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Filed under: Economy, Foreign Policy, Israel, Middle East, National Security, Progressivism | Tags: The "Peace Process", The State of Israel, U.S. Foreign Policy
Barack Obama's first trip to Israel as President of the United States started off with the presidential limousine breaking down because his people put the wrong fuel in it. A metaphor? Probably.
Mr. Obama has long-expected one of his signature achievements as president would be producing peace in the Middle East by bringing the "peace process" to a satisfactory conclusion. He has believed the Israeli-Palestinian conflict to be the cause of all Middle East problems, and he would just demand they sit down and talk.
Obama had some nice words in a speech to the Israeli people, then talked down to them. Then he had the extraordinarily bad judgment to give a speech in Ramallah on the West Bank, in front of a gigantic banner of Yassir Arafat, He actually said this:
I think it's important for us to work through this [peace] process, even if there are irritants on both sides. The Israelis have concerns about rockets flying into their cities last night. And it would be easy for them to say, you see, this is why we can't have peace because we can't afford to have our kids in beds sleeping and suddenly a rocket comes through the roof. But my argument is even though both sides may have areas of strong disagreement [sic], may be engaging in activities that the other side considers to be a breach of good faith [sic], we have to push through those things to try to get to an agreement — because if we get an agreement then it will be very clear what the nature of that agreement is: There will be a sovereign Palestinian state, a sovereign Jewish State of Israel.
And those two states I think will be able to deal with each other the same way all states do. I mean, the United States and Canada has [sic] arguments once in a while, but they're not the nature of arguments that can't be solved diplomatically. And I think we can keep pushing through some of these problems and make sure that we don't use them as an excuse not to do anything.
Can he possibly believe that the problems between Israel and the Palestinians is in any way similar to our arguments with Canada? His arguments with Stephen Harper over the Keystone XL must have been far more acrimonious than we knew. Talk about trivializing murder! The Palestinians bring up their children to be terrorists, extolling being a suicide bomber.
Israel's demands have always been simple. Stop shooting rockets at us, and recognize the Israeli's right to their own state. Obama added:
[T]he United States remains committed to realizing the vision of two states, which is in the interests of the Palestinian people, and also in the national security interest of Israel, the United States, and the world. We seek an independent, a viable and contiguous Palestinian state as the homeland of the Palestinian people, alongside the Jewish State of Israel — two nations enjoying self-determination, security and peace.
A viable and contiguous Palestinian state? There is no peace process. And the troubles between Israel and the Palestinians is not the reason for conflict in the Middle East. I heard on the radio that some 30 percent of Palestinians would prefer to live in Israel.
The State Department announced that they will unblock $500 million in aid to the Palestinian Authority. Congress froze funding for the Palestinian Authority in the wake of the PA's attempt to unilaterally declare statehood via the United Nations. Despite President Obama's request to PA President Mahmoud Abbas not to go to the International Criminal Court to seek sanctions against Israel, Abbas, now in the ninth year of his four-year term, had vowed to do so.
Filed under: Capitalism, Economy, Education, Energy, Israel, Middle East, Terrorism | Tags: Mitt Romney's "Gaffes", Only in the Liberal Media, The State of Israel
The marvelous Michael Ramirez tells the story better in one perfect cartoon than I do in a whole column. See all his work at Investors.com. (Click to enlarge)
Mitt Romney, according to the liberal media, committed a horrible gaffe last week in Jerusalem by commenting on the relation of culture to Israeli economic growth. Saeb Erekat, correctly understanding an implied criticism of Palestinian culture, called Mr. Romney a "racist" and complained that Palestinian economic problems were due to the Israeli occupation. Liberal analysts were quick to jump in to explain that Mr. Erekat's words meant that Mr. Romney. has disqualified himself as a broker for peace.
There's perennial argument buried in there, economists argue about whether development is caused by cultural advantages or by natural advantages like access to primary resources and resistance to disease. If economists has a sure recipe for economic advancement, we'd all be more advanced than we are, and economists wouldn't have as much to argue about.
Israel is an interesting case. A tiny country with no natural resources was an economic backwater even in the says of the Ottoman Empire. It became a highly developed nation on culture alone. As Todd G. Bucholtz wrote once in the Wall Street Journal:
And then there is Israel today. It may be settled by God's chosen people, but He chose not to give them a drop of oil while gushers sprout across Arabia. And its terrain doesn't naturally grow enough green for a sprig of parsley on your dinner plate. Yet the land blooms. In the race for development would you rather bet on a country with tons of zinc or one with a couple of extra IQ points and a free flow of ideas?
The influence of plentiful oil did not change the nature of Arab economies. It did not fuel economic development that benefited all, but led to crowded cities. The oil rich economies of Libya and Iraq have social structures much like oil-lacking Egypt and Syria. Change is feared, and the culture is authoritative. But Arab populations have grown and prospered where Jews settled — in Jerusalem, Tel Aviv, Hebron, and remained stagnant where they didn't. The Palestinian population is among the best-educated and most competent in the Arab world, and under Israeli rule (the hated occupation) the West Bank was one of the 10 fastest growing economies in the world in the 1980s.
Many Palestinians regard Jewish economic leadership as an attack on their pride. Their situation might be far different if they quit firing missiles into Israel, and concentrated on their own development. When liberal reporters and analysts denounce Mr. Romney for his "gaffe, they should recognize there are Palestinian entrepreneurs who wept when Yasser Arafat rejected Israel's peace offer at Camp David in 2000, and who know the costs to their peoples of politicians intransigence.
They would do far better to recognize the dishonest response of Mr. Erekat, and stand up for their own country instead of trying to create controversy.
The culture in Israel, that free flow of ideas and entrepreneurial spirit, has discovered vast new deposits of natural gas off their coast, developed a thriving high-tech industry, and has much to offer their neighbors.
Filed under: Foreign Policy, Freedom, History, Israel | Tags: Mitt Romney, The Obama Administration, The State of Israel
Mitt Romney was just in Israel, and in a speech said he was happy to be in the capital city of Israel, Jerusalem. This is notable because Jay Carney, hapless press secretary, twisted himself into knots recently to avoid admitting that Jerusalem was the capital of Israel. A witless representative of the State Department actually said that it was to be determined by negotiation. Just stop it. You are embarrassing us.
Israel is a sovereign state. Jerusalem is not only its historic capital, Israel says that Jerusalem is its capital. They are the only ones who get to decide. It's their country.
The United States does not get to decide what is the capital of Israel. Jay Carney does not get to decide. President Barack Obama does not get to decide. Secretary of State Hillary Clinton does not get to decide, and the witless State Department woman does not get to decide. And stateless Palestinians don't get to decide. If they can stop shooting rockets and trying to kill people, they might someday get their own state.
Washington DC is the capital of the United States. If the Congress of the United States should decide, with the approval of the people, that we should move the capital to Plato, Missouri (which is the population center of the country) — then that would be the capital — but for the present, it remains in Washington DC, where Congress decided to put it, back in July, 1790.
It's all really very simple. Can we stop being stupid.
Filed under: Freedom, History, Israel, Middle East, United Nations | Tags: History, The State of Israel, There Is No State of Palestine
Filed under: Foreign Policy, Freedom, Israel, National Security, The United States | Tags: American Foreign Policy, Michelle Bachmann, The State of Israel
Michelle Bachmann has been a long-time and consistent supporter of the State of Israel. It is refreshing to see an American politician, and presidential candidate, take a firm stand in supporting our allies. These Republican women are a force to be reckoned with. Brains, beauty, loyalty, common sense and clarity.
(h/t: Powerline)
Filed under: Foreign Policy, Freedom, Israel, Middle East | Tags: Peace in the Middle East, Prime Minister Benjamin Netanyahu, The State of Israel
Israeli Prime Minister Benjamin Netanyahu gave a magnificent speech before a truly supportive joint session of Congress this afternoon. It is an excellent speech, the text is here. One very memorable passage:
Of the 300 million Arabs in the Middle East and North Africa, only Israel's Arab citizens enjoy real democratic rights. Now, I want you to stop for a second and think about that. Of those 300 million Arabs, less than one-half of one percent are truly free and they're all citizens of Israel. This startling fact reveals a basic truth: Israel is not what is wrong with about the Middle East, Israel is what is right about the Middle East.


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8 Essential Design Tools For UX Newbies to Make Work Easier
As a UX designer, we will need to get familiar with the essentials of user experience, from user research to wireframing to collaboration to designing a final product. In this post I'm going to cover the UX design tools you'll need for every aspect of your work as a UX designer, from beginning to end. Hopefully, it will simplify the way you work and make your lifer easier.
User Research
User Research focuses on understanding user behaviors, needs, and motivations through observation techniques, task analysis, and other feedback methodologies.
Surveys and questionnaires are great ways to gather information.
Survey Tool: SurveyMonkey
SurveyMonkey is one of the best provider of survey software. There is a free version available with limitations, but the free version is still a very handy tool and allows up to 10 questions per survey. SurveyMonkey is pretty straightforward and fairly easy to use. It allows you to select from many pre-written questions. For basic surveys, I think SurveyMonkey is a great choice.
Usability Testing
Usability testing is a technique used in user-centered interaction design to evaluate a product by testing it on users. Usability testing is the best way to understand how real users experience your website or application.
Usability Testing Tool: Userlytics
Userlytics is a remote user testing tool that provides "Picture-in-Picture" videos of real people speaking their thoughts as they test and interact with websites, mobile apps and prototypes, including competitor assets. The service works for all types of digital applications, whether browser based, mobile apps, desktop applications, videos, emails, static images, etc. You can choose to have the participants provided to you, or you can source them yourself. You can also access experienced usability and user experience analysts to design your UX test and/or to prepare an executive summary report with usability and user experience recommendations.
Prototype Design
Wireframing tools make creating a website or application fundamentally easier. UX designers use wireframes and prototypes to create the products logic. It simplifies the communication between UX designers and clients and saves us much time on product development.
Rapid Prototyping Tool: Mockplus
Mockplus is an excellent tool to prototype app and website. It can be used to prototype for mobile, desktop and web apps quickly. Building an interactive prototype with Mockplus is much easier compared to an old prototyping tool like Axure or Justinmind. The intuitive drag-and-drop UI makes it possible to start using the tool immediately. Even the first-time users can master it without having to go over tutorials and training manuals. If you are looking for a UX tool that is cheap and allows to create interactive prototypes in a minimum of time, I recommend using Mockplus.
Communication is one of the critical skills of the UX designers. Want to improve communication with your team? Or work remotely but still stay in touch? That's where collaboration tools come in.
Collaboration Tool: Red Pen
Red pen is a lightweight tool which lets you upload a file and share it with clients and team members for feedback. You can ask colleagues and clients for feedback by giving them a private link, or inviting them via email. It very easy for designers to get feedback and approve artwork in a professional manner.
Design Style Guides
Most projects can benefit from having a style guide. Using a design style guide ensures consistency throughout a project. Some style guides focus on specific topic areas such as graphic design, including typography. Website style guides cover a publication's visual and technical aspects along with text.
Tool: Frontify
Frontify is a web design tool that helps designers create branding and style guides for their projects. The user can provide better documentation without wasting a lot of time on the process. An in-browser color picker is included along with an automatic color name proposal. What makes Frontify standout is that it is a place for itself by combining web design and development tools as well as a tidy, streamlined interface. Users can communicate quickly and gather valuable input easily.
Other Design Resource
Free Icons: iconfinder
Iconfinder is basically an icon search engine that anyone can use for free. According to Iconfinder, it now hosts the worlds largest collection of premium icons. It provides millions of beautiful icons to web designers and developers. All the icons are available to download for free in SVG, PNG, AI, or CSH. It is also an online marketplace for buying and selling premium icons.
Screen Specifications: Screen Sizes
Screensiz is very helpful to quickly find the screen specifications of the most popular devices and monitors currently on the market.
Color Picker: Adobe Color Wheel
Color selection can be one of the hardest parts of UX design, especially when you've just started. Adobe Color Wheel is an easy to use design tool. Upload a picture, you're then given an accurate color palate. You can not only upload to the cloud, but can also pull your own themes, or themes created by others. This means that if you're not feeling particularly inspired, you can have a look at themes that others have uploaded, pull one to your device, and adjust it to your tastes.
Originally published at www.mockplus.com.

subset: commoncrawl


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How to Handle Emotional Changes during Puberty
You make plans with your friend and she cancels on you because she has a sore throat, and you worry incessantly that she's mad at you.
You show your art project to your brother, and he rolls his eyes, and you start balling. Your parents are driving you crazy. You're happy one minute. You're sad the next.
Any of this sound familiar? You are going to experience a lot of emotional changes during puberty. And all of this is normal.
The reason you're experiencing this is because the hormones that are responsible for all those changes going on in your body, are also working overtime on the inside of your body. On your mind and your emotions.
All of this is normal. Mood swings. Emotional changes. Feeling upset. Feeling angry. Feeling happy.
And you can feel these things all at once at all different times. And it can go from one emotion to the next very quickly and very easily.
This is a normal part of puberty. And, a lot of it is, I imagine, has to do with your hormones. There are things you can do to try to cope with these emotional changes.
One of them is just speak to someone that you trust. Knowing that other people are going through this, and I promise you they are, goes a lot in helping you to make it through and cope with these changes.
Another is, try not to react immediately. Try to count down from ten to one, if you can. And while this may seem, like, very obvious advice, just taking a time out to relax and to give yourself a minute to breathe, may not trigger such an emotional reaction. That's really important too.
Also, try go get enough sleep. People that don't get enough sleep tend to have emotional issues and mood swings that are much worse than people who are well rested.
Exercise is so important. It goes a long way in controlling your mood swings.
And, finding things that make you relax. Whether it's yoga, Pilates. Whatever it is. Drinking camomile tea. Anything that works to relax you will make you get through this time of emotional change in puberty which, by the way, is normal, much more easily than not.
And just remember. We all go through it. We've all been there. And you're going to make it too.


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Euro-zone business activity expansion nears three-year peak according to Markit Economics
In the euro area growth has increased according to the Markit Economics latest composite index which is at a reading of 54.0 in April. The latest reading was the highest since May 2011 and supports the theory that the region may be beginning to finally exit the deep and long recession the area has endured over recent years. The German reading for the Markit Flash Germany Composite Output Index rose from 54.3 in March to 56.3.
Asian equities opened higher following a positive session in the USA, but gains were reduced after the latest signs of a slowdown in China. HSBC's preliminary purchasing managers index for China's manufacturing sector hit 48.3, signalling that activity contracted for a fourth month in April.
The Australian dollar dropped by the most in a week, falling by as much as 0.9 per cent against its US counterpart to US$0.9302, after consumer price inflation for the first quarter trailed economists' expectations, lessening the chances of an interest rate hike.
Euro-zone business activity expansion nears three-year peak
Growth of business activity in the euro area economy accelerated to its fastest for just under three years in April, leading to a return to job creation across the region. The Markit Eurozone PMI® Composite Output Index rose from 53.1 in March to 54.0 in April, according to the flash estimate, which is based on around 85% of total survey replies. The latest reading was the highest since May 2011. The PMI has now been above the 50.0 no-change level for ten consecutive months, signalling a continuous expansion of business activity since last July. With new orders also growing in April at the fastest rate seen since May 2011.
Economic upturn in Germany's private sector accelerates in April
German private sector companies reported solid activity growth at the start of the second quarter, as highlighted by the Markit Flash Germany Composite Output Index rising from 54.3 in March to 56.3. The latest reading was the second-highest in nearly three years and stretched the current period of growth to 12 months. Survey participants commented that an improved economic environment and increased order intakes were the main contributors to the latest expansion. The acceleration in output growth was broad-based by sector with both manufacturers and service providers signalling sharper expansions.
HSBC Flash China Manufacturing PMI
Key points Flash China Manufacturing PMI. at 48.3 in April (48.0 in March). Two-month high. Flash China Manufacturing Output Index at 48.0 in April (47.2 in March). Two-month high. Commenting on the Flash China Manufacturing PMI survey, Hongbin Qu, Chief Economist, China & Co- Head of Asian Economic Research at HSBC said:
The HSBC Flash China Manufacturing PMI stabilised at 48.3 in April, up from 48.0 in March. Domestic demand showed mild improvement and deflationary pressures eased, but downside risks to growth are still evident as both new export orders and employment contracted.
Australia Consumer Price Index
MARCH KEY POINTS THE ALL GROUPS CPI rose 0.6% in the March quarter 2014, compared with a rise of 0.8% in the December quarter 2013. Rose 2.9% through the year to the March quarter 2014, compared with a rise of 2.7% through the year to the December quarter 2013. OVERVIEW OF CPI MOVEMENTS the most significant price rises this quarter were for tobacco (+6.7%), automotive fuel (+4.1%), secondary education (+6.0%), tertiary education (+4.3%), medical and hospital services (+1.9%) and pharmaceutical products (+6.1%). These rises were partially offset by falls in furniture (-4.3%), maintenance and repair of motor vehicles (-3.3%).
Market snapshot at 10:00 am UK time
The ASX 200 closed up 0.70%, the CSI 300 down 0.10%, the Hang Seng closed down 0.85% and the Nikkei closed up 1.09%. Euro STOXX is down 0.18%, CAC down 0.35%, DAX down 0.12% and the UK FTSE is up 0.09%.
Looking towards the New York open the DJIA equity index future is up 0.05%, the SPX future is down 0.01% and the NASDAQ future is up 0.04%. NYMEX WTI oil is down 0.20% at $101.55 per barrel with NYMEX nat gas down 0.21% at $4.73 per therm.
Forex focus
Australia's dollar declined 0.9 percent to 92.84 U.S. cents early in London from yesterday, after touching 92.73, the weakest since April 8th. It sank 0.9 percent to 95.27 yen. The yuan was little changed at 6.2403 per dollar, after earlier touching 6.2466, the weakest level since December 2012.
The U.S. dollar was little changed at 102.61 yen from yesterday, when it touched 102.73, the highest since April 8th. It bought $1.3833 per euro from $1.3805. The shared currency traded at 141.95 yen from 141.66, having risen 0.6 percent over the previous six sessions. The Bloomberg Dollar Spot Index, which tracks the U.S. currency against 10 major peers, was little changed at 1,011.45 from yesterday.
Australia's dollar fell against all of its 16 major peers after data today showed the nation's consumer prices increased less than economists forecast.
Bonds briefing
Five-year notes yielded 1.76 percent in pre-sale trading early in London. If the yield is the same at the auction, it would be the highest for the monthly offerings since May 2011. Benchmark 10-year yields were little changed at 2.71 percent. The price of the 2.75 percent note due in February 2024 was 100 3/8. Treasury five-year debt was the worst performer among U.S. government notes and bonds over the past month before a $35 billion sale of the securities today.
The U.S. sold $32 billion of two-year notes yesterday at a higher-than-forecast yield, leaving the primary dealers with their biggest share of the auction in almost a year. The notes yielded 0.447 percent, versus the average forecast of seven of the 22 primary dealers in a Bloomberg poll for 0.442 percent. Primary dealers bought 57.7 percent of the securities, the most since May.
Japan's 10-year yield was little changed at 0.61 percent. Australia's slid five basis points to 3.95 percent. A basis point is 0.01 percentage point.
« I'm going to try FX trading once more what should I do differently this time? New home sales in the USA unexpectedly crash by 14.5% in March as US production rises at fastest pace for just over three years in April »


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Texoma Regional Blood Center
3911 Texoma Parkway Sherman, TX 75092-1925
According to the US Food and Drug Administration (FDA), there have been no reported or suspected cases of transfusion-transmitted COVID-19. No cases of transfusion-transmission were ever reported for the other two coronaviruses that emerged during the past two decades (SARS and MERS-CoV).
Routine blood donor screening measures that are already in place – which may include travel deferrals – should prevent individuals with clinical respiratory infections from donating blood.
TRBC does have a sanitation policy in place. However, to ensure donor safety in this uncertain time, the staff has been instructed to be extra vigilant, sanitize donor areas, screening rooms, and chairs, after each donor departs.
All blood drive sponsors/hosts should continue to hold blood drives. Please remember that in times of disaster or public health crises, it is the blood on the shelf that saves lives. Healthy donors must continue to donate to maintain an adequate blood supply.
ALL healthy individuals are encouraged to make an appointment to donate. If the outbreak of coronavirus continues to spread, additional challenges may arise, which could potentially reduce the number of eligible donors which is why those healthy individuals are encouraged to donate now.
If you are not able to give, encourage others to do so!
/Files/Images/For Immediate Release - Press 12.03.2020.pdf
Press Release 03/12/2020
Attention Blood Donors,
As cities and counties could be moving towards a shelter in place order, please know that blood donation is considered essential travel.
Please click the link below to download or print the attached letter that will serve as evidence of your essential travel for blood donation.
Thank you,
The Staff at TRBC
/TRBC Letter Designating Employees, Donors and Couriers for Essential Business - 3.30.2020(1).pdf


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Stephen Steffes (DLR),
DLR, Germany
|dSPACE Magazine 3/2010, Dec 2010
While developing a new space glider, the German Aerospace Center is investigating new heat shield technologies in their SHEFEX II program. A nose cone mounted on the tip of a high-altitude research rocket is scheduled for launch in early 2011 to test a new type of heat shield constructed from fl at panels. This will be easier to maintain and much less expensive than the heat shields on current spacecraft. The navigation system for the reentry nose cone, which carries the payload, is undergoing thorough prior testing on a dSPACE system.
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Monday, Monday
Monday, January 12, 2009
Aaaa..ne maram ponedeljkov! Še posebej če ti gre že zjutraj vse narobe in po možnosti prespiš budilko, tako da se celoten tedn začne stresno in že v samem začetku čakaš na konec! No, upam da ste tale ponedeljek začeli mirno in uspešno, brez večjih pretresov in vam je tako dan hitro minil :D lep teden!
Aaaa, I hate mondays! Especially if everything goes wrong already in the morning and you (for example) sleep through the alarm, so that the new week starts stresfully and you are already waiting for the end (right at the beggining)! Well I hope you all started this Monday peacefully and successfully, without major problems, so that the day passed by quickly :D have a great week!
3 comments:
- LeopardFreak said...
i really like both of these looks. don't hate me for saying i don't like your boots. but i guess when there's snow and ice outside style does not rule over practical. anyway, i really like these two outfits. and i love that necklace:D
- January 13, 2009 at 10:29 PM
- Gracie said...
that necklace is so pretty!!
- January 18, 2009 at 5:13 PM
- Deanna said...
I love your outfits. Where do you shop? All of your jewelry is beautiful.
- January 30, 2009 at 12:20 AM
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Tank, the Woos, the cybersibes and some others posted this morning about donating treats to local rescues and shelters.
Our human thought this was a good idea, so she bought a big box of treats and dropped it by the North Valley Animal Care and Control Adoption Center on her way in to her office.
Because she had time, and because we are all still very sad at our house, she thought she would walk around and visit all the dogies.
Well, they only had ONE. Kobe, a gorgeous 9 month old male rottie. All full of himself and handsome. He was marked as a 'stray.'
The cute little volunteer took him out of his cell and our human visited with him. He was bouncy and curious and liked getting petted and scratched.
It's just too soon. We are all still too sad. And you truly have to have all your emotional ducks in a row when you bring a new dog into your house. Especially a rottweiler.


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The second-lowest silver plan is one of the most popular plan choices on the marketplace and is also the benchmark that is used to determine the amount of financial assistance individuals and families receive. Based on preliminary 2018 rate filings, the second-lowest silver premium for a 40-year-old non-smoker will range from $244 in Detroit, MI to $631 in Wilmington, DE, before accounting for the tax credit that most enrollees in this market receive.
. . .


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This is the Best Silicone-Free Primer for Oily Skin
Two things bother me about most primers.
One, many of them that claim to be "mattifying" don't actually, er, do that.
And two, pretty much all of them include silicone, an ingredient that can clog your pores and make everything worse.
Well, big news. BIG news.
For years, I've been looking for a decent silicone-free primer to no avail. (Well, I did find something from an obscure natural skincare company, but I may as well have been applying water to my face for all the good it did.)
But today, I am happy to announce that I've just finished testing a new mattifying primer that miraculously DOES mattify—and without those darn silicones to boot!
Meet Becca's Ever-Matte Poreless Priming Perfector:
Becca is a beauty line out of Australia that's all about perfecting the skin, which is right up my alley.
The specific claim with this Primer is that it's like "liquid blotting paper." It specifically targets oil-prone areas and minimizes pores for up to 12 hours. TWELVE!
The stuff in here that replaces silicone is something called "EverMat," a complex of vegetal-derived ingredients that help to reduce sebum production. It's also free of oil, alcohol and fragrance. Sweet!
This is what it looks like out of the tube:
The texture is like a soft, non-oily gel and it has a slight whiteness to it, but that goes away when you spread it out on skin.
Once it dries down, you immediately feel a difference. It is as dry as dry can be.
In fact, if you run your finger over the area, it even tugs a tiny bit, like it's sucked up all the moisture already. The texture is noticeably changed, and it's almost like it tightens your skin up.
The tugging side effect doesn't last more than a minute, though, before it's just nice and smooth—so no worries about makeup going on all weird and splotchy on top of the primer.
So how well does Becca's Primer work at oil control? I've been testing it underneath my tinted moisturizer/CC cream/foundation for a while now, and because I walk a lot, I do give my makeup a very good run for its money. (Like, arriving at my destination semi-sweaty kind of testing.)
With this primer underneath, I feel like my coverage has never slid off, and I've never felt compelled to blot myself with powder in the ladies' room. It just hasn't been a problem. Oh, and you can apply this either underneath your makeup or on top for touch-ups.
A few final tips/observations:
- Don't buy this if you have dry skin and zero oily areas. It'll just dry your skin out way too much and feel uncomfortable. My skin is combo, so my forehead and chin are hardy enough to take the oil-sucking capabilities of this primer. I tested it on my cheeks for a whirl a couple of times, and while it does hide pores well, it did feel too drying for me there.
- It works well for spot oil control. I'll be sticking to wearing this on my T-zone only. Don't feel like you always—or ever—need to put it on your entire face.
- Make sure to wash it off well. This is a key problem with silicone primers—if you don't remove them with a really good cleanser (like an oil-based one that cuts through the silicone), they're left sitting on top of your skin and you don't even know it. I know this is not silicone, but I'd still recommend a thorough cleanse after you wear this, just to be on the safe side. Since it's so VERY effective, you want to get it all off later, so skin can breathe.
- Do a test-drive if you are acne-prone. I've had no issues at all, but you just never know with these things. Someone on Makeup Alley did report breakouts. So, see if you can get a sample to test on a smaller area of your face before you commit.
- I'm not sure about the slight white tint on darker skin tones. Does it show up or disappear? Please let me know if you've tested.
Where To Buy
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It's summer time! Don't you love it? Sandals, dresses, and swimming pools. One of my favorite parts of summer is the food. I love barbecues and enjoying a beer in the warm sun. A delicious burger and some chips. Yum.
Speaking of barbecue and chips- I just tried the new Green Giant Chips Multigrain Sweet Potato Chip Barbecue flavor and the Roasted Veggie Tortilla Chip Garden Ranch. They were so good! My two favorite kinds of chips are tortilla chips and sweet potato chips, so naturally I couldn't wait to taste these.
My favorite part about these chips is that they actually have real veggies in them. The flavor is so good that they don't have that typical "healthy" taste to them.
I found the chips had the perfect balance of salty, flavorful, tangy, crunch, and even a hint of spice. Everything I want in a good chip. I think both flavors would taste excellent with a chicken sandwich with a slice of swiss cheese and a summer wheat beer!
My daughter really enjoyed the Sweet Potato chips! These chips are definitely a great choice for healthy snacks for kiddos, too. They are made with Whole Grain Corn Flour and Sweet Potatoes. The Green Giant chips have 14g Whole Grain, are made with real veggies, have 0g trans fat, and have 40% less fat than regular potato chips. So, if your going to let your child have some chips, these are a healthy alternative!
Try them out. Let me know your thoughts!
I was selected for this opportunity as a member of Clever Girls Collective and the content and opinions expressed here are all my own.


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Know what you are eating and where it comes from!
We are a small farm in Gepp, Arkansas. Bob has been raising cattle for over 40 years . We switched to totally Grass Fed and Finished about 15 years ago. Our goal is to supply beef that you can trust to taste good, and be good for you. We use no antibiotics or hormones on the beef you buy, and best of all, it won't be full of the "solution" which is so prevalent in the beef you find at your local grocery store. When you eat our beef, we think you will be able to see the difference immediately.
We want to supply you with a wholesome product that you can trust.
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Eat Healthy!


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Friends, whether you're a pro, a weekend warrior, an aspiring handywoman, or even a seasoned DIYer, it's critical to keep safety, efficiency and convenience in mind when it comes to tackling any job, big or small, in and around the house. So when I discovered a new "power" tool that addresses all three of those things, it put a spring in my steel toe work boots.
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Got A DIY Question? Ask-The-Expert!
If you have a DIY home repair, maintenance or improvement question for Norma, now is your chance to ask-the-expert and have her answer. Your burning question may just be the "star" of an upcoming Fix-It Friday column.
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Wolverine CAG Meeting
Plainfield Township Charter Hall
6161 Belmont Ave NE, Belmont, MI 49306
Thursday, September 19, 2019
Members Present
A.J. Birkbeck
Jenny Carney
Lance Climie
Fletcher Johnson
Gail Mancewicz
Susan Marschall
Grant Medich
Jonathan Miner
Thomas Sapkowski
Kelly Sheeren
Michael Shibler
Cameron Van Wyngarden
Sandy Wynn-Stelt
Diane Russell, USEPA
Doug Sarno, Facilitator
Agenda Items
- Overview of Eat Safe Fish Program
- Update of the EPA Community Involvement Plan
- Update on House Street and Tannery Removal projects
Doug Sarno called the meeting to order at 6:03 PM.
Overview of Eat Safe Fish (ESF) Program
Laura Gossiaux, MPH, BSN, RN, of the Michigan Department of Health and Human Services provided this overview.
The first fish advisories in Michigan were issued in 1970s. We test chemicals related to different industries, Mercury is most tested for.
Most chemicals we test are bioaccumulative in that fish eat contaminated food and that can accumulate through the food chain. PFAS sometimes work a little differently in that we see higher concentrations in smaller fish.
The Chemicals we look for are persistent, they remain present in our environment, even those that have not been used in a long time. They bioaccumulate in our food and even in our bodies when we ingest those foods.
The ESF program uses scientific data along with health advisories to keep people informed. Most common contaminants are mercury, PCB, dioxins and now PFAS.
We are looking at areas where environmental investigations are ongoing and areas with high levels of fishing.
Eat Safe Fish is an advisory, it does not require people to follow the guidelines
We collect fish through partnerships with EGLE and DNR. They will collect the fish and we prepare and test them. We prepare it in the way most people eat them, they are frozen and stored and then tested individually for the chemicals of concern.
EGLE biologists and MDHHS toxicologists review the tests and update the ESF guide with new information based on the results. ESF guidelines don't get updated each year, changes to levels of contamination happen slowly over time.
The MI serving basics are customized for each person based on body weight. The serving sizes included in the guide are equivalent to 2 oz of fish for each 45 pounds of body weight.
Guidelines are customized by type of fish and water body, tables for area lakes were included in the presentation.
PFOS is most often tested for because it tends to drive the health concerns in fish.
The Ponds at 4300 Cannonsburg Road and the Belmont gravel pits were noted as Do Not Eat.
CAG: Why is there no advice for trout?
State: Samples have been collected and data are being evaluated.
There are more fish and more waterbodies that we have not tested and this is where we use our state-wide guidelines.
We also look at Eat Safe Wild Game and create advisories for deer. At present, one deer advisory exists in the state.
The science behind our guide and all of our materials is available at Michigan.gov/eatsafefish. The Division of Env Health hotline is 800-648-6942.
CAG: Rockford Dam has not been sampled since 2013, is there more sampling scheduled?
State: These contaminants tend to be very persistent and don't change that quickly, also there will be sampling as part of the cleanup that we have access to. We will look at the decreasing trends once the remediation is complete.
CAG: Do you test surface water too?
State: That is mostly done by EGLE, we are focused on the human health risks. EGLE has done a lot of surface water sampling and we can get a presentation on that moving forward. Those ponds with do not fish advisories are pretty much the worst case scenario, it is a captive system, all of the contamination flows in but very little leaves.
CAG: Is there signage where there is an advisory?
State: We don't typically have signage except at do not eat sites, the ponds are private property so we don't always have signs there but we do in this case.
CAG: Does EGLE have its own labs?
State: The DHHS lab is in Lansing, EGLE also has its labs in Lansing, we both can do PFAS analysis. DHHS does fish testing and some drinking water, EGLE is specifically designed to conduct EPA drinking water method of testing. Venison and game are all done at DHHS, but nothing scheduled at this time.
CAG: What about PFOS in plants?
State: We are beginning to look into that, there is research happening around the world but we are not set up for that yet. There is a plan to allow citizens to bring personal water samples to the state lab, that should be announced in the next month or so.
CAG: What is the turnaround time for sampling?
State: A week or two, we have more local capacity now than we did int the past.
CAG: Should there be more signs, it would be good to have more information to alert people to the fish concerns?
State: The guidelines do change a bit so we don't use signs as much as the brochures and on-line information.
CAG: Brown Trout and Brook Trout are the primary species in the Rogue River and need to be tested.
State: We will take a note of that. Sometimes it is a function of how much of a species we can catch.
CAG: This is a great topic for a CAG recommendation.
CAG: What is the difference between the under and over 18" fish?
State: The concentrations in the larger fish just don't meet the advisory levels in that case.
CAG: Thank you for letting us know about a cost-effective way for folks to get their well water tested, we look forward to that.
Public: PFOS is detected in the water, isn't it safe to know that the fish has been contaminated?
State: Not necessarily, lots of contaminants in the water do not necessarily accumulate in the fish. There are a lot of variables both in the water and for the individual fish species that determine if contamination bioaccumulates in fish.
Public: I got a mailer for free water testing from a company called rain soft, what is this all about, will it test for PFOS?
CAG : Lots of folks got those, this is just advertising for water filters, probably not going to look for specific hazardous contaminants like PFOS.
CAG: Should we look at collecting data that individuals get for their wells? There are real privacy concerns here, but it might be worth exploring.
Cleanup Workplans
OSC Jeff Kimball was not available for this meeting or next due to scheduling conflicts but he would be willing to schedule something with a committee or group that wants to discuss this topic.
The CAG will identify members who want to serve on a technical committee, then identify possible meeting dates to connect with Jeff.
Update on Community Involvement Plan
Diane Russell, US Environmental Protection Agency presented this information.
What is a Community Involvement Plan?
A site specific strategy to enable meaningful community involvement.
Both a document and a planning tool with actions to be taken throughout the course of site activities, a living document that changes as work moves forward. The CIP is developed based on community interviews and EPA's community involvement handbook.
The draft CIP is posted on the EPA web site www.epa.gov/mi/wolverine-world-wide-tannery.
EPA looking for public comments on the report and on our findings so we can be as accurate as possible. Comments will be accepted between now and October 19.
Is there a role that the CAG would like to play in implementing these activities? One of the functions of a CAG is to communicate to the larger community which could include helping to create and distribute materials, host meetings and events, and other activities.
What we heard in our Interviews?
Interviews were conducted summer and fall of 2018. Key concerns and comments were:
- PFAS and water
- Lots of concerns about trust in government. This is an area where the CAG can really help, in getting a wide range of folks around the table.
- How people get their information, finding trustworthy sources of information
CAG: it would be interesting to see how people's attitudes and trust change over time, this would be a good thing to look at, this would be an interesting activity.
EPA: This was not a quantitative assessment so we would not be able to make a direct study of it, This might be another area where the CAG could play a role.
Engagement Goals
- Provide information to the community.
- Achieve frequent and early opportunities for input.
- Identify and share resources for impacted community to help achieve all goals.
Information Methods
- EPA web site
- CD ROM at Repository at Krause Memorial Library
- Community Involvement Plan
- Mailing Lists
- Fact Sheets
- Informational brochures
- In the moment videos
- News Releases
- Real-time data sharing when possible.
Information/Input Methods
- Tours
- Educational partnerships
- Public meetings
- Participate in local community group meetings
- Plan or participate in local events
- CAG meetings
- Stakeholder meetings between EPA, EGLE, and local government and organizations.
Formal Input Methods
- Comments during formal comment periods
- Prepare and issue a responsiveness summary.
Share Resources and Methods
- CAG facilitation
- Technical resources
- Redevelopment resources.
Please email comments Diane Russell by October 19 at firstname.lastname@example.com.
CAG: Are the workplans the type of things that will go out for public comment?
EPA: No, they are not for comment but they are public documents.
CAG: Is there a copy of the shoreline plan where they are collecting the leather scraps?
EPA: Yes, that was one of the links shared
CAG: Will you be publishing all the comments on the CIP?
EPA: No, this is an informal process, we will review all of your comments and make all appropriate changes to the CAIP, but we only do formal comments for formal remedy selection processes.
CAG: For what types of issues do you send press releases?
EPA: These come out of our press office, we do a press release on public meetings, CAG meetings, big milestones and announcements. All press releases are posted at our web site.
CAG: The CAG will also be doing local press releases moving forward.
CAG: Can we get a more detailed map of the area that is affected?
EPA: We do have a little challenge of making sure we are not providing personally identifiable information, don't want to have personal property identifiable.
Public: We just need more detail on the map so we can see what you are talking about and how we might be affected.
State: We don't want to create plume maps off of residential well data, we are getting a better picture from additional sampling wells now so that sort of information will be coming.
Public: Is the CAG creating a web site and Facebook page?
CAG: Yes, this is in the works.
Public: The wolverine CAG sounds like you work for the company?
CAG: The site pretty clearly describes us, we are aware of the challenge in the name but want to make sure everyone knows our role.
Project Timelines for House Street, Tannery Property, White Pine Trail
Brent Ritchie, EPA Technical Contractor provided an overview of upcoming work on the Tannery and House Street projects.
This information is draft, the exact work progress will be determined by the ultimate contractor hired by Wolverine to do the work. There is a lot in flux still but letting you know where we are as of right now.
House Street
Data still coming in, plan is to start installing the fencing next week.
Tannery Property, White Pine Trail
In the final stages of a contractor selection for the cleanup work. Bid requests went out and three contractors have submitted bids. EPA has to agree with the final selection. Site prep and mobilization comes next and you will start to see equipment and preparation for excavation, they will be building some temporary roads and doing some tree removal, this up front work will take a few weeks. The individual contractors will decide where they want to begin the work based on their best approach and timing of the mobilization, probably the end of September.
CAG: What will happen with the trees and vegetation?
EPA: As long as it is not contaminated, the contractor will probably decide what to do with it. I am not certain exactly how it will be managed, I will ask about this.
The specific steps will be determined in the future. Brent showed a draft timeline and some maps to currently planned activity.
CAG: How long will the trail be closed?
EPA: Still waiting for the permits for this closure, request was for 9/27 but they won't close it until they have to, probably the following week. Re-opening will depend on a number of factors. We will have to take verification samples to ensure it is clean before backfilling and paving. If asphalt plants are closed for the winter then the trail will stay closed until spring when the asphalt is available. Working on a detour process (showed a map).
CAG: Who is going to let public businesses know about this closure?
EPA: This will be discussed to make sure people get notices they need.
We have a mid-December target for completing excavation of the different areas of contamination. A minimum restoration plan will be done this spring to do some planting, then a final restoration plan will also be prepared, EPA has not seen this plan yet.
CAG: The City of Rockford is going to get all the complaints on this, we really have to be much better about communication on this stuff so everyone sees the information they need. The CAG communication committee will really need to help coordinated between the CAG and the City and the EPA and Wolverine.
CAG: At House St. they are digging up Chromium, this is not a PFAS cleanup right
EPA: That is correct, they will only be digging a few feet, all hazardous waste will be going off site to a licensed facility.
This is really disappointing that the community has not gotten the information that they need. We must find a way to immediately notify the community. Can we get something in the paper for Monday. Get something to the Squire by Monday for the Thursday paper.
There is a lot of confusion and we need to work through that. Grant will call the City of Rockford and the Squire to understand what they are planning and that the CAG will be seeking to provide some information and a press release.
The CAG will also send a letter to Wolverine to talk about what the community expects from them. We need to get all of this to a better place.
CAG Committee Reports
Committee reports and action was postponed until the next CAG meeting.
The Meeting Adjourned at 8:50


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Made with a blend of five super grains that include gluten free oats, quinoa, buckwheat, amaranth, and millet, Energy Bars have rich chocolate chunks to deliver an added bit of sweetness. 10g of protein and 35% less sugar.
Nutrition facts available upon request.
Case Pricing
Product Details
- Packaging: 72 items per case (6 inner boxes of 12)
- Item Size: 2.1 oz.
- Selling Price: $3
- Payment Options: Learn more
- Delivery: 3-10 business days. Free shipping
Related Fundraiser
Calculate Your Profit
Have a question?
How it Works
How do we raise money?
Your group profits when your participants sell Energy Bars to their friends and family.
How do we pay?
Since product is ordered up front, you have the following payment options:
- Purchase order: If you're a public school, you can order Energy Bars without having to pay up front. A purchase order is a legally binding document between us and your group. Payment is due within 15 days of receipt of product. This gives you time to collect enough money to pay your bill. You then keep the rest as profit. Go to purchase order form
- Credit card: Use our secure checkout process to pay for your product up front. We accept VISA, MasterCard, American Express, or Discover. Select our 'Add to cart' button at the top of the page to get started.
- Check: Mail in your payment. Your product will ship once your check clears. We accept a personal check, money order, or cashier's check. Submit our payment form and we'll email you an invoice along with our mailing address.
Order Energy Bars at a discounted price and then sell them at full retail. The difference is your profit.
Do you offer pricing discounts?
Yes we offer volume discounts. For more information see our 'Case Pricing' table at the top of the page.
How soon can we start?
Orders deliver within 3-10 business days.
How long is the fundraiser?
We recommend giving your sellers 1 week to sell their product allocation and turn in the money.
TIP: To ensure timely and accurate money turn-in, use a tracking sheet.
How much should I order?
The size of your order depends on the number of participants in your group and how many items you want them to sell. Since orders ship 6 inner boxes to the case, consider issuing 1 box to each seller.
To determine how many cases to order, divide the number of participants in your group by 6. Round up to the next case number if needed.
You can also use our 'Profit Calculator' at the top of the page.
Do you take back unsold product?
We do not accept returns. Our goal is to maintain the same high level of product freshness for every customer. The USDA also has very strict guidelines that we must adhere to.
TIP: Consider issuing unsold snack bars to participants who volunteer to sell them in exchange for a portion of the profit.
Can participants earn prizes?
We don't offer any prize programs with our Energy Bars fundraiser.
Product Information
What do the bars sell for?
We suggest selling them for $3.00 each.
How many units per case?
72. Each case contains 6 inner boxes of 12.
What is the size?
2.1 oz each.
How long do they stay fresh?
Guaranteed shelf life is 4 months.
Are the bars healthy?
KIND® bars are high in nutrients. While they do contain a little added sugar, it's low compared to other similar product lines. Energy Bars contain only 5 grams of added sugar.
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Nut allergies are the body's immune response to the proteins found in nuts. The body tries to fight them off because it treats them as a potential threat. This response is an allergic reaction.
Energy Bars contain almonds, peanuts, and soy. They may contain tree nuts and sesame seeds and nut shell fragments.
Making Sales
Is there a minimum order?
There is a 2 case minimum order requirement.
How much money can we make?
Estimating your profit is easy. Consider the following example.
A sponsor with 65 participants wants everyone to sell 1 inner box each (12 units):
65 participants x 1 boxes / participant = 65 boxes
65 boxes x 12 units / box = 780 units
780 units x $3.00 / unit = $2,340 gross sales
$2,340.00 x 40% profit = $936.00 profit
The profit would be 40% because you would need to order 11 cases (Volume discounts apply):
65 participants x 1 boxes / participant = 65 boxes
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QUICK TIP: Enter your group size and participant goal into our 'Profit Calculator' located in the top right sidebar.
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3-10 business days.
Where do orders ship to?
Energy Bars ship out of our New Jersey warehouse to all lower 48 states.
How is our order packed?
Orders ship by the case.
Is there a shipping fee?
All orders ship for free. You also receive free shipping on any reorders.


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Synergistic Antitumor Effect of Dichloroacetate in Combination with 5-Fluorouracil in Colorectal Cancer
Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been recently demonstrated as a promising nontoxic antineoplastic agent that promotes apoptosis of cancer cells. In the present study, we aimed to investigate the antitumor effect of DCA combined with 5-Fluorouracil (5-FU) on colorectal cancer (CRC) cells. Four human CRC cell lines were treated with DCA or 5-FU, or a combination of DCA and 5-FU. The cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The interaction between DCA and 5-FU was evaluated by the median effect principle. Immunocytochemistry with bromodeoxyuridine (BrdU) was carried out to determine the proliferation of CRC cells. Cell cycle and apoptosis were measured by flow cytometry, and the expression of apoptosis-related molecules was assessed by western blot. Our results demonstrated that DCA inhibited the viability of CRC cells and had synergistic antiproliferation in combination with 5-FU. Moreover, compared with 5-FU alone, the apoptosis of CRC cells treated with DCA and 5-FU was enhanced and demonstrated with the changes of Bcl-2, Bax, and caspase-3 proteins. Our results suggest that DCA has a synergistic antitumor effect with 5-FU on CRC cell lines in vitro.
1. Introduction
Colorectal cancer is one of the most common malignancies worldwide [1]. Other than surgery, treatment for CRC patients relies primarily on chemotherapy, especially the patients with advanced CRC. Among the chemotherapeutic agents for CRC, 5-Fluorouracil (5-FU), which is a classical chemotherapy agent, has been the first line regimen for treating CRC over several decades [2, 3]. However, 5-FU alone is poorly selective to tumor as well as highly toxic to bone marrow, gastrointestinal tract, and skin when used at the therapeutic dose [4].
Metabolic abnormity is one of critical hallmarks of cancer [5]. As early as 1920s, Otto Warburg observed that cancer cells generally use glycolysis rather than oxidative phosphorylation for energy [6]. Thus, the metabolic switch to anaerobic respiration through glycolysis from pyruvate, rather than pyruvate conversion to acetyl-CoA by action of pyruvate dehydrogenase (PDH) in aerobic glucose metabolism, becomes a preferential phenotype of cancer progress. PDH can be inactivated by pyruvate dehydrogenase kinase (PDK) in many glycolytic phenotypes including cancer, while inhibition of PDK switches metabolism to aerobic oxidation which is proved to be disadvantageous to tumor growth [7].
Dichloroacetate (DCA) is a prototypical inhibitor of mitochondrial PDK. By blocking the enzyme, DCA decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. This property has led to trials of DCA for the treatment of lactic acid accumulation disorders [8]. Recently, studies have demonstrated that DCA suppresses tumor growth via inhibition of PDK [9–11]. Michelakis and his colleagues found that DCA restored mitochondrial function, thus restoring apoptosis, killing cancer cells in vitro, and shrinking the tumors in the rats [12].
Combination chemotherapy has been used widely. 5-FU is usually combined with other antineoplastic agents and radiation to enhance its antitumor effect. The clinical insufficiency appears to be caused from resistance of 5-FU and severe side effects. The strong and selective induction of apoptosis suggests that the PDK inhibitor DCA may potentiate the inhibitory effect of anticancer drugs, thus exceeding the efficacy of current treatment. Herein, we aimed to examine the combined antitumor effects of DCA with 5-FU on the CRC cells, in hoping of assessing a relatively effective and safe regimen potentiated for CRC treatment.
2. Material and Methods
2.1. Cells and Regents
The human colon cancer cell lines LS174T, LoVo, SW620, and HT29 were purchased from American Type Culture Collection (Manassas, VA, USA). Cell culture reagents were purchased from Gibco-Invitrogen (Carlsbad, CA, USA). Cell lines were maintained in Dulbecco's Modified Eagle's medium or Leibovitz L-15 medium containing 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 g/mL streptomycin in a 37°C, 5% CO2 humidified incubator. 5-FU and DCA was purchased from Sigma-Aldrich Co. ltd. (St. Louis, MO, USA), dissolved in deionized water to make 1 mol/L working solution, filter-sterilized, and subsequently diluted in growth medium for treatment.
2.2. Cell Viability Assay
Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (Sigma-Aldrich). Cells were seeded into 96-well plates ( cells per well) and incubated under standard growth conditions overnight from 60% to 70% confluence. Cells were then treated with DCA alone (final concentration 0–90 mM) or with DCA combined with 5-FU (5–200 μM). After a 48-hour treatment, cells were incubated at 37°C for another 4 hours with MTT (20 μL per well) and the absorbance at 490 nm was measured in a Bio-Rad Model 550 plate reader (Hercules, CA, USA).
2.3. Analysis of Drug Interaction
The interaction between DCA and 5-FU was analyzed by using the median effect principle described by Chou and Talalay [13, 14]. The program enables calculation of combination indices (CIs) which, when smaller than 1, equal to 1, or greater than 1, indicate synergism, additivity, or antagonism, respectively, between two drugs. CIs were calculated by where and are the concentrations of DCA alone or 5-FU alone, giving % growth inhibition, and and are the drug concentrations in combination inhibiting cell growth also %. and were calculated by the median-effect equation: where is the median-effect dose, is the fraction affected, and represents the slope of the median-effect plot.
2.4. Cell Proliferation Assays
Immunocytochemistry was carried out with bromodeoxyuridine (BrdU) (BD Bioscience, San Jose, CA, USA) in vitro. Cells were propagated on coverslips in 12-well plates under standard growth conditions. After 24 hours, various concentrations of DCA, 5-FU, or a combination of two drugs were added. Cells were serum-starved for 12 hours in growth media containing 0.5% FBS to reset the cell cycle to G0 phase, and then cells were pulsed for 2 hours with 10 μmol/L BrdU in growth media. Subsequently, the cells were fixed, washed, and stained according to the manufacturer's instruction.
Cell cycle analysis was determined indirectly using propidium iodine (PI, BD Bioscience) staining by flow cytometry (FACScan, Becton Dickinson, San Jose, CA, USA). Cells were seeded into 6-well plates and cultured with or without 10 mM DCA or 20 μM 5-FU. After incubating for 48 hours, cells were harvested with 0.25% Trypsin-EDTA (Invitrogen, Carlsbad, CA, USA). Then, cells were fixed with 70% alcohol for 24 hours at 4°C and washed twice with phosphate buffer saline (PBS). RNAase (100 μL; 1 mg/mL) (BD Bioscience) was added, and cells were incubated in a 37°C water bath for 30 minutes. After staining with 200 μL PI (50 μg/mL), cells were held at 4°C for 30 minutes. Finally, cells were analyzed by flow cytometry.
2.5. Apoptosis Assay
Apoptosis was detected by flow cytometry with annexin-V-FITC (BD Bioscience) and PI. Cells were seeded into 6-well plates. After a 48-hour incubation with or without drugs, cells were washed and resuspended in 0.5 mL PBS buffer. After staining with annexin-V-FITC and PI, cells were analyzed by flow cytometry in three independent experiments.
2.6. Western Blot
Cells were harvested and total proteins were extracted with RIPA buffer containing protease inhibitors. Total protein (50 μg) was subjected to 10% or 12% SDS/PAGE, and the resolved proteins were transferred electrophoretically to PVDF membranes (Millipore, Bedford, MA, USA). Membranes were blocked for 2 hours with 5% nonfat milk in TBS buffer containing 0.05% Tween-20 (TBST) at 4°C. Membranes were then incubated with antibodies to Bax, Bcl-2, Caspase-3, and GADPH overnight at 4°C. After washing in TBST, the membranes were incubated with their respective secondary antibodies for 1 hour. Membranes were then incubated with SuperSignal West Femto Maximum Sensitivity Substrate (Pierce, Rockford, IL, USA) for 1 minute and imaged using a Gel Doc XR system (Bio-Rad). All of the antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).
2.7. Statistics
All data are expressed as means ± standard deviation (SD). Statistical analysis was performed using the SPSS 13.0 software (SPSS, Chicago, IL, USA). Differences between two groups were determined by paired-samples -test or independent-samples -test (two-tailed) as indicated. Differences among groups were analyzed by one-way analysis of variance (ANOVA). was considered statistically significant.
3. Results
3.1. Viability of CRC Cells Treated with DCA Alone or in Combination with 5-FU
To determine the effect of DCA on CRC cells, cells were exposed to DCA (0–90 mM) for 48 hours. The result showed that inhibitory effect was dose dependent. As shown in Figure 1, the inhibition of viability of cancer cell lines treated with 50 mM DCA was as follows: SW620 (46.73% ± 5.21%), LoVo (30.94% ± 3.57%), LS174t (54.59% ± 3.93%), and HT29 (55.31% ± 3.35%). We treated cells with 5-FU (20–100 μM) and found that the viability of SW620, LoVo, LS174t was inhibited significantly except HT29, with its viability inhibition not obvious under 80 μM 5-FU. When treated with these two drugs simultaneously, the viability of aforementioned CRC cells was significantly decreased compared with DCA or 5-FU alone (IC50 values are shown in Table 1).
3.2. Synergistic Effects of DCA Combined with 5-FU in CRC Cell Lines
The viability of CRC cells were decreased in the presence of 5-FU and DCA. DCA potentiated the inhibitory effects of 5-FU on CRC cells, and the influence of DCA on effects of 5-FU was dose dependent (Figure 1). Interaction between 5-FU and DCA was analyzed with median effects method. The combination of DCA and 5-FU produced synergistic or additive effects depending on the range of cell kill level (Fa). All of four CRC cell lines indicated synergistic effect with 5-FU and DCA. The synergism was statistically significant in LS174t at inhibition levels of 50% and 80%, achieving CI values from 0.46–0.61, and in HT-29 cell line at inhibition levels of 50 and 80%, with CI values in the range from 0.42 to 0.52. In SW620 and LoVo cells, CI values at 50% and 80% inhibition levels were 0.64–0.75 and 0.75–0.94, respectively, (Figure 2).
3.3. DCA Increased the Efficiency of Antiproliferative Effect of 5-FU
To confirm that decreased cell viability was due to reduced proliferation, immunocytochemistry, and flow cytometry were employed. Cells were treated with 10 mM DCA combined with 20 μM 5-FU. As expected, cells treated with DCA demonstrated reduced proliferation compared with untreated cells. The number of BrdU positive cells on four CRC cell lines after treatment with 5-FU and DCA were 11.4 ± 2.12, 13.55 ± 3.10, 12.84 ± 1.34, and 18.83 ± 1.45, respectively, which were lower than that treated with 5-FU or DCA alone (, see Table 2). In addition, treatment with DCA potentiated the cell cycle arrest in G1 phase. When treated with DCA and 5-FU, cells blocked in G1/S phase were more than that of incorporated with DCA or 5-FU alone (Figure 3).
3.4. Increased Apoptosis Induced by DCA Combined with 5-FU in CRC Cells
To further investigate the decreased viability of CRC cells treated with combination regimen, apoptosis was determined by flow cytometry. As shown in Figure 4, DCA alone increased the proportion of apoptosis CRC cells. When treated with 10 mM DCA, the apoptosis rates of four CRC cell lines were 15.72 ± 1.63%, 11.32 ± 0.74%, 9.77 ± 0.53%, and 14.52 ± 1.00%, respectively, while the apoptosis rates were 9.14 ± 119%, 8.82 ± 0.41%, 10.31 ± 0.71%, and 7.27 ± 0.96% with 5-FU. When combination of DCA and 5-FU was applied, the apoptosis rate was much higher than 5-FU or DCA alone (), which indicated apoptotic effect was increased via combination DCA and 5-FU (Figure 4).
3.5. Changes on Apoptosis-Associated Molecules Stimulated by DCA and 5-FU
To confirm that increased apoptosis induced by combination therapy was due to modified expressions of apoptosis-associated molecules, western blot assay was applied. In Figure 5, the results indicated that 5-FU or DCA decreased the expression of Bcl-2 in four CRC cell lines compared to PBS controls, and the combination of DCA and 5-FU decreased Bcl-2 expression significantly as compared with DCA or 5-FU alone. Conversely, the expressions of Bax and caspase-3 were significantly increased in the four CRC cell lines treated with combination of DCA and 5-FU compared to their single usage. The most obvious increasing of Bax expression was detected in LS174t cells, while in LoVo it appeared that caspase-3 expression increased most (Figure 5).
4. Discussion
In the present study, we demonstrate that DCA not only reduced cell viability and proliferation, but also have the synergistic antitumor efficiency with chemotherapeutic agent 5-FU in vitro in CRC cells. Meanwhile, DCA has no significant effects on noncancerous cells. Furthermore, we showed that DCA-induced apoptosis contributes to its synergistic antitumor effect. Compared with DCA or 5-FU alone, combination usage of these two drugs promotes apoptosis of CRC cells.
5-FU is a chemotherapy drug used to treat several types of cancer, including colorectal, breast, esophageal, and stomach [15]. However, 5-FU–related toxicity is a serious and common issue for many cancer patients, with myelosuppression and gastrointestinal toxicity being the most commonly observed side effects [16]. The clinical activity of 5-FU is modest at standard doses, and in general, dosing is limited by the safety profile. As a result, we are usually left with the dilemma of making decisions about the therapeutic dose of 5-FU. Various strategies have been developed to enhance the clinical activity of 5-FU, such as biochemical modulation [17], alterations in scheduling of administration [18], and the use of combination therapy [19–22].
DCA is an odorless, colorless, inexpensive, relatively nontoxic, small molecule. It has been in clinical use since 1969 for treatment of lactic acidosis via boosting the ability of mitochondria to generate energy and reducing lactic acid accumulation [23]. DCA has been considered as a potential cancer therapy regimen since a Canadian group found that it caused regression in several cancers, including lung, breast, and brain tumors [24, 25]. When given to cancer cells, the cells switched from glycolysis to mitochondrial energy production. What's more, functional mitochondria help cells recognize functional abnormalities and trigger cell death due to its inhibition of tumor growth and induction of apoptosis in certain cancer. In the present study, we found the same viability inhibitory effect in CRCs, which was dose-dependent and various with different degrees of tumor differentiation. The results also indicated that low-dose DCA exerts a synergistic effect with chemotherapeutic agent 5-FU in halting growth of CRC cells, which was quantitatively analyzed according to Chou-Talalay method.
The results of cell proliferation also demonstrated that DCA enhanced the antiproliferational effects of 5-FU. The number of BrdU positive cells was decreased when treated with 5-FU or DCA, while the BrdU-stained cells were decreased significantly when treated with combination of 5-FU and DCA compared with their single usage. Meanwhile, the growth inhibition of CRC cell was accompanied by cell cycle arrest. Combination of DCA and 5-FU induced cell cycle arrest in G1/S phase in CRC cell lines, whereas 5-FU induced arrest in G1 phase was not obvious. The induction of cell cycle arrest may result from inhibitory ability to synthesize or repair DNA, which may lead to cell apoptosis.
DCA appeared to exert biochemical effects consistent with reversing the Warburg effect and killing cancer cells. We found that DCA-induced CRC cells apoptosis, which is orchestrated with the previous DCA studies. Importantly, the combination of DCA with 5-FU increased the number of apoptotic cells compared with 5-FU alone, demonstrating that DCA inhibited cell growth via apoptosis.
Many factors mediating apoptosis converge to activate the critical effector the caspase-3, which is considered as the key protease of caspase family in mammalian cell apoptosis [26]. It always exists as a 23 kD inactive precursor in cytoplasm, which is activated during apoptosis and takes part in apoptosis induced by multiple factors. Caspase-dependent apoptosis pathway mainly includes mitochondria pathway, death receptor pathway, and endoplasmic reticulum pathway [27]. And the mitochondria pathway is controlled and regulated by the Bcl-2 family of proteins [28, 29], which are divided into two parts, the antiapoptotic members (Bcl-2) and proapoptotic members (Bax) [30]. Recent study indicates that the Bcl-2 inhibits apoptosis via inhibiting Bax removing to mitochondrial outer membrane [31]. We investigated the expression of caspase-3, Bcl-2, and Bax in protein level and the result of western blot showed that the expressions of caspase-3 and Bax were increased, while the expression of Bcl-2 was decreased in the combination of DCA with 5-FU treatment, comparing with the single treatments. These results suggested that the apoptosis induced by the combination of DCA and 5-FU might be related with caspase-dependent mitochondria pathway. Previous investigations suggested that the induction of apoptosis by DCA resulted from returning the dysfunction of the mitochondria and NFAT-Kv1.5 pathway [9, 12], which focused on the same point as present study that was mitochondria-mediated apoptosis.
This work was supported by the National Natural Science Foundation of China (NSFC, no. 30873015). J. Tong and G. Xie contributed equally to this work.
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text:
September 2017 Editor's Note: ONE STEP FORWARD, TWO STEPS BACK
Author: Maggie Washo
How about this one?" asked Catherine, CH2's art director.
"The Lowcountry is not ready for the shaving cover," I replied.
"But it was from 1965. Everyone will know it's a throwback tribute," Catherine said.
"They aren't ready," I said, walking out of her office.
We were discussing cover options to get people's attention for our Women in Business issue, a much-anticipated sellout issue, which occurs every other August.
Over the next few days, I mulled over her proposed cover idea. I presented it to several women. "That's a fun idea" seemed to be the consensus. "Not too edgy for our area?" I would ask, pushing for the answer I wanted to hear. "Of course not," was the reply.
My mom was born in the '50s, so I asked her. She smiled. "That's fun."
"Do you think it's too edgy for this area?"
"No. But what are you trying to say?"
"I'm not trying to say anything. We've paid homage to several iconic covers over the years; this would just be another one. It's fun to see who makes the connection."
"I like it," she replied. "Go for it."
I wasn't sold yet. As the person on the receiving end of ALL irate phone calls and e-mails from incensed readers, I knew better. Someone was not going to get it.
I compromised.
"Go ahead and do it," I told Catherine. "But we aren't going to mail it to anyone. We'll just put it on stands. If someone wants to pick it up, great. Let's do some 'safe' covers for the actual mailings." ("SAFE" meaning covers that couldn't be misconstrued as a political statement or be overly polarizing.)
So, we hired a model who resembled the one featured on this classic Esquire cover, and did our best to replicate it, including altering our logo to mirror the Esquire logo.
It is something we've done multiple times over the past 11 years. In the summer of 2008, Michael Phelps became a household name when he triumphed at the summer Olympics, bringing home eight gold medals for his superior aquatic abilities. Two months later, in a pictorial about how to create children's costumes on a budget, we recreated the Michael Phelps' Sports Illustrated cover with an eight-year-old boy. It was a hit.
The Saturday Evening Post's style was another we chose to emulate in July of 2011. We commissioned Mark Staff to photograph a dad grilling hamburgers, with his daughter sharing her ice cream cone with a puppy—very Norman Rockwell. The cover shot was done in vignette, with our logo and type slightly altered to more reflect the style of The Saturday Evening Post.
In July of 2013, we celebrated our second Women in Business issue with our entirely female staff balanced on scaffolding, painting the CH2 logo onto our cover. This was done "in the style of" or as an homage to the Chicago Greatest Hits album cover. I think it's important to note that we weren't trying to make a statement that women could be painters…of course they can. It's 2017, and women can choose whatever career path they desire.
In the summer of 2015, we tipped our hat to Vogue. Taylor Kent, CH2 Rocks the Triangle winner, was made up like a vintage cover girl, and again, our type and logo were altered.
There are more examples, but those are a few of my favorites throughout our history.
In addition to the shaving cover for our August issue, we shot what I considered our "safe covers." The same model we hired to recreate the iconic shaving cover was used to represent various professions featured within our Women in Business special section: a doctor (see page 63 of August issue); a general contractor (see page 53 of August issue); a financial advisor (see page 50). To achieve this graphically, we used universally recognizable props: a Wall Street Journal turned to the MONEY section, a white coat and stethoscope, a hard hat and blueprints.
We went to print.
We asked our readers which cover they preferred. Men seemed to like the shaving one. One gentlemen had this to say: "I vote for the cover with the woman shaving. It declares visually that women are equal to men and ready to take on the world." As a rule, the women e-mailing tended to favor the stockbroker or "the one with the dog."
After putting out more than 200 covers, I expected this. I've said for a while now that if you want to run out of magazines early in the month and get more views online, you put one of these three things on your cover: 1) A beautiful young woman. 2) Food. 3) A dog. (in exactly that order). If you really want to blow someone's mind, put all three together on the cover. For all of you out there trying to start a magazine, there's your cover recipe.
You're welcome.
Here are CH2's Top 10 covers of all time, based on percentage of views, clicks, and the amount of time the reader spent perusing each issue:
As you can see, this past issue is number one. It shot to number one in less than seven days. But it has a pretty young woman and a dog, so like I said, no big surprise here.
But then something began to happen on Facebook that did surprise me. There was outrage over our cover choices—and not the shaving one. A few women found it "sexist," and "demeaning to women," and thought the cover photos portrayed "women acting as men."
"Women acting as men." That statement really struck me. Did some of our readers feel that a woman couldn't be a doctor, stockbroker or general contractor? When another woman wrote that the covers looked like "a model playing dress up as if to indicate that she is a woman doing men's jobs," the enormity of what these women were expressing hit me like a lightning bolt. They didn't think, as a gender, that we had come very far at all. In their minds, this was a woman "playing dress up," not a woman in business who was getting paid to do a job (modeling is her career).
There were several comments about our cover model dressing as a man (by the way, she was wearing a dress) because she was wearing a tie. As a woman who has worn a tie as a fashion statement on many occasions, I found this kind of interesting as well. Women have been rocking ties for years now. I find it to be a nice alternative to a necklace on occasion and definitely a look that gets attention. It is worn by servers (male and female) in fine dining establishments around the world. But perhaps what was more alarming was women telling other women what they should and shouldn't wear to be properly represented as a successful "woman in business." ONE STEP FORWARD, TWO STEPS BACK.
Every time I have a visceral reaction to something, I try to dig deeper to find out why. I'm not talking about the normal stuff that we should all be upset about (like murder, child abuse, mistreatment of animals, etc.). I'm talking about things that I find offensive or hurtful, but in general, most people do not. I try to get to the root of my emotions and see where the hurt stems from. In my case, it's usually attached to some past slight or hurtful experience that I can't seem to forget/ forgive/ shake.
The August covers (quite by accident) became a Rorschach test for our readers. The opinion you formed looking at those covers mirrors how you perceive women in business. And I have to admit, that scared me a little when I read a few of the comments on Facebook. Because if that's the case, we haven't come nearly as far as I thought we had.
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