P53 mutation hinders cancer treatment response

Jan. 25, 2013 ? Scientists from the National Cancer Centre Singapore (NCCS) have discovered the workings of the gene that has been hindering treatment response in cancer patients. This discovery was made after 5 years of studying the mutant form of the p53 gene, the major tumor suppressor in humans, which is generally found mutated in over 50% of all type of human cancers.

The dominant-negative (DN) effect of the mutant p53 gene in cancers was found to affect the outcome of cancer treatment modalities. DN effect is a phenomenon whereby one copy of mutant p53 that exists in cancer cells inhibits the tumor suppressor activity of the other wild-type p53 copy when they co-exist. The result is that a patient may either have poor response or earlier relapse of tumours after their treatment.

The research findings is significant in that it offers hope to improve cancer treatment outcomes by selectively inhibiting mutant p53's DN effect through several methods by generating selective and specific inhibitory molecules specific for some of the common hot-spot p53 point mutations. There are currently no drugs or compounds that can alleviate DN effects of mutant p53.

In order to understand the specific roles of mutant p53 DN properties in regulating acute treatment response and long-term tumourgenesis, a team of five researchers led by NCCS Prof Kanaga Sabapathy, the Principal Investigator in the Laboratory of Carcinogenesis and Head of the Division of Cellular & Molecular Research from NCCS, carried out experiments by generating genetically engineered knock-in mouse strains expressing varying levels of mutant p53. The results showed that DN effect is observed after acute p53 activation by a variety of chemotherapeutic drugs and irradiation, thereby affecting anti-cancer treatment. This breakthrough came after five years of intensive research.

It was found that mutant p53 have DN effects in a cell-type and dose-dependent manner, especially during acute p53 activation where p53 levels are elevated. Based on the above observations, efforts to generate specific inhibitors for the common hot spot p53 point mutations are underway. The inhibition of mutant p53 expression in cells carrying a wild-type and mutant p53 alleles can improve response to chemotherapeutic drugs.

In a further study, the researchers also questioned the possibility of the mutant p53 acquiring new functions (or Gain of Function) to drive carcinogenesis, transforming normal cells to cancerous cells. Their investigation comparing cells from genetically engineered mouse strains expressing 2 different types of p53 mutations: the R172H mutation versus the R246S mutation, which showed that Gain of Function (GOF) was found only in the former. This showed that GOF of mutated p53 is specifically dependent on mutation-type but not across all kinds of genetic mutations, highlighting diversity in properties of the different types of p53 mutations, thereby indicating that mutations found in human cancers can behave differently, and thus, need to be carefully assessed prior to treatment.

Thus, the existence of mutant p53 certainly has a negative impact on cancer treatment, whether it is through DN effect or GOF. Prof Sabapathy said that the team is now embarking on more research to determine the possibility of targeting mutant p53 without affecting wild-type p53 in human cells, paving way to clinical trials in the future to test the efficacy on cancer therapeutic response.

The research was supported by grants from the National Medical Research Council of Singapore and the Singapore Millennium Foundation to KS. The publication has been accepted and published by Cell Press, publisher of biomedical journals, in the journal Cancer Cell, on Dec. 10, 2012. Prof Sabapathy also teaches at the Duke-NUS Graduate Medical School.

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The above story is reprinted from materials provided by SingHealth, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Ming?Kei Lee, Wei?Wei Teoh, Beng?Hooi Phang, Wei?Min Tong, Zhao?Qi Wang, Kanaga Sabapathy. Cell-type, Dose, and Mutation-type Specificity Dictate Mutant p53 Functions In?Vivo. Cancer Cell, 2012; 22 (6): 751 DOI: 10.1016/j.ccr.2012.10.022

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/most_popular/~3/EAuE68IgufU/130125111331.htm

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New Treatments for Age Old Wrinkle Problems - Anti-Aging

In the last 20 years our approach to the signs of facial ageing has come a long way. There was a time when good skincare meant buying a decent moisturiser and using it twice a day. This is still important and a vital foundation. However, there are many more sophisticated options for beating those unwelcome lines and wrinkles, as well as tackling ageing hyperpigmentation, poor skin condition and sun damage. These solutions are so effective that they have become relatively commonplace and a popular part of many women, and men's skincare regimes.

Article by Health-and-Fitness:Anti-Aging Articles from EzineArticles.com (c) Health-and-Fitness:Anti-Aging Articles from EzineArticles.com - Read full story here.

Source: http://anti-aging.fitnessthroughfasting.com/anti-aging/new-treatments-for-age-old-wrinkle-problems.php

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Kate Hudson & Matt Bellamy Look Cozy & Cute!

Kate Hudson and Matt Bellamy step out in Santa Monica! Check out more pics of Hollywood's tightest twosomes

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Video: Study: smokers have shorter life expectancy than nonsmokers

>>> and good news and bad news on the smoking front. from the "new england journal of med sichb," they state flat out, smokers lose at least one decade of life expectancy over nonsmokers on average. the encouraging news here is quitting before 40 reduces the smoking-related death risk by 90% compared to continuing on as a smoker.

Source: http://video.msnbc.msn.com/nightly-news/50567471/

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Q&A: Obama lacks clear edge in next fight with GOP

WASHINGTON (AP) -- President Barack Obama had a clear political edge in his fight with Republicans over the fiscal cliff, and used it to his advantage. In the upcoming battle over federal borrowing and spending, the leverage will be more evenly divided and the outcome less predictable.

In the fiscal cliff fight, Obama wanted to block automatic New Year's Day tax increases on everyone but the country's highest earners. Republicans were trying to protect upper-income people from those tax hikes, but eventually gave in because they didn't want to be blamed for the higher middle-class taxes that a stalemate would have triggered.

Next come three deadlines that will almost certainly become entwined.

The government will run out of cash in about two months. The Obama administration will need congressional approval to borrow more money or face a first-ever federal default, threatening global, economy-rattling consequences.

House Speaker John Boehner, R-Ohio, and Senate Minority Leader Mitch McConnell, R-Ky., have said they won't agree to a debt-limit extension without an accord to cut spending. Just as adamantly, Obama says the government's debt ceiling must be raised and he won't negotiate over it, though he says he would bargain over spending cuts and tax increases to reduce federal deficits.

At around the same time, automatic cuts to defense and domestic programs are due to begin after winning a two-month reprieve in the fiscal cliff deal. And in late March, money financing federal agencies expires and new legislation will be needed to prevent a government shutdown. Republicans are sure to use both those measures to try forcing Obama to accept more spending cuts.

Here's a look at the political pressures each side brings to the battle.

Q: Would Republicans or Democrats really force a federal default just to get their way in a fight over spending?

A: Most wouldn't and it seems unlikely. But they came close two years ago.

As the government neared its debt ceiling in the summer of 2011, the two sides battled to the brink. They finally agreed to about $1 trillion in 10-year spending cuts and created a congressional "supercommittee" to find an additional $1.2 trillion in deficit reduction. The panel produced nothing, triggering a like amount in automatic, across-the-board cuts that Obama and many lawmakers are still trying to find a way to skirt.

That 2011 fight created plenty of worry that the White House and congressional Republicans could become so deadlocked and adamant that they would plunge the government into default. That concern hasn't receded, especially with a fresh infusion of conservative Republicans to join the GOP's tea party-powered 2010 freshman class. That group has proved hard for party leaders, especially Boehner, to control.

This time, many in Washington see threatening default as an empty tactic. The potential consequences are too dangerous, including higher interest rates and tighter credit that would wound the economy and make it costlier for the government to borrow money for a long time.

Q: Then what's the problem?

A: Both sides have reason to think the other will have to cave in. And each has core supporters insisting that this time, their leaders must not yield.

Conservatives angry over the New Year's Day fiscal cliff deal, which boosted income taxes on top earners, want the GOP to block further tax increases and force deep spending cuts, including on costly federal benefit programs like Medicare. Liberals eager to cash in on Obama's re-election say it's time to push hard for his agenda of protecting federal programs and to raise taxes on the wealthiest Americans even more.

Q: What leverage does Obama have?

A: Far more than in the 2011 debt limit fight.

Back then, Obama was worrying about getting re-elected in 2012 and had no interest in a stalemate that could destabilize an already frail economy. Republicans had high hopes of capturing the Senate, hopes that might be enhanced if the economy weakened further. And Boehner's new House majority had momentum and was throwing its weight around.

Yet when the smoke lifted from that fight, polls showed the public largely unhappy with Republicans, considering them too inflexible. Now, Democrats are on offense following Obama's re-election, Democratic gains in the House and Senate and an economy that continues gathering strength, though slowly.

Also helping Obama: The fiscal cliff fight left the GOP divided and Boehner weakened. Most Senate Republicans backed the final compromise between McConnell and Vice President Joe Biden while most House Republicans defied Boehner and opposed it, raising questions about his effectiveness in leading them this year. In addition, the business community, an influential contributor and constituent of the GOP, strongly opposes a federal default. Powerful groups like the U.S. Chamber of Commerce are already making it clear to both parties that lawmakers must raise the debt ceiling, and Democrats think that pressure will be felt by Republicans.

Q: What makes Republicans think they can prevail?

A: They are united around the goal of shrinking the budget. Insisting on spending cuts in return for a debt limit extension is exactly what the GOP wants to make the upcoming fight about. Polling suggests that on those issues, voters seem more inclined to back Republicans. Surveys show most people don't like the idea of extending the government's borrowing limit and back the concept of cutting federal spending, at least until specific programs are targeted.

In addition, after the 2011 debt limit fight, Standard & Poor's downgraded the nation's credit rating for the first time and indicated it might do the same if lawmakers didn't find additional deficit reduction. Republicans say this puts further pressure on Obama to yield.

Q: What about the fights over preventing budget-wide spending cuts or a government shutdown?

A: Both parties think those two prospects will prompt a search for savings that will eventually be tied to raising the $16.4 trillion ceiling on government debt.

GOP lawmakers are trying to create leverage by saying that unless there's a deficit-reduction deal, they're willing to partly shut down the government and live with the automatic spending cuts ? which are divided evenly between defense and domestic programs. They interpret the fiscal cliff deal as setting a final figure for new tax revenues and say the focus should be put back on spending cuts.

Democrats believe a federal shutdown would hurt Republicans politically, as it did in the 1990s when the GOP Congress battled President Bill Clinton. Obama insists that additional spending cuts must be coupled with higher taxes on corporations and wealthy Americans to produce a "balanced" package. Polling showed the public backed him when he sought higher taxes on the wealthy in the fiscal cliff fight.

Source: http://news.yahoo.com/q-obama-lacks-clear-edge-192040164.html

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All-Central Florida football: Apopka, Dr. Phillips standouts are Players of Year

Zack Darlington and Matt Milano rarely have spoken to each other, but they respect what the other can do on the football field.

They were not the only ones.

Darlington, Apopka's junior quarterback, is the All-Central Florida Offensive Player of the Year after emerging during the playoffs to lead the Blue Darters to the Class 8A state championship.

Milano, a senior safety for Dr. Phillips, is the area's Defensive Player of the Year. He led Central Florida's top-ranked defense and is committed to sign with Boston College.

"He plays with heart," Darlington said of Milano. "You can tell he gives everything on every play. I couldn't even give a handoff without him being in the backfield. He is the best player we played against."

Milano said of Darlington: "He is trying to win every play. That is what makes him a great player. He never gives up. You can say he has the will to be the best."

They faced each other twice this season, in a season opener and a state semifinal.

Darlington (6-1, 190), who injured his right wrist during a second-round playoff game against Timber Creek and missed four regular-season games with a sprained right ankle, threw for 1,725 yards and 19 touchdowns ? 11 of which came during the playoffs. He also rushed for 708 yards and 10 touchdowns.

Darlington did not miss any games because of the wrist injury.

Milano (6-0, 200) led a Dr Phillips team whose strength was its defense. He had 100 tackles, including 18 for loss, and three sacks.

"[Zack] did a great job of staying in the pocket," said Rick Darlington, Apopka's coach and Zack's father. "He looked very calm with people all around him. Add that to the fact he is a legitimate running threat.

"If he wasn't injured, he would have rushed for 1,000 yards and passed for 2,000 yards. We have never had that."

Some of Milano's best performances came during the playoffs. On the first defensive series of the first playoff game against Tampa Wharton, Milano stepped in front of a pass, intercepted it and returned it 23 yards.

On the next play, Eric Harrell scored on a 5-yard run.

Milano had two interceptions in that game, which DP won 28-15.

"That pick stands out in my mind," Milano said. "That set the tone for us for that game, and maybe for the playoffs.

"As with any team, it was our goal to make it to the state championship game. We came close. We made it to the state semifinal and lost to a really good team that won the state championship. I have no regrets."

Darlington's emergence as a state-champion quarterback didn't seem like it would happen when he was 10 years old and playing Pop Warner football. He was moved to wingback because he couldn't throw a football.

That changed by the time he reached eighth grade. After watching hours of videos, working with his father and growing 11 inches in three years, he moved to quarterback.

"God blessed me with a season I could not have dreamed about,'' Darlington said.

jrwilliams@tribune.com or 352-742-5921

Source: http://www.orlandosentinel.com/sports/highschool/os-hs-all-central-florida-players-of-year-20130112,0,6770635.story?track=rss

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Eliteratur-Blog ? Blog Archive ? Sales Training What it Really Takes ...

Sales Training ? What it Really Involves to Effectively Train Sales Representatives

Is your current sales training program teaching your workforce to be unsuccessful? While it is really not the intention of your sales training program, lots of companies are a failure in working on the correct skill sets needed by sales individuals in order to achieve exceptional sales results.

Useful sales training programs deal with the main sales steps, but also lay emphasis on the importance of the sales individual?s attitudes, behaviors, and techniques. Other than the original training presented, reliable sales firms provide continuing strengthening of these standards and strategies through coaching and support.

What it Requires to Successfully Train Salespeople

Regrettably, there aren?t any easy fixes around to make improvements to sales productivity overnight. Enhancing your company?s sales performance calls for a modification in behaviours, and it requires a sizable investment from all of the stakeholders. Getting your business prepared to put together this investment is a three step endeavor:

. Step 1: Obtain the commitment within your over-all management team. Without having this commitment, changes to your existing sales training program are going to be ineffective. Everybody, from the top of the business downward, has to be committed to creating adjustments. In order to secure commitment, invest some time teaching the over-all management group with regards to the need for the modification, who?s going to be involved in executing the transformation, and ways in which these transformations are going to impact the profits of the firm. When your team has obtained a solid idea of the new programs being put in place, they need to be promoted across the firm. And, when the latest sales training in Overland Park has been applied, efforts to fortify the new principles must be carried out in order to make sure that new habits are establishing themselves.

. Step 2: After you have obtained the commitment of your management team, you will need to secure commitment from your sales staff. Many sales programs do not succeed due to a seen limited management buy-in in the eyes of the marketing and sales staff. It is why Step One is to focus on management initially. So as to achieve success, management has to invest the required energy, time and financial resources into the financial success of the program. As soon as the sales force perceives the level of commitment to the program, they are going to buy-in.

. Step 3: Once the brand new sales training program has been put into practice, a plan to deliver ongoing help and reinforcement needs to launch. Adjustments to procedures don?t deliver instant results. Ongoing refresher training has to be offered! Role-playing or practice routines offer sales persons the opportunity to put into practice what they have been taught. And, integrated recognition programs reward the sales persons achieving good results with the use of the new systems. Each one of these efforts help place overall attention upon the long life of the program.

The level of sales performance being accomplished is frequently a direct reflection of the sales training being given. In order to improve your organization?s sales productivity, you need to be prepared to dedicate the time, resources, and energy to make basic changes in your sales training program.

If you are looking for exceptional sales training in Kansas City or somebody to take care of your sales techniques in Kansas City then this sales training company really should be your very first call.

Source: http://www.eliteratur-blog.de/2013/01/sales-training-what-it-really-takes-to-effectively-train-sales-people/

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