers, viewers, etc. to report the news in a responsible way. Unfortunately, this does not always happen.
I heard a DJ on the radio say that he heard that the people who were close to Robin Williams are now saying that warning signs of suicide were there. The DJ then went on to ask the question, "why didn't those people get him some help?" It is public knowledge that Robin Williams was seeking help for both his addiction and his severe depression. However, "help" doesn't fix the problem overnight or miraculously make a person feel instantaneously good again. "Help" requires hard work over a period of time. Sometimes when a person is in such a depressed state, they start to feel hopeless, which means that they don't believe there is any hope that things will ever get better. At that point, they may decide that asking for or accepting further "help" will not do any good. They just want to do something that will end the pain.
Another problem with that question is that it implies that those closest to Robin Williams are somehow to blame for what happened. People who are bereaved by suicide feel a variety of emotions, guilt being one of the strongest ones. The truth is that none of us, no matter how much we think we matter or how influential we think we are, have enough power to cause another person to take his or her life. However, not being able to comprehend exactly what the person who died by suicide was feeling, leaves those closest to them wondering what they could have done differently to prevent the death by suicide. Questions like this only add to the guilt those bereaved by suicide already feel.
I realize that what this DJ said was in no way meant to be accusatory or hurtful to those closest to Robin Williams. I bring it up simply to point out that the issue of suicide is not a simple one and our choice of words when someone dies by suicide is very important.
The most important message from this tragedy is that "help" is available. The first step is knowing when and where to find the help. A good way to begin the helping process is to reach out to Long Island Crisis Center's 24/7 hotline at 516-679-1111. It is free, anonymous and confidential. Or call the National Suicide Prevention Lifeline at 1-800-273-8255 if you're outside the Long Island area.
There is no need to wait until you get to the point where you feel hopeless. There is no need for family or friends to feel hopeless about getting help for someone they care about.
Theresa Buhse
Associate Executive Director, Long Island Crisis Center
Friday, 21 November 2014 00:00
At the eleventh hour on the eleventh day of the eleventh month, residents and community members joined with the Floral Park American Legion to honor veterans at the annual Veteran's Day ceremonies at Memorial Park, following a march down Tulip Avenue to the park with the members of the veterans of the Legion post, American Legion Auxiliary members, Sons of the American Legion, Boy and Cub Scouts from Troops 482 and 678 and local officials.
During the ceremony, a plaque was dedicated in memory of General Kazimierz Pulaski and others of Polish heritage who have served in the U.S. military. The plaque dedication was led by members of the Polish American Congress, Long Island Division, President Grzegorz Worma and Honorary President Richard Brzozowski. An invocation was delivered by Father Peter Rozek of St. Hedwig Church, followed by a POW-MIA ceremony by Post 334 Vice Commander Matthew Cacciatore.
Thursday, 20 November 2014 00:00
While parking around Long Island Rail Road train stations is typically a challenge, even on a regular work day, the holidays create more of a struggle for commuters in search of parking spots. LIRR spokesman Salvatore Arena said that ridership between Thanksgiving and New Year's Day increases by at least 10 percent; last year it was by 12 percent. Though the MTA is adding more trains to the schedule, that doesn't ease the parking situation, which is operated not by the LIRR, but by individual municipalities in each town.
"Every station is different," Arena said. "A good part of our parking is in the hands of the locality. They set the rules essentially."
Floral Park Memorial PTSA Fall Fest Fundraiser
Friday, November 21
Buy A Meal, Wag A Tail
Saturday, November 22Hanging of the Greens and Potluck Luncheon
Sunday, November 23
1959: The Year The Music Stopped Playing
Written by Michael A. Miller, firstname.lastname@example.com
The Eccentric Heiress Of 'Empty Mansions'
Written by Mike Barry, email@example.com
Yellow Margarine And A Pitch For The Ages
Written by Michael A. Miller, firstname.lastname@example.com


text:
Single door with one hanging rod and shelf Color: Gray or beige
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- China Yuki
- Set of 90 pictures
- Download full set in zip
- Add to favorites
China Yuki is a hot Asian model. She looks like a kid and really capitalizes on it too. She comes in the club in her fuck me outfits and the guys are all over her! She makes a good living at it especially with the older guys. They really pour on the bucks when she puts on the innocent act for them. If she is lucky she will look young for a long time. I should get her in as a waitress just for the novelty.
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@ Idols69.com - High definition AV Idol website...


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March is Cabaret Month Gala
Hell's Kitchen
Wed Mar 6 2013
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Can't find your city? Try Time Out World for great nights out and all that's going on near you – wherever you are in the world.
Magazines and Visitor Guides are also available in Malta, Porto and Muscat.
Hell's Kitchen
Wed Mar 6 2013
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Kate's Reviews > Kamisama Kiss, Vol. 10
Kamisama Kiss, Vol. 10
by Julietta Suzuki
by Julietta Suzuki
Kate's review
Aug 25, 12
Read in August, 2012
** spoiler alert ** The conclusion of the Kurama tengu mountain event ends with new knowledge of Nanami's power and versatility in her tochigami abilities. It is also a great volume to see Tomoe's thoughts on Nanami and the new romantic foil possibility in this volume.
Sign into Goodreads to see if any of your friends have read Kamisama Kiss, Vol. 10.sign in »
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Cryptic Staff Favortism of the Community Podcasts
View Single Post
Archived Post
Lt. Commander
Join Date: Dec 2007
Posts: 120
# 43
Originally Posted by
Mav, I'm sorry to say your Original post has pretty much eliminated any chance of me listening to the RSA podcast again. I'm sorry, but this sort of reaction is incredibly unprofessional.
If you want to feel slighted by Cryptic, you have every right... but as someone that works in media, I can tell you sincerely that airing out this sort of stuff in a public forum reflects poorly on your podcast as a whole.
I have to agree with this. I haven't worked in media since grad school, but what lilravegirl is saying was true back in the 80s and 90s -- and I presume is just as true today.
Respectfully, Mav, I know where you're coming from, but airing your grievances like this is unprofessional and -- IMO -- is unlikely to result in a resolution of the sort you're probably seeking.


text:
Most of the photos on this site were extracted from reference images (high-resolution tiffs, 20 to 200 megabytes in size) from the Library of Congress research archive. (To query the database click here.) Many were digitized by LOC contractors using a Sinar studio back. They are adjusted by your webmaster for contrast and color in Photoshop before being downsized and turned into the jpegs you see here.
Vintage photos of:
The Young Men's Shop in Washington, D.C., 1921. "We give you FREE a two-dollar bill with every pair of shoes." View full size. National Photo Co.
Dead Letter Office, probably in Washington. D.C. September 22, 1922. Somebody claim those tires! View full size. National Photo Company Collection.
Miss Laura Bryn, daughter of the Norway's ambassador to Washington, gets into her car on November 2, 1922. View full size. National Photo Co. Collection.
Miss Louise Johnson, from 1920. Her somewhat damaged appearance is maybe appropriate since the Shorpy Mid-Atlantic office is just coming back online after an agonizingly long Internet outage. View full size. National Photo Company.
Miss Hazel Jones and Miss Marion Cameron in 1922. View full size | Zoom in on their driving ensemble. National Photo Company Collection.
"The license plate is almost as large as her automobile, but Miss Mary Bay likes her car because it is easy to park. Miss Bay is shown braving the traffic of Washington." January 29, 1924. View full size. National Photo Co. Collection.
"Fire Wreck." January 5, 1921, in Washington, D.C. Back in April we posted this view of the same crash, at Columbia Road and Sherman Avenue, of the fire chief's Chevrolet. View full size. National Photo Company Collection.


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These Animals Should Not Be Best Friends – Our Hearts Just Exploded
What are all of these animals doing living together? It seems like it might be a scene from a Saturday morning cartoon, but it's really just the amazing Rocky Ridge Refuge.
What are all of these animals doing living together? It seems like it might be a scene from a Saturday morning cartoon, but it's really just the amazing Rocky Ridge Refuge.
Looks like an everyday, ordinary house in the UK, right? At first glance, you'd be right. But it holds a unique secret that's only revealed when you go into the backyard.
Ever wondered how Buffy, Willow, Xander and the rest of the Scooby Gang wound up after their adventures in Sunnydale?
Ah, high school. We're so, so, sooooooo glad we're not in high school anymore.
Kevin Arnold. Winnie Cooper. Paul Pfeiffer. You remember what they looked like as kids, right? What about now, 20 years later?
Well, they look pretty darn good, if you ask us. And not just the kids
There are plenty of cute, cuddly creatures in nature that look like they'd be great sources of the warm and fuzzies. Unfortunately, a lot of those adorable animals can also kill you in the most hardcore of ways. Here are 10 Ridiculously Cute Animals That Could Kill You.
Perhaps those Disney filmmakers are a bit more subversive than we thought.
Hey, if you don't want your mug shot taken, don't get arrested!
I didn't think I would get it, but I wound up with a piece of history in my home.
'The Goonies' was an ensemble movie all the way, and the seven actors who played the ragtag gang of young treasure hunters all delivered memorable performances. In fact, most of them used 'The Goonies' as a springboard into long careers in TV and film, and even the ones who didn't have found success in other venues.
"Cats always land on their feet," as the saying goes. Well, not all cats.
The bikini bridge happens when a woman lies on her back and her pelvis protrudes in a way that the waistband of her bikini bottoms lift up from her lower abdomen.


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United States
The impoverishment of industrial workers in America
By Jerry White, 25 November 2014
Recent reports highlight the historic reversal in the living standards of American workers that underlies Obama's supposed economic recovery.
Brooklyn residents outraged at police killing of Akai Gurley
By Sandy English, 25 November 2014
The killing of unarmed Akai Gurley by a police officer in Brooklyn has sparked widespread revulsion in the housing project where he died.
Obama fires Defense Secretary Hagel
By Patrick Martin, 25 November 2014
The ouster of Secretary of Defense Chuck Hagel is an expression of the growth of tensions within the administration amidst a series of foreign policy crises.
Iran nuclear talks extended
By Keith Jones, 25 November 2014
Washington has extorted significant concessions from Tehran and calculates that more can be won by continuing to cripple Iran's economy, while holding in reserve the threat of military action.
Who is responsible for violence in Ferguson?
By Andre Damon, 24 November 2014
The protracted wait for a grand jury proceeding has been accompanied by intimidation and threats on the part of local, state and federal officials.
Iranian nuclear talks at impasse as deadline approaches
By Peter Symonds, 24 November 2014
The US has been demanding heavy restrictions on Iran's nuclear programs in return for any lifting of sanctions that have crippled the country's economy.
Twelve-year-old boy killed by police in Cleveland, Ohio
By Samuel Davidson, 24 November 2014
The child was playing with a toy pistol in a playground when he was fatally shot by police officers.
Senate hearings on Wall Street crimes: The bankers rule
By Barry Grey, 24 November 2014
The two hearings were exercises in political theater, with politicians posturing as critics of Wall Street and bank executives and Fed officials making little effort to conceal their contempt.
Teamsters sell out strike by port truck drivers in southern California
By Marc Wells, 24 November 2014
Truck drivers at the ports of Los Angeles and Long Beach ended an eight-day strike against unfair practices and wage theft.
Chicago commuter rail agency approves a decade of fare hikes
By Jeff Lusanne, 24 November 2014
Metra's board of directors has approved a plan to raise fares 68 percent over the next 10 years.
After historic blizzard, death toll rises and floods threaten Buffalo, New York
By Michelle Ryan, 24 November 2014
As residents continue to dig out, warming temperatures accompanied by heavy rains could lead to widespread flooding.
Obama's "reform" and the criminalization of immigrants
By Patrick Martin, 22 November 2014
The executive action issued by the White House treats undocumented immigrants as criminals and maintains their status as super-exploited workers without elementary democratic rights.
Ahead of grand jury decision in Ferguson
Obama administration dispatches 100 FBI agents to St. Louis
By Andre Damon, 22 November 2014
FBI agents arrested two men in the Ferguson, Missouri area Friday evening, allegedly for seeking to buy explosives.
US manufacturing wages plummet
By Gabriel Black, 22 November 2014
Six years after Obama's ascendancy, a report by the National Employment Law Project summarizes the sharp decline in manufacturing wages amidst the supposed "economic recovery."
North Korea releases two jailed Americans
By Ben McGrath, 22 November 2014
The dispatch of US intelligence chief James Clapper to Pyongyang indicates that more was discussed than the release of the Americans prisoners.
Obama announces right-wing immigration "reform" in national address
By Patrick Martin, 21 November 2014
In a contemptible speech, the chief representative of the corporate and financial aristocracy carried forth on the need for immigrants to "play by the rules" and be held "accountable."
Wall Street banks and commodities fraud
By Joseph Kishore, 21 November 2014
A new US Senate report documents yet another aspect of the criminality that pervades the American and global financial system.
Police arrest Ferguson protesters ahead of ruling in Michael Brown case
By Andre Damon, 21 November 2014
The arrests came as an official for the St. Louis Police Officer's Association said that Darren Wilson and his lawyers do not expect an indictment for the killing of the unarmed teenager.
Massive snowstorm cripples Buffalo, kills ten
By Michelle Ryan, 21 November 2014
A massive lake-effect snowstorm has left ten people dead, thousands without power, and many stranded in the Buffalo, New York region.
Missouri carries out ninth execution of the year
By Kate Randall, 21 November 2014
Missouri Governor Jay Nixon refused to grant the condemned inmate clemency, and the US Supreme Court turned down his appeal for a stay.
Los Angeles schools superintendent backs "parent trigger" privatization scheme
By Adam Mclean and Marc Wells, 21 November 2014
Under the guise of empowering parents, the "parent trigger" law is part of a drive, funded by multibillionaires and backed by the unions, to privatize public education.
Obama's speech in Australia: A threat of war against China
By James Cogan, 17 November 2014
Every word Obama spoke about the economic and political agenda of American imperialism was a lie.
Cost of Obamacare coverage to rise in 2015
By Kate Randall, 17 November 2014
People who bought Affordable Care Act plans last year could face premium increases of as much as 20 percent unless they switch plans.
Toxic gas leak at Texas Dupont plant kills four
By James Brewer, 17 November 2014
The deadly chemical methyl mercaptan is regulated by a host of federal and state agencies.
100,000 fewer US families receive housing aid due to budget cuts
By Tom Hall, 17 November 2014
The reduction in aid has taken place even as the need for assistance has increased.
Decision imminent on whether to indict Ferguson cop in killing of Michael Brown
By Andre Damon, 15 November 2014
A coordinated campaign by the media and state and local officials to justify the killing of Michael Brown has been combined with threats to call in the National Guard.
Volkswagen opens backdoor entry for UAW at Tennessee plant
By Tom Eley, 15 November 2014
Assured that the organization will do its bidding, VW is preparing to defy a vote by workers and install the UAW at its Chattanooga plant.
Port truck drivers strike in southern California
By Marc Wells, 15 November 2014
Truck drivers went on strike last Thursday at the ports of Los Angeles and Long Beach over poverty pay and wage theft.
City workers denounce Detroit bankruptcy ruling
By Shannon Jones, 15 November 2014
In contrast to the official celebration by the political and corporate establishment, workers are reacting to the ruling with bitterness and anger
Florida governor presides over 20th execution in first term
By Kate Randall, 14 November 2014
Chadwick Banks was the eighth prisoner in Florida, and the thirty-second in the United States, to be put to death this year.
Notes on police violence in America
Fatal police shooting in Ann Arbor, Michigan
By E.P. Bannon, 14 November 2014
A 54-year-old Ann Arbor man asked police to escort his girlfriend out of his home. Instead, they shot her multiple times.
The Detroit bankruptcy ruling: Suspending democracy to impose the dictates of Wall Street
By Tom Carter, 14 November 2014
The decision by federal bankruptcy judge Steven Rhodes is a landmark ruling, establishing a pseudo-legal framework for suspending democracy and the rule of law.
The Death of Klinghoffer dramatizes 1985 hijacking of Achille Lauro
By Fred Mazelis, 14 November 2014
John Adams's opera is a worthy addition to the contemporary operatic repertory.
After flight attendants reject contract, American Airlines makes offer to pilots
By Shannon Jones, 14 November 2014
Initial reports indicate pilots are overwhelmingly opposed to the proposal, which removes profit-sharing.
Obama-Xi talks underscore US war threat in Asia
By Patrick Kelly, 13 November 2014
New military "confidence-building mechanisms" resolve none of the issues underlying Washington's confrontation of China.
The illegitimate US election
By Joseph Kishore, 13 November 2014
The low voter turnout in last week's US election reflects popular hostility toward the Obama administration, the political establishment and both big-business parties.
Two years after the Libor scandal
Banks get token fines for rigging global foreign exchange rates
By Andre Damon and Barry Grey, 13 November 2014
Major international financial institutions, with the knowledge of at least one central bank, conspired to rig the multitrillion-dollar foreign exchange market.
Mumia Abu-Jamal, rights groups sue over Pennsylvania's "Mumia Law"
By Ed Hightower, 13 November 2014
A lawsuit was filed Monday challenging Pennsylvania's recently enacted Revictimization Relief Act.
Atlanta Symphony musicians agree to concessions after nine-week lockout
By Fred Mazelis, 13 November 2014
The latest contract follows a pattern across the US, but there is also growing anger at the corporate stranglehold on culture.
The Detroit bankruptcy ruling: A new chapter in the class war against workers
By Jerry White, 12 November 2014
The federal bankruptcy judge's ruling sets a precedent to use the pretext of a "financial emergency" to suspend democratic rights and impose unpopular measures on the working class.
US Medicare "open enrollment" period highlights attacks on health care
By Fred Mazelis, 12 November 2014
Profit interests continue to undermine one of the last remaining Great Society reforms of the 1960s.
Obama calls for more Australian, allied troops for Middle East war
By James Cogan, 11 November 2014
Planning is undoubtedly underway for bloody attacks to retake major Iraqi cities currently controlled by ISIS.
After the US elections: An intensification of war and social counterrevolution
By Joseph Kishore, 10 November 2014
The Republican victory last Tuesday was not the result of a surge in popular support for the Republican Party or its right-wing policies. It was the result of the collapse of the Democrats.
US Supreme Court to hear challenge to Obamacare subsidies
By Kate Randall, 10 November 2014
The Supreme Court's decision to hear King v. Burwell comes just days before the beginning of open enrollment for the second year of the Affordable Care Act.
AIG lawsuit reveals global economy on the brink
By Gabriel Black, 10 November 2014
The US government's bailout of insurance giant AIG in September 2008 channeled tens of billions of dollars to the largest Wall Street banks.
Judge approves Detroit bankruptcy plan
By Jerry White, 8 November 2014
In a thoroughly undemocratic ruling, Judge Steven Rhodes sanctioned the city's restructuring plan, setting a precedent for attacking the rights of public sector workers throughout the country.
After elections, Washington plans escalation of Middle East war
By Bill Van Auken, 7 November 2014
The push for a new Authorization of the Use of Military Force is aimed at preparing a war that will be far wider and even more protracted than those launched over a decade ago.
New York Governor Cuomo wins reelection in record low turnout
By Fred Mazelis, 7 November 2014
The election reflected workers' growing disgust with the Democrats, as well as the increasingly depraved character of big business politics.
Justice Department imposes wrist-slap "reforms" on Albuquerque police after series of shootings
By Stuart Winter and D. Lencho, 7 November 2014
The settlement does not hold any of the officers who participated in the string of police murders criminally accountable.
Bloomberg report names Atlanta and New Orleans as the most unequal cities in the US
By E.P. Bannon, 6 November 2014
A recent report released by Bloomberg listed the 50 most unequal cities in the United States.
Republicans win control of Senate in US congressional elections
By Patrick Martin, 5 November 2014
The result is a debacle for the Democratic Party and the Obama administration and presages a further shift to the right in official Washington.
Another shakeup hits US nuclear missile command
By Bill Van Auken, 5 November 2014
The firing of two commanders and the administrative punishment of a third follow a long string of crises and scandals in a command whose job is nuclear annihilation.
New warnings of war in Asia
By Peter Symonds, 5 November 2014
A report released this week draws details scenarios that could trigger a conflict in the East China Sea.
Portland, Maine: Five young workers die in apartment fire
By John Marion, 5 November 2014
Maine's deadliest fire in 30 years could have been avoided.
The political issues posed by the US midterm elections
By Patrick Martin, 4 November 2014
By agreement between the Democrats and Republicans, there has been no discussion in the election campaign of the stepped-up program of war, austerity and attacks on democratic rights that will unfold after November 4.
US state prison population soars as education spending plummets
By Kate Randall, 4 November 2014
If state corrections spending had been held at mid-1980s levels, US states would have $28 billion more each year to allocate to education and other social spending.
Warner Brothers to slash over 10 percent of its workforce
By Kevin Martinez, 4 November 2014
The studio is expected to lay off over 1,000 workers as part of a $200 million cost-cutting plan.
US blocks Australian participation in China-backed bank
By Nick Beams, 4 November 2014
Washington's intervention, objecting to the bank on strategic grounds, points to the escalating military drive against China.
Mass water shutoffs continue in Detroit
By Shannon Jones, 4 November 2014
Nearly 30,000 households in the city have had their water service disconnected so far this year.
Justice Department seeks massive expansion of FBI hacking powers
By Thomas Gaist, 3 November 2014
Proposed changes to legal restrictions on government surveillance would authorize the FBI to infect computers worldwide with ultrasophisticated surveillance malware.
Report to UN condemns US government's "international criminal program of torture"
By Thomas Gaist, 1 November 2014
The report to the UN Committee Against Torture calls for criminal prosecutions of all top US military and civilian officials implicated in the post-9/11 torture regime.
US election campaign staggers to the finish line
By Patrick Martin, 1 November 2014
Only one thing about the election is certain: whatever the division of power in the US Senate, House of Representatives, state governorships and state legislatures, the official two-party system will continue its inexorable shift to the right.
Republican-led purge of voter rolls targets seven million people
By our reporter, 1 November 2014
An investigative report by Al Jazeera America reveals that 27 state governments, most of them Republican-led, have joined in an effort to disqualify seven million registered voters.
Deadly SpaceShipTwo crash follows explosion of unmanned Antares rocket
By Bryan Dyne, 1 November 2014
The two space disasters in the span of one week highlight the growing prominence of private companies in space missions.
Detroit Medical Center to outsource housekeeping in cost-cutting drive
By Shannon Jones, 1 November 2014
The DMC has a long history of aggressive downsizing and cost-cutting going back to the tenure of now-Detroit Mayor Mike Duggan as CEO
Top officials at New York City's Rikers Island prison resign amid brutality scandal
By Sandy English, 31 October 2014
The resignations follow revelations of widespread violence, neglect and torture at the prison.
Judge backs Stockton, California bankruptcy plan ending retiree health care payments
By Jerry White, 31 October 2014
A federal bankruptcy judge on Thursday approved a restructuring plan that will eliminate health care benefits for 2,400 retired city workers and their families.
NSA chief calls for more "permeable" barrier between state and tech corporations
By Thomas Gaist, 31 October 2014
The distinction between government surveillance agencies and "private sector" technology corporations increasingly exists in name only.
St. Louis police stock up on riot gear ahead of grand jury decision on Brown killing
By Ed Hightower, 31 October 2014
Police in St. Louis County spent $172,669 since August on tear gas, rubber bullets and other riot equipment.
Notes on police violence
Video shows "firing squad" police killing of Michigan man
By EP Bannon and Tom Hall, 31 October 2014
A recently-released video shows a group of Saginaw, Michigan police officers firing dozens of rounds at a 49-year-old homeless man.
The CIA torture cover-up continues
By Eric London, 31 October 2014
The highest echelons of the state are engaged in an unconstitutional plot to hide from the public the harrowing torture methods employed by the CIA.
The trade unions and the Detroit bankruptcy
By Jerry White, 30 October 2014
The Detroit bankruptcy has provided yet another demonstration of the anti-working class character of the unions, which function as instruments of the ruling class and the state.
US Federal Reserve ends "quantitative easing" program after funneling trillions to financial markets
By Joseph Kishore, 30 October 2014
The expected move by the Fed was accompanied by the pledge to keep interest rates at their current near-zero rates for a "considerable time."
Obama uses Ebola doctors as campaign prop
By Patrick Martin, 30 October 2014
The media event at the White House, five days before the congressional election, was aimed at giving US imperialism a "humanitarian" face.
Federal jury convicts friend of Boston Marathon bombing suspect of lying to the FBI
By John Marion, 30 October 2014
Robel Phillipos, an acquaintance of Dzhokar Tsarnaev, faces up to 16 years in federal prison despite not being involved in the bombings.
US-Japan conflicts stall Obama's Trans-Pacific economic pact
By Mike Head, 28 October 2014
The impasse points to the underlying conflicts between the interests of the US and those of its current allies such as Japan.
US child poverty remains at highest rate in 20 years
By Andre Damon, 27 October 2014
A report published in the medical journal JAMA Pediatrics found that nearly one in four US children lives in poverty, and a similar proportion do not get enough to eat.
The US elections and the American plutocracy
By Patrick Martin and Barry Grey, 27 October 2014
Popular alienation from the political system coincides with the ever more naked domination of both parties and manipulation of elections by a handful of multi-millionaires and billionaires.
Judge orders Philadelphia officials to negotiate school cuts with teachers union
By Nick Barrickman, 27 October 2014
A judge barred the School Reform Commission from unilaterally revoking a contract covering 15,000 Philadelphia teachers.
Two killed, four wounded in Washington school shooting
By Christine Schofelt, 27 October 2014
The shooting in Marysville, Washington is at least the eighth school shooting in the US this semester.
Albuquerque authorities seek to dampen public outrage over police violence
By D. Lencho, 27 October 2014
Since 2010, Albuquerque police officers have shot more than 40 people, with most of the victims being unarmed and mentally ill.
The California drought: A tale of two cities
By Evan Blake and Gabriel Black, 27 October 2014
The California drought has left thousands of people without access to drinking water while the super-rich are trucking in water to maintain their private lakes and gardens.
Pennsylvania's "Mumia Law": New attack on political prisoners and new threat to freedom of speech
By Ed Hightower, 25 October 2014
The "Revictimization Relief Act" is a thoroughly reactionary piece of legislation that will allow crime victims and their families to sue prison inmates for engaging in constitutionally protected speech.
No cause yet determined in Pennsylvania house fire
Hundreds mourn victims in a candlelight vigil
By Samuel Davidson, 25 October 2014
Fire officials have yet to release the cause of the tragic fire that swept through an old wood-frame house in McKeesport, killing four children and two adults.
Democratic Senate candidates sound right-wing themes in pre-election debates
By Patrick Martin, 24 October 2014
In a series of campaign debates last week, Democratic candidates for the US Senate vied with their Republican opponents in their support for militarism and budget-cutting.
Democrat Tom Wolf and the Pennsylvania gubernatorial race
By Douglas Lyons, 24 October 2014
Pennsylvania voters are faced with no real choice for governor in the November 4 elections.
The carve-up of Detroit
By Jerry White, 23 October 2014
As the bankruptcy of Detroit enters its final chapter, the plunder of city assets by Wall Street speculators grows ever more shameless.
Blackwater mercenaries convicted for role in 2007 Iraq massacre
By Thomas Gaist, 23 October 2014
The crimes of the Blackwater mercenaries were a product of the illegal invasion of Iraq by the US government, for which the entire political and military establishment is guilty.
US media campaign to exonerate cop who killed Michael Brown
By Andre Damon, 23 October 2014
The Washington Post and St. Louis Post-Dispatch published coordinated leaks from grand jury proceedings, claiming they substantiate the story of Ferguson, Missouri police officer Darren Wilson.
Lawsuits allege Alabama prison inmates left to die of treatable diseases
By Tom Hall, 23 October 2014
Jailers in Madison County, Alabama deliberately denied health care to inmates with treatable illnesses in order to cut costs, according to three recently filed lawsuits.
Census report: Half of Americans poor or near poor
By Andre Damon, 22 October 2014
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BOCHIC DOES BAGS: Bochic is branching out from fine jewelry and entering the handbag market with a new line of evening clutches. The move marks the brand's first expansion outside of jewelry. The New York-based company will introduce the initial collection in September with three styles inspired by Fifties film noir: Alicia, Gilda and Madeleine. Each style includes intricate gold handles made in Rome, with the base done in some variation of crocodile, python, serpentine and sting ray.
Referring back to the brand's origins, each style features a jewelry detail, using enamel and precious stones to create ringlike clasps and additional embellishments. Each style is handmade in Florence, with price points starting at $2,500. The collection will be sold worldwide through a series of trunk shows and similar events, as well as on the Bochic site.


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The Welsh version of System of a down, made by me and my sister in marks and spencer.
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2: Oes, mae system ar y dde gyda proper bo.
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Cancers 2010, 2(2), 624-641; doi:10.3390/cancers2020624
Published: 20 April 2010
Abstract: Since diagnosis at an early stage still remains a key issue for modern oncology and is crucial for successful cancer therapy, development of sensitive, specific, and non-invasive tumor markers, especially, in serum, is urgently needed. Midkine (MK), a plasma secreted protein, was initially identified in embryonal carcinoma cells at early stages of retinoic acid-induced differentiation. Multiple studies have reported that MK plays important roles in tumor progression, and is highly expressed in various malignant tumors. Because increased serum MK concentrations also have been reported in patients with various tumors, serum MK may have the potential to become a very useful tumor marker. Here, we review and discuss the possibility and usefulness of MK as a novel tumor marker.
1. Introduction
Midkine (MK), a heparin-binding growth factor, was originally reported to be the product of a retinoic acid-responsive gene during embryogenesis [1,2]. In 1988, Kadomatsu et al. first isolated an MK cDNA clone by differential hybridization and reported that MK was intensely expressed in early differentiation stages of embryonal carcinoma cells [1]. Because the RNA was originally detected only in midgestation mouse embryos and the kidney in adults, MK was initially called "midgestation embryo and kidney (MK) gene" [2]. During the two decades since the discovery of MK, substantial advances have been made in understanding the biological activity and molecular basis of MK. It is well-documented that MK is a multifunctional peptide which, together with pleiotrophin (PTN), forms a structurally distinct family of heparin-binding growth factors [3]. Interestingly, despite its high expression during embryogenesis, MK is not detectable in healthy adults and only re-appears in the body as a part of the pathogenesis of diseases [3]. Moreover, the most intriguing feature of MK is its massive expression in advanced tumors with surprisingly-high frequency. In this review, we describethe molecular genetic and biological significance of MK, especially focusing on malignant tumor, and introduce the possibility of MK as a novel tumor marker.
2. Midkine
2.1. Molecular Genetic Characterization
The human midkine gene is located on chromosome 11q11 and encodes a 13-kDa protein rich in a basic amino acid and cysteine [4,5,6]. MK is widely conserved from Drosophila to human [7]. Human and mouse MK sequences are extremely highly conserved: 87% of amino acids are identical and all amino acid changes are conservative except for an insertion [8]. MK is composed of two domains: an N-terminally located domain (MK 15–52), and a C-terminally-located domain (MK 62–104) flanked by intra-domain disulfide bridges [9] (Figure 1). The three dimensional structure of MK has been clarified based on the structures of the N-terminal half and C-terminal half molecules determined by NMR [10]. In the C-terminal half of human MK, two heparin-binding clusters, namely cluster I (K79, R81 and K102) and cluster II (K86, K87 and R89), have been identified [10,11]. Cluster I is especially essential for the recognition of heparin sulfate as well as chondroitin sulfate proteoglycans, and responsible for multiple biological functions, such as neurite outgrowth, fibrinolysis, and nerve cell migration [11,12,13].
It is also well-documented that the expression of MK is developmentally regulated [1,2]. MK is highly expressed in the midgestation period in response to retinoic acid, whereas its expression becomes low or undetectable in normal adult tissues [3]. In the promoter region of the MK gene, there is a functional retinoic acid-responsive element, which is responsible for the MK expression induced by retinoic acid [14,15]. The 5' regulatory region of the MK promoter also contains two binding sites for Wilms' tumor suppressor gene (WT1) [16]. The WT1-responsive element near the transcription start site of the MK promoter is required for reduction of MK expression by WT1. In addition, the transcriptional activity of the MK promoter is regulated by cell growth in part through p53-dependent pathways [17]. Recent studies also revealed that MK expression is regulated by hypoxia, cortisol, growth factors, and cytokines via a nuclear factor-κB (NF-κB) dependent pathway [18,19,20]. The precise regulatory mechanism underlying the tight regulation of MK expression remains to be elucidated.
2.2. Mechanism of Action
MK, a secreted plasma protein, initiates signaling through the ligand-dependent activation of receptors to participate in regulating diverse biological processes [7]. Several MK-binding cell surface proteins, including syndecans, integrins, protein tyrosine phosphatase ζ (PTPζ), anaplastic lymphomakinase (ALK), and low-density lipoprotein (LDL)-receptor-related protein (LRP) [7,21], have beenidentified. MK strongly binds to syndecan proteins, namely syndecan-1, -3, and -4 [22,23,24]. The binding of MK to syndecans is mediated by the heparan sulfate chains. PTPζ is a receptor-type protein tyrosine phosphatase of which the extracellular domain carries chondroitin sulfate chains, and the intracellular domain exhibits protein tyrosine phosphatase activity [7]. The chondroitin sulfate chains on its ectodomain of PTPζ are essential for MK-binding [13]. The interaction between MK and PTPζ activates phosphoinositide 3-kinase (PI3-kinase) and extracellular signal-regulated kinase (ERK) for osteoblast cell migration and neural survival [25,26]. ALK, a transmembrane tyrosine kinase, was identified to be a receptor for MK and PTN [27,28]. By binding of MK to ALK, PI3-kinase and ERK are activated for intracellular signaling and regulate cell growth [28]. In addition, LRP has been identified as a membrane protein, which was purified from the MK-affinity column [29]. LRP is a member of the LDL receptor family that accomplishes endocytosis of a diverse array of ligands [30]. LRP1 mediates MK endocytosis, and endocytosed MK enters the nucleus where it exerts anti-apoptotic activity [31]. Chen et al. reported that MK exhibits strong affinity for the N-terminal half of the second domain among the four ligand-binding domains of LRP1, and plays an important role in anchorage-independent cell growth [32]. Taken together, these receptors described above may regulate the biological activities of MK either independently or cooperatively. Further investigations are needed to specify the functional interaction and complex formation between these receptors.
2.3. Biological Significance
During the midgestation period of embryogenesis, MK plays important roles in the development of tooth, lung, kidney, bone and nerve tissues [33,34,35,36,37,38]. Morphogenesis and cell differentiation were inhibited in tooth germs cultured in the presence of neutralizing antibodies for MK [33]. In development of embryonic mouse lung, MK showed a weak effect on branching morphogenesis, but exhibited an effect in restoring development of mesenchymal tissue [34]. MK was also involved in kidney development via the molecular cascade of the epithelial conversion of the metanephric blastema [36]. In addition to the specific functions of MK in development, extensive evidence has also accumulated that MK has a huge variety of biological function, such as transformation, neural survival, tissue remodeling, cell growth, differentiation, cell migration, and carcinogenesis [3,7,19,39,40]. Kaneda et al. reported that MK exhibits nerve cell adhesion and guidance activity for neurite outgrowth via the heparin-like domain on nerve cell surface heparan sulfate proteoglycan [41]. MK, which has neuroprotective activity and neurite extension, expresses strongly cerebral infarct and Alzheimer's disease [25,42,43,44,45]. After ischemic injury, MK is up-regulated by astrocytes in the surviving region of the cerebral cortex and the hippocampal CA1 subregion, suggesting that MK may contribute to the survival of injured neurons [43,46,47]. In the inflammatory response, MK promotes the cell migration of inflammatory cells, specifically macrophages and neutrophils [48,49]. In addition, MK expression increases at intraperitoneal adhesions after surgery and cardiac remodeling after myocardial infarction [50,51,52]. Most importantly, MK is significantly up-regulated in various malignant tumors and plays crucial roles in carcinogenesis [53,54,55,56]. Thus, due to its multifunctional properties, MK is deeply involved in the pathogenesis of various diseases, especially malignant tumors.
In accordance with its high expression in various malignant tumors, MK exerts cancer-related activities in the process of carcinogenesis, including transformation, fibrinolysis, cell migration, cell survival, anti-apoptosis, and angiogenesis [7,25,29,39,57,58,59,60,61]. Kadomatsu et al. reported that NIH3T3 cells were transformed by overexpression of MK, and formed tumors in nude mice [39]. MK serves as a mediator of retinoid and cooperates with basic fibroblast growth factor (bFGF) to enhance fibrinolytic activity of endothelial cells [57]. MK enhances the plasminogen activator (PA)/plasmin levels in bovine endothelial cells in a dose- and time-dependent manner, and the fibrinolytic activity can be achieved through this up-regulation of urokinase-type PA expression [57]. In addition, cell migration-promoting activity of MK has been demonstrated in neutrophils, osteoblastic osteosarcoma cells, neural cells, macrophages, and smooth muscle cells [13,38,40,49,58,62]. In primary neuronal cultures, MK inhibited caspase-dependent apoptosis via the activation of ERK and PI3-kinase [25]. Qi et al. also reported that MK rescued Wilms' tumor cells from cisplatin-induced apoptosis by regulating Bcl-2 expression [63]. Furthermore, angiogenic role of midkine has been shown by the observation that MK transfection into the breast carcinoma line, MCF-7, accelerated tumor growth, and increased tumor vascularity after implantation of the cells in nude mice [64]. Taken together, these distinct observations not only bring new insights into the novel biological roles of MK, but also open up novel therapeutic targets for the various malignant tumors.
3. Midkine as a Novel Tumor Marker
Numerous studies have demonstrated that MK expression in various malignant tumors is significantly higher than that in normal tissues [53,54,55,56]. Overexpression of MK at both mRNA and protein levels was reported in a variety of human malignancies, such as oral, gastrointestinal, hepatobiliary, lung, thyroid, bladder, cervical, ovarian, and prostate cancer [53,55,56,65,66,67,68,69,70,71,72,73]. Moreover, MK protein expression has been shown to be strongly correlated with poor prognosis in patients with neuroblastomas, astrocytomas, pancreatic head carcinomas, or gastrointestinal stromal tumors [74,75,76,77]. It should be noted that normal tissues of human adults show restricted expression of MK, whereas most carcinoma specimens express MK at significantly high levels in a tissue type-independent manner [53,54,64,78]. In addition to the characteristics of MK expression, because MK protein is a plasma-secreted protein, MK concentrations in blood may increase in patients with malignant diseases. Enzyme-linked immunoassay (EIA) has allowed measurement of MK levels in blood, and increased blood MK concentrations were reported in patients with malignant tumors, including hepatocellular, gastric, and lung carcinoma [79,80]. A series of findings suggests that MK in blood may have potential to become a sensitive and useful tumor marker. Accordingly, Ikematsu et al. reported that higher plasma MK concentrations in patients with neuroblastoma were strongly correlated with poor survival [81]. Thus, it is suggested that blood MK concentrations may also become a novel diagnostic marker for predicting prognosis of patients with various cancers described in this section.
3.1. Neuroblastoma
Neuroblastoma is the most common extracranial solid tumor in children, comprising between 8% and 10% of all childhood cancers, and accounts for 15% of all childhood cancer deaths, indicating the poor prognosis of many of the tumors [82,83]. A number of genetic and biological features have been recently investigated in an effort to reveal the pathogenesis of neuroblastoma and to identify useful tumor markers. Many prognostic studies have identified several tumor markers associated with overall or disease-free survival, including MYCN copy number, tyrosine kinase A (TrkA) expression level, ploidy, and deletion or loss of heterozygosity of chromosome 1p and gain of chromosome 17q [82]. However, because invasive diagnostic procedures, such as a tumor biopsy, are required for these tumor markers [83,84], development of more useful and non-invasive tumor markers is urgently needed to improve the prognosis of patients with neuroblastoma.
Various studies have confirmed that MK is highly expressed in neuroblastoma [74,81,86]. Nakagawa et al. first reported that MK mRNA expression was elevated in neuroblastoma specimens at all stages [74]. In agreement with its high mRNA expression, the plasma MK concentrations become elevated with advancing neuroblastoma stages [81]. A higher level of MK was correlated with MYCN amplification, low expression of TrkA, diploidy/tetraploidy, and older age, which are known prognostic factors for neuroblastoma, indicating that the elevated plasma MK concentrations is correlated with poor prognostic factors of neuroblastomas. Furthermore, Ikematsu et al. also confirmed there was a striking correlation between high plasma MK level and poor prognosis [86]. Analysis for sporadic neuroblastoma cases also showed that the MK level was also remarkably higher than in non-tumor controls, and correlated with the statuses of MYCN amplification and stage. A significant correlation was also observed between high plasma MK level and poor prognosis of sporadic neuroblastoma. Taken together, these reports strongly support that plasma MK level is a prognostic factor for neuroblastoma.
3.2. Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is a common primary cancer of the liver. HCC, endemic to Asia and Africa with a rising incidence in Western countries, is one of the most common and aggressive cancers worldwide [87,88]. The high mortality associated with HCC is ascribed to the difficulty to diagnose at an early stage. Indeed, although HCC patients diagnosed at an early stage and thus receiving curative resection exhibit a significantly improved life prognosis, most symptomatic HCC patients are diagnosed at an advanced stage, precluding their chance for surgical intervention [89,90]. Therefore, early diagnosis has been considered as the most important factor to achieve long-term survival for HCC patients.
Even though α-fetoprotein (AFP) and protein induced by vitamin K absence-2 (PIVKA-II) are one of serologic markers widely used for diagnosing HCC patients, the elevated serum AFP is only observed in about 60% to 70% of HCC patients and, to a lesser extent (33–65%), in patients with smaller HCCs [92]. Moreover, non-specific elevation of serum AFP has been found in 15% to 58% of patients with chronic hepatitis and 11% to 47% of patients with liver cirrhosis [92], indicating the necessity of developing a specific and sensitive HCC biomarkers. Aridome et al. first reported that the MK mRNA level was higher in HCC specimens than in the corresponding non-cancerous tissues [67]. By immunohistochemical analysis, high expression of MK was observed in specimens from HCC patients [68]. A highly sensitive EIA for MK revealed that 0.6–0.8 ng/mL of MK was detected in serum samples in the majority of HCC cases, whereas the MK levels in the sera of normal human subjects were low or undetectable [79]. In addition, the overexpression level of MK in HCC with intra-hepatic metastasis was significantly higher than that in HCC without intra-hepatic metastasis [92]. It is noteworthy that a significant increase in serum MK is associated with HCC patients, including those with normal serum AFP concentrations [93]. The measurement of serum MK concentrations allows for distinguishing normal and cirrhosis individuals from HCC patients, including those with normal AFP and small tumors from two independent cohorts. Therefore, the combined score of multiple markers, such as MK and AFP and/or PIVKA-II, may improve the prediction accuracy of identifying HCC patients.
3.3. Esophageal Squamous Cell Carcinoma
Esophageal carcinoma is one of the most lethal malignant tumors in the gastrointestinal carcinoma family [94]. Once diagnosed with esophageal squamous cell carcinoma (ESCC), the prognosis is very poor, with a five-year survival rate below 10% [95,96]. Thus, identification of the novel sensitive markers with the use of a relatively non-invasive technique, are needed for detecting the presence of ESCC early. The MK mRNA level is higher in esophageal carcinoma specimens than in the corresponding non-cancerous tissues [67,78]. Likewise, esophageal tumor specimens were positively stained with anti-MK antibody by immunohistochemistry, while surrounding normal esophageal tissues in these specimens were not stained [97]. Additionally, Shimada et al. revealed that MK expression by the tumor was significantly associated with high level of serum MK and high serum MK concentrations were associated with tumor size, immunoreactivity, and poor survival [98]. It should be noted that the positive rate of serum MK concentrations was significantly higher than any of conventional markers, such as carcinoembryonic antigen (CEA), SCC antigen (SCC-Ag), and cytokeratin 19 fragment (CYFRA21-1). Multivariate analysis indicated that S-MK is an independent prognostic factor [98]. Since serum concentrations of some types of growth factors are useful to predict treatment response and patients' outcome in ESCC, serum MK may be a useful prognostic marker for ESCC.
3.4. Oral Squamous Cell Carcinoma
Oral cancer is one of the common types of human cancer [99,100]. Because the survival rate for patients with oral cancer still remains poor, improved survival of patients with oral cancer requires better techniques for the prediction of prognosis. Oral squamous cell carcinoma (OSCC), the most common of several types of oral cancers, is associated with bad prognosis. Although previous studies have demonstrated the usefulness of tumor-associated antigens for primary diagnosis of OSCC, no tumor markers have given a precise prediction of prognosis [78,101]. Ota et al. provided the direct evidence that serum MK concentrations may have the potential to become a very useful tumor marker in OSCC [66]. Serum MK concentrations were significantly higher in patients with OSCC than in healthy controls. Patients in high serum MK groups showed a significantly lower five-year survival rate compared with patients in low serum MK groups. MK expression in blood and cancer tissues is indicative of a strong relationship with malignant potential, and high expression suggests a bad prognosis. Serum MK concentrations may thus be a useful marker not only for cancer screening but also for predicting prognosis of OSCC patients.
3.5. Breast Cancer
Breast cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations [102]. Although well-established clinicopathological factors show strong overall association with patients' prognosis and outcome, it has become clear that patients with similar features may show distinct outcomes and vary in their response to therapy [103]. In order to improve the poor prognosis of breast cancer, molecular biomarkers including hormone receptors and human epidermal growth factor receptor 2, are assessed and used in routine clinical practice currently [104]. Although several additional biomarkers are extensively studied, only few biomarkers are useful. Ibusuki et al. demonstrated that measuring plasma MK levels in combination with conventional markers provided statistically significant improvement in the diagnosis of breast cancer [105]. Plasma MK levels were abnormally elevated in patients with breast cancer compared to healthy controls. Increased levels of MK were correlated with menopausal status and nuclear grade in primary invasive breast cancer without distant metastasis. In addition, cancer detection rates based on MK levels were higher than those based on three conventional markers including CEA, carbohydrate antigen 15-3 (CA15-3), and Nation Cancer Center-Stomach-439 (NCC-ST-439). Moreover, detection rates of breast cancer using a combination of two conventional tumor markers (CA15-3/CEA, CA15-3/NCC-ST-439, or CEA/NCC-ST-439) with MK was significantly higher than those using combination of three conventional tumor markers. Further clinical validation studies are needed to establish the clinical significance of MK in the plasma of patients with breast cancer.
3.6. Pancreatic Cancer
Pancreatic cancer is one of the most aggressive malignancies and has a five-year survival rate of 1–4% [106]. Although surgery is the only curative treatment for patients with pancreatic cancer, only approximately 10–20% of patients have surgically resectable disease at the time of initial presentation, and even in these cases, the five-year survival rate is only 20%. Therefore, development of novel diagnostic methods is urgently needed for the patients to undergo the surgery at the early stage of the disease. Ohhashi et al. investigated the feasibility of quantitative analysis of MK mRNA by quantitative real-time RT-PCR (qRT-PCR) as a promising tool for pancreatic cancer diagnosis [107]. Several pancreatic cancer cell lines originating from metastatic lesions, such as KP-3, AsPC-1, SUIT2, and CFPAC1, showed especially high levels of MK mRNA expression. The median value of MK mRNA expression in pancreatic cancer tissue was 5.4-fold higher than those of pancreatic non-neoplastic tissues. These data suggest that quantitative analysis of MK mRNA provides an objective and sensitive evaluation and may be a promising modality for the diagnosis of pancreatic cancer and the prediction of its prognosis. Further investigation on correlation between elevated plasma MK concentrations and prognosis of pancreatic cancer will strengthen the usefulness of MK as a novel prognostic marker.
4. Conclusions
In this review, we described the unique biological features and clinical significance of MK, particularly focusing on the possibility of MK as a novel tumor marker. More additional studies have demonstrated that a truncated form of MK (t-MK), which lacks exon 3 encoding the N-terminus, is also found at both mRNA and protein levels in various tumors, including colon, breast, gastric, liver, and kidney, but not in normal specimens [108,109,110,111,112,113]. Because the frequency of the t-MK expression increases during tumor progression, t-MK may also be utilized as a tumor marker, especially to detect metastatic foci [111,114]. Furthermore, due to its biological significance in carcinogenesis, there is a growing body of evidence that MK can be regarded as a candidate molecular target for therapy against human carcinoma. Indeed, antisense MK oligodeoxyribonucleotides show anti-tumor activity for neurofibroma derived-cells and mouse rectal carcinoma cells [114,115]. Small interfering RNA (siRNA) mediated inhibition of MK expression also has an antitumor effect in prostate and gastric cancer [116,117]. In addition, MK promoter-based conditionally replicative adenovirus therapy for MK high expressing tumors has been attempted recently [118,119,120,121,122,123]. The 5' regulatory region of the human MK promoter regulates and determines its tumor-specific MK expression. Because of the tumor-specific MK expression, the MK promoter-thymidine kinase gene exhibits a less side effect, indicating that a suicide gene delivery under the control of the MK promoter is a high potential strategy for cancer therapy. Collectively, a series of evidence described above strongly support the possibility of clinical application of MK (Figure 2). Understanding more biological feature and clinical significance of MK may not only bring new insights into the development of a sensitive and specific tumor marker, but may also open up novel therapeutic strategies for a large number of diseases.
This work was supported by Grants-in-Aid for Scientific Research (B) 17390254 (Y. Ando) and (B) 17390541 (M. Shinohara) from the Ministry of Education, Science, Sports, and Culture of Japan. We are grateful to Kazutoshi Ota, Satoru Shinriki, and Tomoko Ota for their helpful input and discussions regarding the manuscript. Appreciation is extended to Cellmid Limited for providing midkine antibodies.
- Kadomatsu, K.; Tomomura, M.; Muramatsu, T. cDNA cloning and sequencing of a new gene intensely expressed in early differentiation stages of embryonal carcinoma cells and in mid-gestation period of mouse embryogenesis. Biochem. Biophys. Res. Commun. 1988, 151, 1312–1318, doi:10.1016/S0006-291X(88)80505-9.
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