You should take into consideration self improvement in your own life. Even so, you may think that there is no need time for this as you currently give a great deal time for you to your household daily. It is vital that one does require time for your self and produce areas that you would like to boost. Check this out report for several recommendations.
Don?t forget to match others on the things which cause them to excellent, even though she or he is an ideal unknown person. Receiving a heartfelt compliment from someone you love is outstanding. But think of how amazing it can feel when someone that you may not even know comes-up to you and gives you with a great match.
On the road to personal development, it?s important to consider your goal and what your location is now, and discover what is definitely the obstacle standing up with your way. What might you do in order to get over this hindrance? The opportunity to see earlier hurdles can be a major factor to leading an effective lifestyle.
Keep the spontaneity in all of the scenarios. If you find that there is much too much anxiety and negativity in your lifetime, do what you could to find the sense of humor from the condition. Sense of humor is actually a speedy and effective way to minimize anxiety and dislodge concern. Laugh your difficulties away.
Everyone needs a hobby. You may have one and need a different one, or maybe you happen to be eaten by work and locate yourself just treading h2o. In any case, now is the ideal time to identify a hobby. Think of what you are considering, and determine how to get involved.
In order to make a serene atmosphere for your self you need to take measures to arrange your home. Many individuals get started their day improperly because they are incapable of get their secrets or their cell phone in the morning. Spending some time to put those items within a designated area will help you begin every day off of well and so produce a far better working day for your self.
Probably the most important ideas to personal growth is always to practice selflessness. By taking a while from daily to help you an individual or just suggest to them that you just proper care, you will start to view the real self inside of you. Make modest sacrifices to get started your journey of self development.
As was talked about initially of the write-up, most people are using personal development strategies to become better folks and are living a lifetime of peace, joy and happiness. Applying the advice on this page is a wonderful way to greater your self and may support get you going on your journey of self improvement.
LOS ANGELES (TheWrap.com) - Paul Thomas Anderson's "The Master," a prestige September release that had been conspicuously missing from the announced lineups of the Toronto and Venice film festivals, will indeed make its North American premiere in Toronto, TheWrap has learned.
According to a person with knowledge of the film's release plans, "The Master" has been added to the Toronto lineup as a special presentation.
The Weinstein Company declined to comment to TheWrap, and representatives of the Toronto Film Festival did not respond to requests for comment.
Earlier on Monday, Deadline reported that the film was added to the lineup at Venice as well.
Last week, the Weinstein Company moved the release of the film, in which Philip Seymour Hoffman plays a charismatic religious leader at least partially based on Scientology founder L. Ron Hubbard, from October 12 to September 14.
The festival bookings will place the film in the thick of the awards race, which unofficially launches with the Venice, Telluride and Toronto festivals. It will also premiere at a time when Scientology has been receiving massive media attention in the wake of the divorce of Tom Cruise and Katie Holmes.
The Toronto Film Festival runs from September 6 through September 16; Venice takes place from August 29 to September 8.
Weinstein opted to move up the release date of "The Master" as soon as Anderson finished the film, his first since the Oscar-nominated "There Will Be Blood."
The move was one of a few recent changes in the fall release landscape. Steven Spielberg's previously unscheduled Disney/DreamWorks film "Lincoln" has now been slated for a November 9 release, while Warner Bros. moved "Gangster Squad" - which is hardly a competitor for the same audience as "The Master" - from September 7 to January 11.
Those moves helped clear space for "The Master," and Weinstein made an additional change by pushing its release of Andrew Dominick's "Killing Them Softly," which was originally scheduled for September 21, to October 19.
Asked whether the Tom Cruise/Katie Holmes divorce had an impact on moving up the release date, the source close to the film said, "Well, it sure as hell helps."
In May, TheWrap reported that Anderson screened the film for Cruise in hopes of heading off a conflict with Scientology. Cruise, who starred in "Magnolia" for Anderson, "had issues" with parts of the film, according to two individuals close to the film.
Weinstein has won the last two Best Picture Oscars, for "The King's Speech" and "The Artist."
Slick marketing is out. ?The frugal, time tested methods of successful direct marketing are back in favor. That means testing on a small scale and making sure you don?t waste your money on any form of advertising or marketing you cannot track and measure.
Maybe it?s time you consider direct marketing your business by phone.
With over-the-phone prospecting you can reach new markets and test new offers in ways that are practical and easy to test.
How to do it? The three tips in this video?will get you started.
The video is quite short ? less than two minutes. ?Take a look. ?I think you?ll find the info?timely and helpful ??especially?in this?economy!
Click to share.
Tags: b2b direct marketing, b2b phone marketing, business to business lead generation, direct marketing, direct marketing business to business, direct marketing strategy, featured, Market Testing, outsourced direct marketing, outsourced sales and marketing, phone marketing
Category: Business to Business Lead Generation, Lead Generation & Appointment Setting, Market Testing Strategies
Arnold Schwarzenegger turns 65 today. The Austrian-born bodybuilder, actor and former California governor has packed a lot of living into those six and a half decades.
The revelation in 2011 that he had fathered a child with a housekeeper and was separating from his wife, Maria Shriver, may have changed some fans' opinions of the actor, but he's still an A-list name. And once he left the governor's office, he was free to return to movies, where he is responsible for some?pretty memorable lines.
Here are a few of our favorites to honor the big guy's birthday.
1. "I'll be back." --"The Terminator
2.? "It's not a tumor!"? --"Kindergarten Cop"
3. "Hasta la vista, baby."? --"Terminator 2."
4. "Get to the chopper!"? --"Predator"
5. "To crush your enemies, see them driven before you, and to hear the lamentation of their women."? --"Conan the Barbarian"
6. "You should not drink and bake."? --"Raw Deal"
7. "Consider that a divorce."? --"Total Recall"
8. "If it bleeds, we can kill it."? --"Predator"
9. "The Iceman cometh!"? --"Batman?and Robin"
10. "Come with me if you want to live."? --"The Terminator"
Various parts and pieces of Apple's next iPhone iteration have been leaking out over the past many months, but nobody's actually gotten a chance to mash them all together into a working representation of what the iPhone 5 might actually look like come its expected mid to late 2012 release date.
Until now, that is.
According to 9to5Mac, the website iLab (whose site is being destroyed with traffic as of this article's creation) has released a number of new photos that reportedly show off a fully assembled iPhone 5. That includes the curved backplane, all of the buttons, the speakers, the screen ? everything.
The caveat? It's only a black iPhone 5 for now, so purists of Apple's classic all-white design will have to wait just a bit longer to see what their shiny new device might look like.
Additionally, we'd like to call attention to the new dock connector found at the bottom of the assembled, alleged unit. While that rumor's been verified for a bit of time now, Apple's decision to swap out its 30-pin connector in favor of a new 19-pin connector will surely require the company to include some kind of adapter in the packaging of the new phone, lest current accessory owners find themselves without any way to connect their devices up to the iPhone 5.
And the reason for the switch? As you'll notice, Apple's moved the headphone connector from the top of the iPhone to the bottom.
That all said, there's a certain strangeness about iLab's assembly ? namely, the raised part between the black panel and screen and the gun-metal sides ? that seems a bit off from Apple's standard design conventions. While some suggest that this might be a sign that iLab's shots aren't real, others are hopeful that it signifies the real iPhone 5, once smashed down, will be even thinner than what's seen in the pictures.
Unless, of course, that is the new look for Apple's new phone.
The iPhone 5 has been rumored to launch anywhere from late September to October, with sources suggesting that it'll be officially unveiled at Apple's August 7 keynote event.
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For more tech tidbits from David Murphy, follow him on Facebook or Twitter (@thedavidmurphy).
For the top stories in tech, follow us on Twitter at @PCMag.
ANAHEIM, Calif. (AP) - Zack Greinke said he would "get lost without a map" in Southern California, but he made himself quite comfortable as he navigated through the clubhouse on his first day with the Los Angeles Angels.
The right-hander dropped his gear in his new locker between fellow pitchers Ervin Santana and Dan Haren and began to settle in on Saturday, one day after he was traded to the Angels by the Milwaukee Brewers.
"This was the first time going through this stuff in the middle of a season, but my first goal was to win games with Milwaukee," Greinke said of the trade rumors leading up to the deal. "It just wasn't working out for us, so we knew that some of us were more likely to get traded than others. But I knew that any team I was going to get traded to was probably a pretty good team."
The arrival of the 2009 AL Cy Young Award winner gives the Angels an All-Star rotation from top to bottom, and renews their confidence for the stretch drive. Greinke now has a chance to return to the postseason one year after he helped the Brewers reach the playoffs with a 16-6 record and 3.83 ERA in the regular season.
Milwaukee dropped back this year and shipped Greinke to the Angels on Friday for rookie shortstop Jean Segura and Double-A right-handers Ariel Pena and Johnny Hellweg.
This is the Angels' third big-name acquisition before the July 31 trade deadline in five years. They got Haren from Arizona in 2010 and first baseman Mark Teixeira from Atlanta in 2008.
The 28-year-old Greinke, who was 9-3 with a 3.44 ERA with the Brewers, is in the final year of a four-year, $38 million contract. Right now, a new deal isn't clouding his thoughts.
"I haven't talked to my agent or anyone since I got traded, but this is an organization that probably everyone in baseball wants to be a part of," Greinke said. "I'm just focusing on playing and hopefully winning as many games as possible. That's all that's going on my mind at the moment."
Greinke will make his Angels debut on Sunday, the same day catcher Chris Iannetta is expected to make his first start off the disabled list after being activated on Saturday.
Greinke's arrival created quite a buzz around the Angels.
"He's a Cy Young Award winner and he's had tremendous success, so it's pretty nice to bring a guy into a rotation that we thought was already pretty good," Angels ace Jered Weaver said. "We had a couple of battles when he was with Kansas City. He's a competitor.
"He wants to win, and he's proven that over the course of his career. He brings a winning mentality," Weaver added. "He's got electric stuff and he's fun to watch, so I'm looking forward to what he brings to the table. I think he can help out, no doubt about it. When you pitch every fifth day, it's hard to contribute day in and day out. But anytime you can have a guy like that, it's definitely a plus."
Greinke made only two previous starts at the "Big A." Both were gems, but neither resulted in a victory.
On May 9, 2009, he allowed a run, four hits and no walks over eight innings. But Joe Saunders beat him 1-0 with a five-hitter for his first major league shutout, ending Greinke's season-opening six-game winning streak. On Aug. 11, 2010, Greinke allowed a run and six hits in eight innings, but had to settle for a no-decision as Weaver also gave up a run in eight innings.
"Against us, Zack's stuff showed up every time we saw him," Angels manager Mike Scioscia said. "He was tough. He has the kind of stuff that lights scouts' eyes up. That's what I remember about him. So we're excited.
"Our rotation at the start of the season had the potential to be as deep as any in baseball. We started off very strong, and then we kind of hit some bumps in the road. And now with Zack coming in, it gives us some depth that will show up as we get into the latter third of the season."
To make room for Greinke on the roster, the Angels optioned left-hander Hisanori Takahashi to Triple-A Salt Lake.
? 2012 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
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A tall task for Phillies
DeMarco: Ruben Amaro had little choice but to sign Cole Hamels to an extension, but in the long run the deal could inhibit him putting enough pieces in place to help the Phillies win in the near future.
QUINCY, Pa. (AP) ? A Pennsylvania man confronting his estranged wife about custody arrangements for their daughter shot the woman to death and killed her boyfriend and his mother, then fled with the 4-year-old girl before the two were found about 250 miles away in Ohio, authorities said.
Kevin Cleeves, 35, of Waynesboro was charged Saturday with three counts of criminal homicide and was awaiting an extradition hearing in the Friday night deaths of 25-year-old Brandi Cleeves, 28-year-old Vincent Santucci and 55-year-old Rosemary Holma.
Pennsylvania state police said in an affidavit that Cleeves told relatives he had been trying to contact his wife to make arrangements to pick his daughter up and went to Santucci's house in Quincy Township to make sure the girl was safe.
Police said Cleeves saw his wife, Santucci and the girl in a car and confronted the couple in the driveway but was ordered off the property.
Authorities said he then opened fire around 9 p.m. Friday, shooting Santucci in the car and then his wife when she jumped out, and finally the older woman as she ran toward him. Police said he took the girl and fled, later telling authorities he was trying to get to a relative's house in Michigan.
An Amber Alert was issued in which authorities said Cleeves should be considered "armed and dangerous as well as suicidal." The alert was canceled hours later, on Saturday, after police in Austintown in northeastern Ohio, outside Youngstown, said the car was spotted in a hotel parking lot off Interstate 80 and later stopped in the parking lot of the Weston Plaza on Route 46, where Cleeves was arrested without incident.
"His 4-year-old daughter was located in the vehicle and was unharmed," police said in a statement.
Court records did not list an attorney for Cleeves, who was in the Mahoning County Jail, police said.
A detective with the Austintown Township police department in Ohio told The (Chambersburg) Public Opinion that an extradition hearing was scheduled for Monday.
UNITED NATIONS (AP) ? A U.N. treaty to regulate the multibillion-dollar global arms trade will have to wait after member states failed to an reach agreement, and some diplomats and supporters blamed the United States for the unraveling of the monthlong negotiating conference.
Hopes had been raised that agreement could be reached on a revised treaty text that closed some major loopholes by Friday's deadline for action. But the U.S. announced Friday morning that it needed more time to consider the proposed treaty ? and Russia and China then also asked for more time.
"This was stunning cowardice by the Obama administration, which at the last minute did an about-face and scuttled progress toward a global arms treaty, just as it reached the finish line," said Suzanne Nossel, executive director of Amnesty International USA. "It's a staggering abdication of leadership by the world's largest exporter of conventional weapons to pull the plug on the talks just as they were nearing an historic breakthrough."
A Western diplomat, speaking on condition of anonymity because of the sensitivity of the issue, also blamed the U.S., saying "they derailed the process," adding that nothing will happen to revive negotiations until after the U.S. presidential election in November.
Chief U.S. negotiator Thomas Countryman refused to talk to several dozen reporters when the meeting broke up.
U.S. State Department spokeswoman Victoria Nuland said in a statement Friday evening that the U.S. supports a second round of negotiations next year.
"While we sought to conclude the month's negotiations with a treaty, more time is a reasonable request for such a complex and critical issue," the satement said.
The draft treaty would require all countries to establish national regulations to control the transfer of conventional arms and to regulate arms brokers. It would prohibit states that ratify the treaty from transferring conventional weapons if they would violate arms embargoes or if they would promote acts of genocide, crimes against humanity or war crimes.
In considering whether to authorize the export of arms, the draft says a country must evaluate whether the weapon would be used to violate international human rights or humanitarian laws or be used by terrorists, organized crime or for corrupt practices.
Many countries, including the U.S., control arms exports but there has never been an international treaty regulating the estimated $60 billion global arms trade. For more than a decade, activists and some governments have been pushing for international rules to try to keep illicit weapons out of the hands of terrorists, insurgent fighters and organized crime.
The U.N. General Assembly voted in December 2006 to work toward a treaty regulating the growing arms trade, with the U.S. casting a "no" vote. In October 2009, the Obama administration reversed the Bush administration's position and supported an assembly resolution to hold four preparatory meetings and a four-week U.N. conference in 2012 to draft an arms trade treaty.
The United States insisted that a treaty had to be approved by the consensus of all 193 U.N. member states.
Ambassador Roberto Garcia Moritan, the conference chairman, said treaty supporters knew "this was going to be difficult to achieve."
He said negotiations failed because some delegations didn't like the draft though "the overwhelming majority in the room did." He added that some countries from the beginning of negotiations had "different views" on a treaty, including Syria, Iran and North Korea.
Amnesty's Nossel accused the U.S. of raising eleventh-hour issues "and wanting more time to consult with itself," which stopped the momentum toward agreement.
Despite the failure to reach agreement, Moritan predicted that "we certainly are going to have a treaty in 2012."
He said there are several options for moving forward in the General Assembly which will be considered over the summer, before the world body's new session begins in September.
Ambassador Jean-Hugues Simon-Michel, who led the French delegation, called Friday's result "the worst-case scenario."
"I'm disappointed but not discouraged," he said. "The ball is now in the court of the General Assembly but the risk is that countries may want to start negotiations from scratch."
Daryl Kimball, executive director of the Arms Control Association, said the General Assembly needs to decide whether to move forward with the treaty text that was close to adoption or reopen old issues.
"What we have now is an uncertain outcome that leaves in doubt the support of the major arms exporters and importers, including the U.S. and Russia, and that needs to be overcome," he said. "This is a delicate moment and it's going to require real leadership on the part of key states including the European countries, Washington and others."
The powerful National Rifle Association in the U.S. has portrayed the treaty as a surrender of gun ownership rights enshrined in the U.S. Constitution. The politically controversial issue has re-emerged since last week's shooting at a Colorado cinema that killed 12 people.
But the draft treaty reaffirms "the sovereign right and responsibility of any state to regulate and control transfers of conventional arms that take place exclusively within its territory, pursuant to its own legal or constitutional systems." And it states clearly that the treaty's aim is to establish the highest standards "for regulating, or improving the regulation of the international trade in conventional arms" ? not domestic trade.
On Thursday, a bipartisan group of 51 senators threatened to oppose the treaty if it falls short in protecting Americans' constitutional right to bear arms. In a letter to President Barack Obama and Secretary of State Hillary Rodham Clinton, the senators expressed serious concerns with the draft treaty that has circulated at the United Nations, saying that it signals an expansion of gun control that would be unacceptable.
During negotiations, the United States objected to any requirement to report on exports of ammunition, and that remains out of the latest draft. It does call for every country to regulate the export of ammunition.
Britain has taken the lead in pushing for a treaty.
Ahead of Friday's meeting, Britain's Deputy Prime Minister Nick Clegg discussed treaty prospects with U.N. Secretary-General Ban Ki-moon in London and both urged the treaty's adoption.
"Global rules govern the sale of everything from bananas to endangered species to weapons of mass destruction, but not guns or grenades," Clegg said. "This anomaly causes untold suffering in conflicts around the world. 1,000 people are killed daily by small arms wielded by terrorists, insurgents and criminal gangs."
The secretary-general said he was disappointed at the failure to agree on a treaty, calling it "a setback." But Ban said he was encouraged that states have agreed to continue pursuing a treaty and pledged his "robust" support.
At the end of the negotiating session, Mexico read a joint statement from more than 90 countries saying they "are determined to secure an Arms Trade Treaty as soon as possible."
Engaging in pay-per-click (PPC) advertising has its own benefits and drawbacks.
Business nowadays is doing different kinds of austerity measures when it comes to advertising their products and services. This is because of high rates of placing ads on print and on television. But there is a fast growing approach that businessmen can utilize to bring their services closer to the people and that is through Internet Marketing.
One tool that is causing Internet marketing popularity is PPC advertising. This is a technique used in search engine marketing that requires one to pay a fee every time someone clicks an ad on your website. Usually this placement is done through a bidding process. If you are a top bidder for your keywords/phrases, you are sure to be on the number one spot on all search engines. Just be sure of the effectiveness of your ad copy to get the most number of clicks you need for your business.
PPC The Pros
You need not be a genius in computer and technology to be able to run this ad campaign.
Immediate results are seen after a few days.
No need to make a website conform to the SEO rules.
Nothing to lose even if you do not top the pages of different search engines. You can still always choose PPC advertising.
You can make use any search engine available.
You can type in any keyword you like.
PPC The Cons
Fixed payments every month to the search engine you choose.
Pay for each click received by your website. At times, visitors are just competitors or people playing pranks on search engines. This hassle wastes money you put in to this advertising.
Inability to pay for the fees next month would mean removal of your website on the paid listings.
This advertising can only be used temporarily because it is difficult to handle in the long run.
Pay-per-click pricing can be costly for long periods of time, therefore, this should be stopped after an ad campaign.
But how exactly PPC advertising can increase traffic, leads and sales?
PRE-QUALIFIED TRAFFIC. All visitors of your website are already considered as a qualified consumer or buyer of your product. PPC advertising leads your customers to you for a lesser cost.
INSTANT EXPOSURE, IMMEDIATE PROFITS. PPC search engines enable you to get your desired results fast. They will have your website live within just a few hours which means immediate increase in sale.
CONSISTENT TOP LISTINGS. This is to get your website on top of the sponsored search results for free. You just have to choose the keywords related to your site and business and place them within your web pages. After this, you are done.
PPC advertising enables advertisers to control their advertising campaigns. Advertisers have effectively targeted their audience and set their own price per click. PPC advertising networks provide the platform to identify the desired audience by geographic setting, topic and industry. These networks have a list of websites of the publishers where the ads will be placed.
Tools are provided by the networks to check how the pay per click limit is working for a certain advertiser. If its still competitive, would it be even listed among the paid search lists or does it generate sales? Of course, if the advertiser made the highest bid, the better chances the ad will be seen in the search engine. These networks too provide protection for the advertisers against click fraud. This advertising set-up allows advertisers to set a daily budget for his ads, thus, less spending for unnecessary clicks. Advertiser will never go over his budget.
In PPC advertising, what are important are the keywords and phrases. You have to select at least 10 ?very specific? keywords that would give you the best traffic in the search. Then, write the ad creatively but straightforward. Tell the truth about your product or service and do not lie. Good thing if your product or service will not disappoint those that are relying on your ad?s promise ? but what if it did otherwise? Important too is the clarity of the ad. Do not use very vague languages. Include important details like the price.
Important! You should also remember to budget your bids. Do not go overbidding because you will only lose your money and do not go so low that your ads will never get the chance to show up. Check your profit against your spending. If you see no progress then most likely you have to drop your ad campaign.
More and more advertisers have been using PPC advertising and it will continue to grow faster than any online advertising techniques. From revenues of $2.6 billion in 2004 to $5.5 billion in 2009, cost per click will dramatically go up as well from $0.29 to $0.36.
PPC advertising is new in online marketing and it is going to continue in the years to come. For advertisers, this means increase revenues with fewer advertising expenses, savings, more sales, good return of investment (ROI) and effective ad campaigns in the days to come.
Traveling to a brand new place requires lot of arrangements. However, the first factor which should be carried out as a component of preparing for the travel is actually buying travel instructions for the place. It is usually good to read to more than one guide for traveling in order to be certain that the details that is furnished is actually correct. However, along with time things have changed significantly and these types of guides have additionally taken a new shape and appearance. Online guides associated to travel and tourism are usually accessible and you can collect all kinds of details with regards to a destination. A lot of travelers and tourists likewise publish their journey experiences and travelogues on the internet so that individuals can read all of them and find ideas or advice.
Travel guides turn out to be very essential in places where right now there is a language problem barrier. Within such countries, it is really essential to have the suitable kinds of guides therefore that moving around will become easy and convenient. A lot of guides likewise have some language help regarding tourists and a few common terms as well as phrases are pointed out so that travelers can easily communicate the very crucial things without any kind of problem in the new country.
Online guides which help in traveling likewise provide total and detailed data about a place, like the climatic conditions, the weather patterns, food habits, lifestyle, spots of interest and similar things. As a result planning the whole trip becomes very easy as well as convenient along with such guides. In fact, the actual total program of the trip can easily be planned with the help associated with proper guides therefore that the entire trip continues to be smooth and hassle free. And also when things are usually prepared in advance, there will be no additional tensions as well. Detailed planning with regard to each day can easily be done. Aside from printed guides, online guides happen to be also great resources of this sort of information.
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How Time Management Games Can Help You Improve Your Life
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When reading reviews of destinations by other travelers, try to identify whether you and the reviewer have the same expectations and circumstances before basing your decision on other travelers? experiences. One person may give negative reviews due to a lack of kid-friendly features and attractions; if you are traveling without children or on a business trip, such a review would not be particularly useful for you personally.
If you enjoy backpacking on your travels, there are a few packing tips that can make your adventures much easier. Try packing lighter items towards the bottom of the bag so that it feel lighter as it rests on your back. It is also smart to pack commonly used items at the top of the bag so they can be easily reached. To lighten the load make sure you only pack the essentials you will need for the duration of the trip. And be sure to have a properly fitted backpack to prevent strain or injury.
If you absolutely cannot leave ?Fluffy? at home, find a vacation that will let you bring her! Pet-friendly vacations are becoming popular, with many accommodations offering special deals for ?pet parents.? Some of these include doggy day-cares, cat spas, and even pet-friendly cruises. Don?t be afraid to bring your furry pals with you- just make sure they are allowed before you do.
The best part of traveling is being able to spend freely once you get to your destination. While the hotel and the flight are usually the most expensive part, the best trips usually involve spending a ton of money out and about. So before you travel set up a savings plan such that you have a fat wallet after paying for the hotel and the flight so you can maximize your enjoyment.
If traveling with a baby, you can use their diaper bag as a carry-on too. It?s not only great for all of your baby gear, but it is a great way to pack your valuables. These types of bags are generally less likely to be targeted for theft. You can also carry waste bags in these that are great for little ones and for use when you are not at a toilet that can flush.
If you are planning to travel to a country in a very different time zone to yours, make sure you factor jet lag into your plans. Having a low key, relaxing first day planned will get your trip off to a good start, and avoid you having to explore when all you want to do is sleep.
You should now see why this hobby and career is very popular. There is so much for you to see and do! There is also a ton of information on how to reap the benefits of each trip. By following these tips, you are well on your way to becoming a smarter and safer traveler.
For more information about travel, plz visit it to find other tips on purchasing something for your travel.
While some published research has hinted at the connection between the sickle cell trait and sudden cardiac death among young, athletic African-American males, which was initially observed in black military recruits 25 years ago, a new study with the first sizeable patient series definitively confirms this risk for these individuals during competitive sports.
The sickle cell trait, for which all U.S. African Americans are tested at birth, affects approximately 8 percent of the population. The Minneapolis Heart Institute Foundation maintains a 32-year-old forensic database, the U.S. Sudden Death in Athletes Registry, which researchers interrogated to determine the frequency, epidemiology and clinical profile of sickle cell trait-related deaths in a large population of competitive athletes for the purposes of this study.
The findings from this registry show there is "convincing evidence of a causal relationship between the sickle cell trait and the deaths of young, black competitive athletes, especially football players," says the study's senior author Barry J. Maron, MD, director of the Hypertrophic Cardiomyopathy Center at the Minneapolis Heart Institute Foundation. The study will be published in the October edition of the American Journal of Cardiology, but currently is available online.
Prior to this registry study, a lawsuit and previous research prompted the National Collegiate Athletic Association (NCAA) to conduct mandatory screening for the sickle cell trait in all division I athletes prior to their participation in college athletics. As of yet, the NCAA has not expanded to the screening program to division II or III athletes, nor has the association shared its data with the medical community.
Of the 2,462 athlete deaths in the U.S. Sudden Death in Athletes Registry, which provides the first and largest published record of athletes who died of sudden cardiac death on an athletic field, 23 occurred in association with the sickle cell trait (ages 12 to 22 years): 21 were male and all were African Americans. The deaths most often occurred in college-aged athletes (19-23 years) during football conditioning drills early in the season, and with those exposed to high environmental temperatures.
"The registry was initially started by Dr. Maron to help the medical community understand why any athlete would collapse on a field," explains the study's lead author Kevin M. Harris, MD, co-director of the Acute Aortic Dissection Program and director of the echocardiography laboratory at the Minneapolis Heart Institute? at Abbott Northwestern Hospital in Minneapolis.
"We decided to assess the connection between the sickle cell trait and sudden death within our large registry," Harris continues. "As a result, we have developed the first sizable series of competitive athletes in whom sickle cell trait was associated with otherwise unexplained sudden, unexpected collapse and death."
Maron, who has been assessing cardiovascular-related deaths of young athletes for approximately 35 years, is surprised at the level of skepticism he's witnessed regarding the sickle cell trait as a cause of sudden in young, black athletes, even in the scientific medical community.
In the study, the researchers concluded that the sickle cell trait "can be associated with largely unpredictable sudden collapse and death and apparent predilection for African American college football players during conditioning. Understanding the risks, mechanisms, and event triggers of the sickle cell trait may allow lifesaving alterations in training methods to be implemented."
In order to implement such lifesaving alterations in training methods, particularly due to the unpredictable nature of sickle cell trait events, there needs to be a greater understanding and acceptance of this lethal connection. "To not acknowledge this link between sickle cell trait and sudden death creates the possibility of a failure to fully protect the athlete community," Maron said.
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Minneapolis Heart Institute Foundation: http://www.mplsheart.org/
Thanks to Minneapolis Heart Institute Foundation for this article.
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Odd-colored lobsters coming in?bright blue, orange, yellow, calico, and white have been turning up in lobster traps in the waters off Maine.?
By Clarke Canfield,?Associated Press / July 23, 2012
This June 2012 shows odd-colored lobsters at New Meadows Lobster in Portland, Maine. Scientists are seeing a boom in the number of blue, orange, yellow and calico-colored lobsters in the past two years, leading them to ask why they're getting more reports of rare-colored lobsters showing up in fishermen's traps.
Rebecca McAleney/AP/File
Enlarge
When a 100-pound shipment of?lobsters?arrived at Bill Sarro's seafood shop and restaurant last month, it contained a surprise ? six orange crustaceans that have been said to be a 1-in-10-million oddity.
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"My butcher was unloading them and said, 'Oh, my gosh, boss, they sent us cooked dead?lobsters,'" said Sarro, owner of Fresh Catch Seafood in Mansfield, Mass. "He then picked one up and it crawled up his arm."
Reports of odd-colored?lobsters?used to be rare in the?lobster?fishing grounds of New England and Atlantic Canada. Normal lobsters?are a mottled greenish-brown.
But in recent years, accounts of bright blue, orange, yellow, calico, white and even split?lobsters?? one color on one side, another on the other ? have jumped. It's now common to hear several stories a month of a lobsterman bringing one of the quirky crustaceans to shore.
It's anybody's guess why more oddities are popping up in?lobster?traps, said Michael Tlusty, research director at the New England Aquarium in Boston.
It could be simply because advances in technology ? cellphone cameras and social media ? make it easier to spread the word about bizarre?lobster?sightings.
It's also likely more weird?lobsters?are being caught because the overall harvest has soared. In Maine, the catch has grown fourfold in the past 20 years, to nearly 105 million pounds last year. If the yield has quadrupled, it would make sense to have four times as many unconventional?lobsters?being caught as well.
Although?lobster?is the No. 1 commercial fishery in the Northeast, there are a lot of unanswered questions about the bottom-dwelling creatures, he said.
"Are we seeing more because the Twitter sphere is active and people get excited about colorful?lobsters?" Tlusty said. "Is it because we're actually seeing an upswing in them? Is it just that we're catching more?lobsters?so we have the opportunity to see more?
"Right now you can make a lot of explanations, but the actual data to find them out just isn't there."
Lobsters?come in a variety of colors because of genetic variations.
It's been written that the odds of catching a blue?lobster?are 1-in-2 million, while orange comes in at 1-in-10 million. Yellow and orange-and-black calico?lobsters?have been pegged at 1-in-30 million, split-colored varieties at 1-in-50 million, and white ? the rarest of all ? at 1-in-100 million.
But those are merely guesses, and nobody knows for sure.
What is known is that colored?lobsters?have shown up in greater frequency in certain areas over the years.
The waters off Cutler in eastern Maine were once a hotbed for blue ones, after 1,500 larvae-sized blue?lobsters?were released in 1990 to use as a tracking tool to determine their survival rates, said Bob Bayer, executive director of the University of Maine's?Lobster?Institute.
The waters off Montauk, N.Y., once had a lot of blue?lobsters?as well, he said, after researchers released large numbers of blue?lobsters?there. The bright-orange?lobsters?that were in Sarro's shipment are believed to have come from the same waters in Canada.
Aside from their color, the?lobsters?are apparently normal in all other ways, Bayer said. They all turn red when they're cooked, except for the white ones since they don't have any pigment, and diners wouldn't notice a difference.
"There's no difference in taste," he said.
Scientists say it's possible the?lobster?population as a whole has a greater percentage of misfits than it did in years past.
The off-colored?lobsters?are more susceptible to predators because they stick out more on the ocean bottom, rather than blending in like normal ones, said Diane Cowan, executive director of The?Lobster?Conservancy in Friendship, Maine.
"But with the predator population down, notably cod, there might be greater survival rates among these color morphs that are visually easier to pick out," she said.
Lobstermen have brought Cowan countless colorful?lobsters?over the years. The prettiest one, she said, was pink and purple.
Just when financial boffins expected ARM's consistent double-digit growth to slow-down, the company has beaten their projections with a 23 percent rise in pre-tax profit compared to Q2 of last year. It made £66.5 million ($103 million) in profit from £135.5 million ($213 million) in revenue from its numerous mobile and low-power processor design licensees. Analysts expected lower performance for the simple reason that the world's biggest chip-makers have warned of tougher "macroeconomic" times ahead -- rival Intel has been careful to dampen people's hopes for its next quarter, for example, and Qualcomm (a major ARM customer) has also reduced its forecasts. Still, it's all just different shades of rolling in it.
A vernier caliper is a popular instrument used to measure the depth of a hole, inner diameter of a pipe or the outer diameter of a cylindrical or round object. This instrument is very vital in industries and laboratories to give accurate measurement on various objects. Digital calipers or electronic calipers are designed without a graduated measuring scale and are the most modern design of vernier calipers. The digital caliper consists of two lower jaws and two upper jaws. Understanding common guidelines on how to measure the inside of a tube with a digital vernier caliper will be helpful for those who are new to this tool.
1. Preparations prior to making a measurement
(a) Soak a clean cloth with cleaning oil and use it to clean and dry the measuring surface of the item to be measured.
(b) Repeat step ?a? to clean and dry the surface of the instrument cover.
(c) The next step involves loosening the locking key of the instrument.
(d) Clean and dry the lower jaw on the right hand side of the digital caliper as in step ?a? and ?b? above.
(e) Repeat step ?d? on the left hand side lower jaw of the instrument.
(f) Soak a clean cloth with cleaning oil and use it to clean and dry the upper jaw on the right hand side of the instrument.
(g) Repeat step ?f? on the left hand side upper jaw of the instrument.
(h) The next step is to close the instrument and turn ?on/of? button to ascertain whether the reading is zero. This is important to ensure standard calibration prior to taking any measurements. It is also vital to do thorough cleaning to ensure there is no gap between jaws which may cause in accuracies in measurements.
(i) The final step in preparation is checking whether all buttons and the LCD display are working well. This is done by simply moving the sliders.
2. Measuring the inside diameter of a tube
(a) The first step is to insert the upper jaws of the vernier calipers into the hollow surface of the tube.
(b) The second step is to open the upper jaws of the instrument to fit properly on the hollow surface of the tube.
(c) Read the measurement directly from the LCD display.
The main advantages of using digital verneir calipers include;
- The measurements are read directly from the LCD display.
- The measurements can easily be transferred to a computer or special printer using a USB cable.
- It is easy to choose between metric and inch measurement using the button.
- It is easy to take incremental measurements by setting 0 at any position.
In summary this instrument is very efficient when measuring the internal and external diameters of objects.
Adam Harte is a writer who specialises in DIY. You can check out his latest website Digital Vernier Caliper where he provides unbiased advice and reviews on different types of caliper.
HIV suppression not as good as previously thought, largest study of viral-load blood tests show
Monday, July 23, 2012
Tens of thousands of Americans taking potent antiretroviral therapies, or ART, to keep their HIV disease in check may not have as much control over the viral infection as previous estimates have suggested, according to results of a study by AIDS experts at Johns Hopkins and the University of Pennsylvania.
In what is believed to be the largest and longest review of viral load test results in people with HIV disease ever performed in the United States, researchers found that the number of people sustaining viral suppression ? consistently, at 400 or less viral copies per milliliter of blood, year after year ? is roughly 10 percent less than previous estimates. The team's findings are set to appear in the Journal of the American Medical Association online July 25. The publication is timed to coincide with the XIX International AIDS Conference in Washington, D.C.
According to senior study investigator and infectious disease specialist Kelly Gebo, M.D., M.P.H., the team's latest findings underscore just how difficult it is to successfully treat HIV disease and prevent its spread even when people are taking effective ART. Gebo says that "if we are not fully suppressing the virus as much as we thought, then we are not fully preventing and reducing the likelihood of HIV transmission, either." Some 426,000 of the estimated 1.2 million Americans infected with the virus that causes AIDS are taking ART and are under the routine care of a physician.
Gebo says that, overall, while ART has improved significantly within the last decade, with once-a-day pill regimens replacing more complicated, multidrug schedules, "our study findings suggest that physicians and other health care providers still need to do more to promote drug adherence among our patients, and make sure people take their antiretroviral therapies as prescribed."
Without that extra effort, she says, "More people are potentially at risk of becoming infected with HIV, and those already on ART are at risk of developing drug resistance, too." Gebo is an associate professor at the Johns Hopkins University School of Medicine and the University's Bloomberg School of Public Health.
As part of the decade-long study, more than 100,000 individual blood test results were reviewed, all obtained with permission from the medical records of 32,483 infected adults. Seventy percent were men. Everyone prescribed ART had their blood viral levels carefully monitored at more than a dozen established HIV clinics, including the Moore Clinic at The Johns Hopkins Hospital.
Among the study's specific findings was that the percentage of participants who tightly controlled their HIV disease was 72 percent in 2010, the last year for which viral load counts were analyzed. This represented a major increase from 45 percent in 2001, but was significantly less than the 77 percent to 87 percent figures widely cited in 2011 reports from the U.S. Centers for Disease Control and Prevention, and in studies by other leading Hopkins and Canadian researchers.
According to study lead investigator Baligh Yehia, M.D., M.S.H.P., M.P.P., a postdoctoral fellow at the University of Pennsylvania School of Medicine in Philadelphia who trained as a medical resident at Johns Hopkins, all previous reports were based on single-year or one-time-only recordings of blood viral levels, rather than a review of every patient's individual test results from year to year. The latter, he says, is a "more accurate" depiction of people's response to ART over the long term.
Other key findings in the latest report were that younger people, ages 18 to 29; blacks; injection drug users; and those without private health insurance were almost twice as likely as older people; whites; men who have sex with men; and those with private insurance to not have fully suppressed blood viral levels.
"Our data shows that while tremendous strides have been made in sustaining viral suppression, physicians and other HIV care providers need to be more vigilant in monitoring the viral loads in young people, African-Americans, injection drug users and those who lack health insurance," says Yehia.
Gebo and Yehia next plan to use their study data to develop programs for helping people with HIV adhere to therapy and keep routine appointments with their physicians. The team also has plans to interview infected people who consistently adhered to ART and medical care, and those who did not, to better understand the reasons behind successful and failed attempts to sustain and tightly control the disease.
Currently, there are more than 34 million people in the world living with HIV, including an estimated 1,178,000 in the United States and 23,000 in the state of Maryland.
###
Johns Hopkins Medical Institutions: http://www.hopkinsmedicine.org
Thanks to Johns Hopkins Medical Institutions for this article.
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
China is a huge, emerging market for the music industry, but currently in it?s infancy, and still immature. Professional assistance is desperately needed due to crippling discouragement Chinese artists have, attributed to the pervasive downloading of music. There is also a huge lack of ?official? presence for foreign artists who are becoming very popular in China. partly due to the challenges of representing themselves in this daunting market. That means huge opportunity for those willing to support, develop and nurture music in China.
At the end of 2011, Pro Soul Alliance announced a new world class recording and production studio in Beijing as our first step. Now we are offering promotion, marketing, sales and distribution both within China and outside to our existing artists and Chinese artists through our local office in Beijing. Unlike other companies offering music services in China, we are based within China, and our local office is staffed with bilingual locals who know the market and culture, and have experience working with Chinese and international artists here.
Our company has been legally registered as a Wholly Foreign Owned Enterprise in China under the name ????????????????? Which translates to ?Respect Truth (Beijing) Culture Consultancy Co. Ltd.?
Because China is a complex and daunting market for a foreign company, we are starting out with the following basic range of services:
For Chinese artists: - Focusing on getting Chinese artists who are ready exposure internationally
- Getting international distribution and sales for Chinese music (iTunes, Spotify, Nokia) - Promotion and marketing for Chinese artists overseas by connecting with interested markets and fans
For International Artists: - Digital distribution for international artists in China (including essential mobile stores China Mobile, Unicom, Telecom) - Promotion and marketing in China focusing on key social networking sites like Weibo, Douban, Youku - Collaboration with Chinese artists and recording traditional Chinese instruments with local professionals
As we continue researching the industry and experimenting with new techniques for promotion and marketing music in China, we will also be offering licensing for Chinese music internationally in Film, TV, and online, expanding their revenue sources. We will also assist Chinese artists who are ready to create their own business and develop music career in China to maximize their profit and control. Of course we will also be able to assist international artists book shows and organize tours in China in future.
We have already begun assisting international artists Elika Mahony, and Hart as well as Chinese artist Abominati get exposure in China.
You can sign up right now for promotion, marketing and distribution in China with the ?Professional Artist Management and Consulting Asia? option on the Get Started section of our website at www.prosoul.com. For artists within China, we have a new website in Chinese with a helpful blog focused on the local market.
For more information, please contact our China artist services manager BeiBei Lei: yinyue@prosoul.com
http://www.prosoul.com/
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Thematic Study Report on Production, Consumption and Circulation of China?s Rice by Provinces
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If you can, check into windows for your home that are energy-efficient. Windows with a better seal will reduce your energy bills, keep road noise out of your house, and limit window condensation.
Use rechargeable batteries instead of disposable ones. Throwing away batteries can result in serious environmental damage. Using rechargeable batteries saves you money on batteries and reduces their environmental impact. Rechargeable batteries will end up saving you hundreds of bucks over their lifetime.
You can cut your energy consumption by a lot if you just cut back on the electricity you use. Unplug appliances whenever you are not going to be using them for awhile. Try turning off the TV and lights when they're not in use. This simple tip will save you money as well.
Your green living journey can start with major home improvements, or it can start with something as easy as using light bulbs that are energy-efficient. Several small projects that you can easily do yourself can add up to saving a lot of energy, with the bonus of saving money on your utility bills. Choose one of these small projects and get started right now!
You can increase the energy efficiency of your home with proper weatherization procedures. You can seal ducts, add in insulation, and put in new windows and cooling systems that are energy efficient so that you can reduce the energy it takes to operate your home. By making these changes, you will make your home more energy-efficient, thereby, saving money on your utility bills.
Spending a little more on green appliances and electronics generally pays off over time. Even though green technology may be costlier, it pays off in the long run when you see cheaper utility bills. It will also pay off in the long run for the environment.
Replace your older appliances with the newer, energy-efficient ones that have Energy Star ratings. To receive an Energy Star rating from the government, appliances must meet minimum efficiency standards, unlike the non-rated appliances you may currently own. Fridges and freezers with the rating use at least 20% less energy, dishwashers use 40% less, and washing machines use at least half the energy of non-rated models.
There are active and passive options for solar energy systems. Passive power is used immediately and is cheaper, but active power has the ability to store energy for later use. Active systems are what you would normally think of when you think of solar--PV cells, mechanical parts, and storage devices. Passive solar power is simply making use of the sun to keep thermal energy in your walls so you can heat your home.
A lot of people think about utilizing green energy; however, there are very few who make an effort to figure out how to incorporate it into their lives. This article gave lots of ideas to begin with, so you can live green for very little money and time.
http://www.SIHomeTours.com Currently Rented ? TBA written details to follow, check back soon! Real Estate for sale in Carbondale, IL Alpha Property Management
http://www.SIHomeTours.com Currently Rented ? TBA written details to follow, check back soon! Real Estate for sale in Carbondale, IL Alpha Property Management
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Key mutations discovered for most common childhood brain cancerPublic release date: 22-Jul-2012 [ | E-mail | Share ]
Contact: Meghan Weber meghan.weber@childrens.harvard.edu 617-919-3110 Children's Hospital Boston
Findings could enable individualized treatment for patients with medulloblastoma
Boston, Mass., July 22, 2012 Researchers at Dana-Farber/Children's Hospital Cancer Center (DF/CHCC) and several collaborating institutions have linked mutations in specific genes to each of the four recognized subtypes of medulloblastoma, the most common malignant brain tumor of children. The discovery, reported July in the journal Nature, provides doctors with potential biomarkers for guiding and individualizing treatment and reveals prospective therapeutic opportunities for countering this devastating malignancy.
The study was conducted by a research team led by Scott Pomeroy, MD, PhD, Neurologist-in-Chief at Boston Children's Hospital and a neuro-oncologist at DF/CHCC; Yoon-Jae Cho, MD, formerly of Boston Children's and now at Stanford University School of Medicine; and Matthew Meyerson, MD, PhD, of Dana-Farber Cancer Institute and the Broad Institute.
Medulloblastomas occur in the cerebellum (the part of the brain that controls balance and other complex motor functions) and are treated with a combination of surgery, radiation and chemotherapy. Though overall survival hovers around 70 percent, most survivors are unable to live independently due to the lasting effects of both tumor and treatment.
Doctors have historically classified medulloblastoma patients as either standard or high risk based on biopsy results, but have long suspected that what we call medulloblastoma could actually be several different diseases. Over the last two years, studies by researchers including Pomeroy and his colleagues have bolstered this view by dividing medulloblastoma into four molecular subtypes based on gene expression profiles and copy number variations. Each subtype has a distinct survival rate, ranging from 20 to 90 percent.
"Not only do we now know how to stratify medulloblastomas genomically, we have a firm grasp of what gene mutations drive each molecular subtype," said Pomeroy, who has spent 20 years trying to understand the biological basis of the tumor's variability. "For the first time, we'll be able to classify and treat medulloblastoma based on molecular typing, providing the best therapy with the fewest long-term consequences."
In this new study, Pomeroy and his team used next generation sequencing technologies to read the full complement of protein-coding genes (also called the exome) of tumors from 92 patients. Within these tumors the team discovered that somatic (that is, non-heritable) mutations occur at very low frequency, one-tenth to one-hundredth of that seen in cancers of adults. Specific gene mutations clustered neatly into the four molecular subtypes, although the majority of genes (88%) were mutated only once in the entire tumor collection. Only 12 genes were mutated in more than one tumor, illustrating medulloblastoma's genetic heterogeneity.
Functionally, the mutated genes fell into two broad categories: genes like Shh and Wnt that play direct roles in molecular pathways controlling cell growth, and genes like DDX3X and GPS2 that play more of a coaching role, modulating the activity of other genes.
Taken as a whole, the study's results confirm the view of medulloblastoma as a family of tumors driven by disruptions in just a few common mechanisms. However, the form those disruptions takethe actual mutations or genomic changescan vary from tumor to tumor.
"The results reflect two emerging genetic themes seen throughout childhood tumors," Pomeroy noted. "First, very low mutation rates, much lower than those seen in adult tumors, and second, the importance of mutations in genes that regulate the function of the cell's growth pathways but which aren't direct components of those pathways."
Some of the study's findings could be translated to patients relatively quickly. For instance, with the main mutations of each subtype in hand, it should soon be possible to rapidly classify individual medulloblastoma patients' tumors and tailor treatment appropriately based on each subtype's known prognosis. In addition, clinical trials of Shh-blocking drugs already under investigation for other cancers could begin within the next couple of years in patients with the medulloblastoma subtype driven by Shh mutations.
Pomeroy credits the high level of cooperation between groups at different institutions studying medulloblastoma as a significant factor in the progress made over the last few years. "Because of our collective efforts, medulloblastoma has gone from an important but obscure tumor to one that we understand better than many other cancers at the molecular level."
###
The study was supported by the National Human Genome Research Institute (grant number U54HG003067), the National Cancer Institute (grant numbers R01CA109467, R01CA105607, R01CA030002, R01CA050661, R01CA154480 and R01CA148699), the National Institute of Neurological Disorders and Stroke (grant numbers R01NS046789 and R25NS070682, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number P30HD18655) the Canadian Institutes of Health, German Cancer Aid, St. Baldrick's Foundation, the Mullarkey Research Fund, the Pediatric Brain Tumor Foundation and the Howard Hughes Medical Institute.
Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's, visit: http://vectorblog.org/.
About Dana-Farber/Children's Hospital Cancer Center
Dana-Farber/Children's Hospital Cancer Center (DF/CHCC) combines the strengths of Dana-Farber Cancer Institute, a world-class cancer institute, and Boston Children's Hospital, an internationally known pediatric hospital. For over 60 years, these two Harvard Medical School affiliates have provided comprehensive care for children and adolescents with cancer. Committed to conducting research to better understand and treat childhood cancers, DF/CHCC is the Children's Oncology Group's only Phase I Clinical Trial site in New England, is a founding member site of the Pediatric Brain Tumor Consortium and is home to one of the world's most sophisticated and accomplished Pediatric Stem Cell Transplantation centers. DF/CHCC also offers comprehensive transitional and long-term survivorship programs to childhood cancer survivors of all ages.
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Key mutations discovered for most common childhood brain cancerPublic release date: 22-Jul-2012 [ | E-mail | Share ]
Contact: Meghan Weber meghan.weber@childrens.harvard.edu 617-919-3110 Children's Hospital Boston
Findings could enable individualized treatment for patients with medulloblastoma
Boston, Mass., July 22, 2012 Researchers at Dana-Farber/Children's Hospital Cancer Center (DF/CHCC) and several collaborating institutions have linked mutations in specific genes to each of the four recognized subtypes of medulloblastoma, the most common malignant brain tumor of children. The discovery, reported July in the journal Nature, provides doctors with potential biomarkers for guiding and individualizing treatment and reveals prospective therapeutic opportunities for countering this devastating malignancy.
The study was conducted by a research team led by Scott Pomeroy, MD, PhD, Neurologist-in-Chief at Boston Children's Hospital and a neuro-oncologist at DF/CHCC; Yoon-Jae Cho, MD, formerly of Boston Children's and now at Stanford University School of Medicine; and Matthew Meyerson, MD, PhD, of Dana-Farber Cancer Institute and the Broad Institute.
Medulloblastomas occur in the cerebellum (the part of the brain that controls balance and other complex motor functions) and are treated with a combination of surgery, radiation and chemotherapy. Though overall survival hovers around 70 percent, most survivors are unable to live independently due to the lasting effects of both tumor and treatment.
Doctors have historically classified medulloblastoma patients as either standard or high risk based on biopsy results, but have long suspected that what we call medulloblastoma could actually be several different diseases. Over the last two years, studies by researchers including Pomeroy and his colleagues have bolstered this view by dividing medulloblastoma into four molecular subtypes based on gene expression profiles and copy number variations. Each subtype has a distinct survival rate, ranging from 20 to 90 percent.
"Not only do we now know how to stratify medulloblastomas genomically, we have a firm grasp of what gene mutations drive each molecular subtype," said Pomeroy, who has spent 20 years trying to understand the biological basis of the tumor's variability. "For the first time, we'll be able to classify and treat medulloblastoma based on molecular typing, providing the best therapy with the fewest long-term consequences."
In this new study, Pomeroy and his team used next generation sequencing technologies to read the full complement of protein-coding genes (also called the exome) of tumors from 92 patients. Within these tumors the team discovered that somatic (that is, non-heritable) mutations occur at very low frequency, one-tenth to one-hundredth of that seen in cancers of adults. Specific gene mutations clustered neatly into the four molecular subtypes, although the majority of genes (88%) were mutated only once in the entire tumor collection. Only 12 genes were mutated in more than one tumor, illustrating medulloblastoma's genetic heterogeneity.
Functionally, the mutated genes fell into two broad categories: genes like Shh and Wnt that play direct roles in molecular pathways controlling cell growth, and genes like DDX3X and GPS2 that play more of a coaching role, modulating the activity of other genes.
Taken as a whole, the study's results confirm the view of medulloblastoma as a family of tumors driven by disruptions in just a few common mechanisms. However, the form those disruptions takethe actual mutations or genomic changescan vary from tumor to tumor.
"The results reflect two emerging genetic themes seen throughout childhood tumors," Pomeroy noted. "First, very low mutation rates, much lower than those seen in adult tumors, and second, the importance of mutations in genes that regulate the function of the cell's growth pathways but which aren't direct components of those pathways."
Some of the study's findings could be translated to patients relatively quickly. For instance, with the main mutations of each subtype in hand, it should soon be possible to rapidly classify individual medulloblastoma patients' tumors and tailor treatment appropriately based on each subtype's known prognosis. In addition, clinical trials of Shh-blocking drugs already under investigation for other cancers could begin within the next couple of years in patients with the medulloblastoma subtype driven by Shh mutations.
Pomeroy credits the high level of cooperation between groups at different institutions studying medulloblastoma as a significant factor in the progress made over the last few years. "Because of our collective efforts, medulloblastoma has gone from an important but obscure tumor to one that we understand better than many other cancers at the molecular level."
###
The study was supported by the National Human Genome Research Institute (grant number U54HG003067), the National Cancer Institute (grant numbers R01CA109467, R01CA105607, R01CA030002, R01CA050661, R01CA154480 and R01CA148699), the National Institute of Neurological Disorders and Stroke (grant numbers R01NS046789 and R25NS070682, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number P30HD18655) the Canadian Institutes of Health, German Cancer Aid, St. Baldrick's Foundation, the Mullarkey Research Fund, the Pediatric Brain Tumor Foundation and the Howard Hughes Medical Institute.
Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's, visit: http://vectorblog.org/.
About Dana-Farber/Children's Hospital Cancer Center
Dana-Farber/Children's Hospital Cancer Center (DF/CHCC) combines the strengths of Dana-Farber Cancer Institute, a world-class cancer institute, and Boston Children's Hospital, an internationally known pediatric hospital. For over 60 years, these two Harvard Medical School affiliates have provided comprehensive care for children and adolescents with cancer. Committed to conducting research to better understand and treat childhood cancers, DF/CHCC is the Children's Oncology Group's only Phase I Clinical Trial site in New England, is a founding member site of the Pediatric Brain Tumor Consortium and is home to one of the world's most sophisticated and accomplished Pediatric Stem Cell Transplantation centers. DF/CHCC also offers comprehensive transitional and long-term survivorship programs to childhood cancer survivors of all ages.
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Public release date: 22-Jul-2012
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