text:
@MISC{Butz99newchallenges, author = {Martin Butz and David E. Goldberg and Wolfgang Stolzmann}, title = {New challenges for an Anticipatory Classifier System: Hard problems and possible solutions}, year = {1999}}
An Anticipatory Classifier System (ACS) is a learning mechanism based on learning classifier systems and the cognitive model of "Anticipatory Behavioral Control". By comparing perceived consequences with its own expectations (anticipations), an ACS is able to learn in multi-step environments. To date, the ACS has proven its abilities in various problems of that kind. It is able to learn latently (i.e. to learn without getting any reward) and it is able to distinguish between non-Markov states. Additionally, an ACS is capable of incrementally building a cognitive map that can be used to do action-planning. Although the ACS has proven to scale up in suitable environments, it depends on certain environmental properties. It believes itself to be the only agent that can change the perceptions received from an environment. Any environmental change is considered and believed to be caused by the executed actions. The ACS learns from the changes by using fixed mechanisms. This paper reveals the properties of an environment that the current ACS assumes to be given. By investigating the problems of the current ACS when violating these properties we believe that this investigation will immediately serve for a better understanding of the ACS and lead to many ideas to improve the current ACS. We will propose some ideas and discuss the important ones in more detail.
Developed at and hosted by The College of Information Sciences and Technology
© 2007-2015 The Pennsylvania State University


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Fall has put a crisp snap in the air, so why not start planning cozy dinners that have a minimum of bother? Think simple: Classic home cooking is something that will surprise even the most jaded guest and allow you to have fun at your own party without fussing too much. I was invited to a dinner at a fancy building on Fifth Avenue and went expecting a long, elaborate affair. Surprise! My hostess offered pasta al pomodoro served buffet style at a big table. Even a personage as august as the late, great Paris socialite Baron Alexis de Redé knew the value of keeping things simple when it came to food. A star-studded luncheon I attended at his apartment in Hôtel Lambert, the grandest house in town, was nothing more complicated than cheese soufflé and a green salad. If you need more inspiration, let me suggest you buy a copy of Park Avenue Potluck (Rizzoli, $35), a timeless, zesty compilation of smart entertaining tips, or its brand new companion, Park Avenue Potluck Celebrations, out this month (Rizzoli, $35). Both volumes feature and delicious recipes from savvy society swans such as Dayssi Olarte de Kanavos and Coco Kopelman. With glamorous gals like those leading the way, how can you go wrong?
Elegant Yet Easy Entertaining
Stylesetter Carlos Mota says fall entertaining should be chic yet simple
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13 Ways To Be A Gracious House Guest
Show your host or hostess how much you appreciate their hospitality with a thoughtful thank you gift.
12 Cocktails Every Wine Lover Should Know
Even if your first love is wine, sometimes the mood simply calls for a cocktail.
The White House Has Nothing On These Famous Presidential Homes
And they'd all be worth quite a lot of money today.
Athena Calderone's Tips For A Chic Rooftop Fête
The Eye Swoon founder orchestrates a whimsical dinner on her Brooklyn terrace.
More From Life + Culture

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text:
Phils, Lee Drop One Against Jays
Posted by Jay Floyd, Thu, March 17, 2011 03:40 PM | Comments: 12
Grapefruiting, Minor Leagues, News, Posts
In Clearwater Thursday, the Phillies dropped a match up with the Toronto Blue Jays, 7-6. The Phillies busted out to an early lead, as Jimmy Rollins singled to lead off the bottom of the first and Shane Victorino followed with a tremendous homerun into the tiki bar area at Brighthouse Field.
Cliff Lee started for the Phillies and looked fairly untouchable early, as he shut down the first eight Blue Jays batters he faced in succession, and stranded a lone runner on base in the 3rd inning. In the 4th inning, however, the Jays' bats seemed to come alive following a throwing error by third baseman Josh Barfield. Five hits and a sacrifice fly later, the Jays had a lead that they would not relinquish for the remainder of the contest, as Toronto defeated Philadelphia by a score of 7-6 on Thursday.
Jo-Jo Reyes would earn the win (1-1), while Cliff Lee took the loss (1-2). Lee singled in his only at bat.
The Phillies donned green caps and jerseys, as they do each year on St. Patrick's Day. More notes on this game lie ahead.
-More pitching: Antonio Bastardo and Mike Zagurski each threw a scoreless inning for the Phils, while Kyle Kendrick spread 7 hits over 3 innings, with 1 strike out, while allowing 2 runs (1 earned) in the contest. Zagurski struck out the side in the 9th.
-Rule 5 guy Michael Martinez slammed his second homerun of the spring and brought his Grapefruit League batting average up to .325 with a 2-for-4 performance on the day.
-Catcher Erik Kratz mashed a pinch homerun in the 8th inning. Kratz, a Telford PA native, is batting .167 with the Phillies this spring.
-Wilson Valdez went 1-for-3 in the game and is now batting .444 on the spring. His 16 hits lead the Phillies in Grapefruit action.
-Freddy Galvis got the Phillies within a run in the 9th inning, when he drove a ball deep to left for a 2-run homerun.
-Other Phillies' spring averages to date…Rollins- .239, Victorino- .341, Ibanez- .308, Delwyn Young- .311, Howard- .256, Mayberry Jr.- .333, Francisco- .341, Ruiz- .130, Barfield- .417.
-The crowd of 10,816 on hand for today's match up was reportedly a record for Brighthouse Field.
-The Phillies are back at it tomorrow in Clearwater against the Pirates at 1:05 PM. The game will be simulcast on Phillies.com and 1210 AM. Then, beginning with Saturday's game against the Orioles, the Phillies will be televised for three straight days.
Posts: 0 brooks
Zaugurski – Please show us your mid-season form. Oh, I forgot you have never lasted in the ML for more than a few appearances.
Last year and more so the year before when he came up for a little bit, he performed well on maybe 1 or 2 outings. After that, you could always ink a few runs for the opposition along with some walks –
No faith in Zags.
Posted: 06:33 AM on March 18, 2011
Posts: 0 Don M
Brooks, I'm pretty sure that when Zagurski was called up before, it was out of desperation – not really becuase they thought he was ready to shred MLB hitters..
Because he's a LEFTY – he gets more looks, and longer looks, becuase he's a rare commodity. His best chance in the Majors is probably as a Lefty Specialist
He's got a decent K-per-9 rate… 32 Ks in 28.1 innings
but his ERA is sky high…and so is his WHIP, as he's walked 16 , and righty's have batting practice against him.
For his brieft career, Lefty's hit .240 .. Righty's hit .339 !!! So every righty that faces him is an All-Star for that at bat
Posted: 08:36 AM on March 18, 2011
Posts: 0 Merlin
Hey guys…got a nice Spring Training wrap-up for the Nats with Jayson Werth that Phils fans should definitely be interested in: http://bit.ly/dFMv87
Posted: 08:36 AM on March 18, 2011
Posts: 0 Don M
What about that is interesting to Phillies fans… that the Nats will be better in 4 years?
Posted: 08:47 AM on March 18, 2011
Posts: 0 Merlin
I don't think it'll be four, I think it'll be much sooner. Also, as a Phillies fan–and I am one, believe me–I think it's important to stay informed especially on the other teams in the division. Not to mention Werth played for the Phils for a few years.
Posted: 09:16 AM on March 18, 2011
Posts: 178 bfo_33
I keep hearing the Nats are going to be good – a nice pipeline,…., but I still don't see a lot of pitching. Strausburg has great stuff, but will he ever be healthy? J. Zimmerman, same boat. Storen seems to have the stuff to be a good closer, otherwise, not a lot of arms. Harper has power, but also seems to be very cocky – will he listen to coaches, can he hit an mlb breaking ball? It also seems like something is missing in their big prospect development – guys get hyped early,then you never hear about them again. The potential may be there, but until they learn to consistently develop prospects (after R. Zimmerman, what difference maker have they developed?), I'll hold off crowning them an official threat. Could be another version of the Marlins – talented, but can't put it together.
Posted: 09:40 AM on March 18, 2011
Posts: 0 Don M
yea im not trying to be a d!ck, but all baseball fans know about the potential the Nats have in a few years…. But they're putting the weight of their franchis on Werth, Strasburg, and Harper . . . . the 2nd just had Tommy John and depending on what scouts you trust, has to change his delivery and will likely lose velocity (but would hoepfully stay away from another surgery) . . .
and Harper, who hit 500 ft HRs with a metal bat in batting practice . . . don't get me wrong, the kid is a natural power hitter .. but lets see what he does against the best pitchers in the game .. he won't get the chance this year, and i'd say he's not a true impact player in his first two seasons, which takes us to the 2014 season
NOW … they have a chance that Ian Desmond and Danny Espinosa are a legit combo, and that Nyjer Morgan learns how to act like a professional . . . but their pitching staff sucks, they need to add somebody really, really badly next year ..not sure who would be available
Posted: 09:56 AM on March 18, 2011
Posts: 178 bfo_33
Love them or hate them, you have to respect the ability of the Braves to evaluate and develop talent. The Nats – not so much. Their two biggest pitching prospects – Strausburg and J. Zimmerman have had Tommy John surgery early in their careers – maybe a fluke, or maybe poor coaching. Signing Werth to that contract also makes me think management lacks judgement.
The Phils aren't perfect, but I don't see the Braves in quite the position to take advantage of it this year – solid but not spectacular starting pitching, and a truly craptacular up the middle defense. Alex Gonzalez is decent, but McCann is there for his bat, McClouth makes Victorino's lines look impressive, and Uggla is, well Uggla. Add in that their best infielder will be in left until Chipper (another minus defender) gets hurt, and you're giving up an extra run per game. Their starting pitching and offense isn't good enough to overcome that. 88-90 wins, will compete for the wild card, but I don't think they are a threat this year. Look for Uggla to be at 3rd or left next year.
Posted: 11:07 AM on March 18, 2011


text:
Mining exploration causes heat in regions
The Victorian Opposition will introduce a motion next week to parliament for a moratorium on unconventional gas exploration licences until there's an inquiry into the impacts of coal seam gas exploration.
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If the motion is passed the inquiry would be conducted over the next 12 months and include consultations with various community representatives, such as farmers, local councils and environment groups.
The Opposition's energy spokesperson, Lily D'Ambrosio, says coal seam gas exploration is fairly new in Victoria and their stance is a response to growing concerns about the techniques used to extract certain gases.
"Fracking (a gas extraction technique)...has raised concerns over the possible impact on underground water supplies and food production," Ms D'Ambrosio says.
"We believe that there is sufficient cause for concern. We know that there is some evidence in Queensland of contaminations that have been found in ground water."
The inquiry the Oppositions is asking for would not cover any of the conventional forms of mining and mining exploration.
Last week an alliance of community groups from towns including Wonthaggi, Bunyip, Toongabbie, Bacchus Marsh and Mirboo North came together to seek legal advice about what information citizens can request from mining companies who hold exploration licenses.
Tracey Anton, a representative of the alliance and Toongabbie landholder, says the group formed because of the lack of information and consultation from the government about the licences which have already been granted.
"To not do anything and just let the government go holus bolus mine the bejesus out of the place, that's not good," Tracey Anton says.
Victoria's Energy and Resources Minister, Michael O'Brien says the Victorian rules regulating gas exploration have been in place for years and have operated effectively.
Exploration licences are subject to an application process which involves advertising in local papers. Licences don't grant mining companies automatic access to land, companies are required to consult with landholders first.
"The reason why we need to have exploration for minerals and resources in this state is because the wealth that we have under our ground...belongs to the people of Victoria," Mr O'Brien says.
The State Government says it's open to reviewing the way communities are informed about mining explorations, but Michael O'Brien has reaffirmed he believes the current process is working.
"There's a reason why we don't have any CSG [coal seam gas] production in Victoria at the moment, that is because our environmental standards and our mining legislation is far more stringent than in other states," he says.
"There's no reason why exploration and indeed mining can't exist peacefully with agriculture and other activities."
The newly formed alliance of community groups are concerned about the impact of mining on agriculture and would like to see areas of land re-zoned and separated from mining.
"They haven't been tested, the laws [on coal seam gas exploration], because no one has actually put in an application for a production stage," Tracey Anton says.
"They're all [opposition and government] playing politics because they would support open cut mining and that's the issue because you're turning the area into a quarry," she adds.
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text:
- Music
- 1100 Crescent Avenue Northeast, Atlanta, GA
Become a Successful Wedding Planner!
Multicultural Wedding & Event Professionals, Inc.
Saturday, April 27, 2013 from 9:00 AM to 5:00 PM (EDT)
The Wedding Business is a $70 Billion dollar industry with the average wedding costing approximately $27,000 according to Basic American Wedding Statistics. There will be approximately 2.5 million weddings this year and these couples will need help. This is an opportunity for you to be of assistance to a newly engaged couple and make great money doing it!
The "Become a Successful Wedding Planner" seminar series will teach you how to
Early registration- $199 before April 19
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Fee includes: Continental Breakfast, Lunch, training materials, wedding binder & handouts, and Free wedding counseling.
REGISTER TODAY by calling 678-786-5480 or visit www.multiculturalwep.com/weddings.
Reseve your seat today, you could be the next celebrity wedding planner!
Our Mission
Multicultural Wedding and Event Professionals, Inc. (MWEP) seeks to enhance the careers of its members and grow their businesses through relationship building, education and professional development and community outreach.
In order to purchase these tickets in installments, you'll need an Eventbrite account. Log in or sign up for a free account to continue.


text:
Book your room at Fleur De Lis Mansion
The Red RoomMax Occupancy: 2 guests
Room (Champagne)Max Occupancy: 2 guests
Suite (Fleur de Lis )Max Occupancy: 2 guests
Room (Royal Suite PH)Max Occupancy: 2 guests
The River SuiteMax Occupancy: 7 guests
The White RoomMax Occupancy: 2 guests
The Jazz RoomMax Occupancy: 2 guests
The Hollywood BungalowMax Occupancy: 2 guests
Get an overview of this hotel3.5-star New Orleans bed & breakfast in Garden District with free breakfast
Located in Garden District, this bed & breakfast is within 2 mi (3 km) of Annunciation Square, Mercedes-Benz Superdome, and Jackson Square. French Market and New Orleans Jazz Park are also within 3 mi (5 km).
Property Features
This bed & breakfast features a spa tub, laundry facilities, and tour/ticket assistance. Free breakfast is provided, as well as free WiFi in public areas, free self parking, and a free manager's reception. Other amenities include a garden and barbecue grills.
Room Amenities
All 8 rooms offer flat-screen TVs with cable channels, plus ironing boards.Information missing or incorrect? Tell us!
Hotel Amenities
Hotel Amenities
Guests can enjoy a complimentary breakfast each morning as well as a complimentary manager's reception. Public areas are equipped with complimentary high-speed wireless Internet access. This New Orleans bed & breakfast also offers a spa tub, tour/ticket assistance, and barbecue grills. Onsite self parking is complimentary.
- Barbecue grill(s)
- Free reception
- Free breakfast
- Free self parking
- Free WiFi
- Garden
- Laundry facilities
- Number of buildings/towers - 1
- Spa tub
- Total number of rooms - 8
- Tours/ticket assistance
- Year Built 1824
Available in some public areas: Free WiFi
Free self parking
Room Amenities
- Access via exterior corridors
- Air conditioning
- Bathrobes
- Cable TV service
- Climate control
- Flat-panel TV
- Iron/ironing board
Where to Eat
A complimentary breakfast is served each morning between 8 AM and 10 AM. A complimentary manager's reception is offered each day.
Hotel Policies
Children and extra beds
- Children are welcome.
You need to know
Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
This property is not fully accessible. Access to one or more rooms may require climbing narrow spiral stairs. For more information, please contact the property using the information on the reservation confirmation received after booking.


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I suggest that you contact the management company of the complex as there may be penalties involved regarding renting out your unit if you have not occupied it for a minimum of two years.
If you have signed an exclusive representation agreement with your agent then you cannot respresent yourself to lease it out until that agreement expires.
Good luck to you!
Laura Feghali
Prudential Connecticut Realty
River Rock Property Management does not offer property management services in your area, however, I would suggest contacting one by searching Trulia's Find a Pro feature. Property managers can offer a lot of valuable services that will ensure you receive the highest possible income for your rental. Good luck, and have fun in Europe.
For a no obligation consulting, please call 203-280-3838. I would be happy to walk you through the process and work on the structure that would work for everyone.
Thank You
Nick Gandhi
Equity Capital Real Estate
(203) 280 3838


text:
Boot Scootin' Juice Ball raises big funds for Kitchen Sage
It was a boot scootin', toe tapin' time at this year's Boot Scootin' Juice Ball. See footage from the fun event, here!
It was a boot scootin', toe tapin' time at this year's Boot Scootin' Juice Ball. See footage from the fun event, here!
Make fitness a part of your life every day with one of these fitness trackers.
Jill Wallace is WOTV 4 Women Fashion Finds expert, specializing in upcycling clothes.
Janis Petrini gives tips on staying healthy at a sedentary job.
Maranda's friends at Priority Health are giving away a LeapBand fitness and activity tracker for kids by LeapFrog.
Bill Steffen share some snow science facts
Visit an Air Zoo weather camp
The Whitecaps are holding Social Media night in June, a time for fans to weigh in on everything they want for the game.
Maranda got a chance to visit Catch Air, a play center for kids 10 and under.
See photos from the 2015 Golden Globe Awards.
Jordan get the scoop on what's happening behind the scenes on "The Bachelor". Take a look.
See photos from this past weekend at the Remodeling show at DeVos Place.
Michele Fife shows easy and relaxing yoga moves to cure a hangover.
Learn the signs of seasonal depression and take steps to avoid it.
Photos of this year's Boot Scootin' Juice Ball at the JW Marriott.
Refresh your skin during the harsh winter with these 5 DIY body scrubs.


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Chuck's Bar-B-Q and Burgers
"The good smell in Evadale" is the tag line painted on a wooden fence beside Chuck's Bar-B-Q and Burgers which sits about thirty minutes north of Beaumont. Folks say the local paper mill produces a stench, and the smoke from owner Chuck Howard's pit is sometimes the only relief. I didn't get a whiff of any pulp, but the "burger" end of the name is what perfumed the dining room just after the lunch hour….


text:
I've created proxy classes using svcutil with a given "sap crm" wsdl file. It worked great and it generated a output.cs. So added this output.cs in my visual studio project und created a simple test application. The test application can be compiled and even run, but I dont know why. I didn't enter any service url.
How can this be and how can i configure the test application to use the propper sap url?
it's a follow up question to this http://stackoverflow.com/questions/2108349/problem-creating-proxy-class-with-wsdl-exe


text:
This 1977 Dodge Tradesman van, available for sale on eBay, has a custom Star Wars mural painted on the side. The van appears to be pretty much falling apart, sadly, but perhaps that's why the bids have only gone just over $1,000. It is a really nice paint job, though. It's a shame that the painted van has fallen out of favor, putting thousands of skilled airbrushers out on the street. Auction Page [eBay.com via Star Wars blog]
Star Wars Shaggin' Wagon for Sale on eBay
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6 Responses to "Star Wars Shaggin' Wagon for Sale on eBay"
Ha! In 1977 I won an airbrushed car mural from a radio station contest. I sold it to my friend for $75 and he had a Darth Vader and a TIE Fighter painted on the hood of his dad's Mustang. It actually looked pretty cool. Wonder whatever happened to that car.
This one baby!
It's the one that will get ya laid!
PS: I would not be anonymouse if I could figure out my sign in name…. you password reset email does not include it.
mmmkay… he claims that the 31-year-old van has only 100,000 miles on it, but he drives it "all the time". I can just imagine this guy buying the van in '77, getting it painted and impressing all the geeky 13-year-old Star Wars fans (like me) in town, driving to gigs, rockin' the van with his girlfriend… then waking up one morning and thinking, "It is the twenty-first century and I am fifty years old." He pops a piece of Nicorette in his mouth, goes out to the carport, and pours a glass of blue milk out onto the gravel for his homey from Tattooine.
Ah, the painted van! In the late '70s there were two highly visible vehicles in my small home town. One was a brown van titled "Ripped Van Winkle" which featured an airbrushed picture of a wizard smoking a pipe, IIRC. The owner of that must have had to be judge sober every time he got behind the wheel because if there's anything that will attract a cop's attention it's an intoxicated wizard on your vehicle.
The other was a purple Lincoln Continental driven by the famous professional wrestler The Sheik. It was more conventional looking, but had a certifiable nutcase behind the wheel.
Falling apart? The Millenium Falcon was a bucket of bolts according to some snooty hoes, but it was still bitchin. BID BID BID.
Just wondering if this van is still for sale i live in canada and am looking for one of these vans to buy and fix up if this van is still for sale email me at email@example.com


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Comparative Corporate Governance
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Financial Regulation and Supervision: A post-crisis analysisThis comprehensive account of financial regulation and supervision in times of crisis analyses the complex changes under way regarding the new financial regulatory structures in the EU. Focusing on the organisation of financial supervision, it deals with the background to the reforms, the architecture of the regulatory system, the likely implications for the financial institutions and the
Comparative Corporate Governance of Non-Profit Organizations
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text: on Nov 7, 2013 @ 12:16 PMNov 7, 2013 @ 12:16 PM PublishedKenney prepares to meet with provinces hostile to his jobs grant program OTTAWA - The federal government's Canada Job Grant proposals are in trouble, officials and opposition critics are warning on the eve of Jason Kenney's meeting with his provincial and territorial counterparts.Seven months after Ottawa first proposed the program in its March 2013 budget, the minister of employment and social development can expect a litany of complaints when he sits down with his colleagues Friday in Toronto.Quebec has even demanded to opt out of the program."They're out on a branch on this one, a very fragile branch," Brad Duguid, Ontario's minister of training, colleges and universities, said this week.Provinces and territories are particularly opposed to Kenney's plan to slice $300 million — about 60 per cent — from the so-called Labour Market Agreement implemented by the Conservatives in 2007.That initiative provided funds to train unemployed workers not eligible for employment insurance and is aimed at aboriginals, immigrants, women, youth, older workers, people with disabilities and those with low literacy levels.The program has been a big hit with the provinces and territories, with provincial officials pointing to a recent joint evaluation with Ottawa that determined those participating in the plan doubled their chances of landing jobs and keeping them.But Kenney has often been dismissive of the Labour Market Agreement, calling it ineffective "training for training's sake." His office has also suggested it plays a part in a supposed Canadawide "skills shortage," a state of affairs described in a recent TD Economics report as being over-stated."They're planning on funding this Canada Job Grant on the backs of our most vulnerable workers," Duguid said."That would be very harmful to those programs and to those vulnerable, marginalized workers if the federal government was to follow through."Duguid said he hasn't seen any evidence from the federal government that it's open to rethinking the job grant program, despite Kenney's recent insistence that he's willing to be flexible on some aspects of the plan — in particular the cost to businesses that participate.As proposed in the budget, the Canada Job Grant would provide up to $15,000 to any business offering a training program. A third of that money would come each from the federal government, the provincial or territorial government and the business itself.Kenney recently suggested the cost could be chopped for small businesses, saying they could pay less if bigger firms agreed to pay more. Ottawa has also proposed to the provinces that the program could be phased in, with only a required 10 per cent implementation in its first year, beginning on April 1, 2014.Kenney's office lauded the program this week and said he looked forward to Friday's meetings."Throughout recent months, productive discussions have already taken place with the provinces to explore flexibility with the program, ensuring unemployed and underemployed Canadians have access to training that is directly linked to a guaranteed job," his office said in a statement."The Canada Job Grant will put a stop to training for the sake of training, and ensure that investments in training are actually linked to employers and available jobs."Duguid disputed the notion that Kenney has been consultative or particularly open to changing course. He said he'd personally only spoken to the minister once, briefly."We've seen the federal government show a little bit of flexibility, but they've yet to move away from their intention to cut these programs, and the provinces and territories are standing up to them and saying that we cannot and will not contemplate doing that," Duguid said."The minister has talked about flexibility and they've taken some very minor measures, but nothing that's close yet to where the provinces would want them to go."Rodger Cuzner, Kenney's Liberal critic in the House of Commons, said there's been no consultation with the provinces on the Canada Job Grant."They're just getting around to meeting with the provinces now," he said. "They've spent millions of dollars advertising this Edsel, and it's being thrashed by the provinces. Had there been new money allocated with the program, it may have stood a chance."Kenney is reading the writing on the wall for the prospects of success for the program, Cuzner suggested."I am sure he's bailing like hell because this ship has many holes," he said. "He'll work to try to save this thing, but it's going to take a significant shift by the government that we haven't heard anything about yet."Duguid insisted the provinces aren't spoiling for a fight."We're now meeting to determine where we go from here. The objective of the provinces and territories is not to strike a fight here, it's to ensure we're providing the best possible training programs that meet the diverse needs of our entire population, from vulnerable workers right through to skilled workers."— With files from Maria Babbage in Toronto.


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Doxorubicin (DXR) is a frontline chemotherapy agent implicated in unintended ovarian failure in female cancer survivors. The fertility preservation techniques currently available for cancer patients are often time and cost prohibitive and do not necessarily preserve endocrine function. There are no drug-based ovary protection therapies clinically available. This study provides the first investigation using dexrazoxane (Dexra) to limit DXR insult in ovarian tissue. In KK-15 granulosa cells, a 3-h DXR treatment increased double-strand (ds) DNA breaks 40%–50%, as quantified by the neutral comet assay, and dose-dependent cytotoxicity. Dexra exhibited low toxicity in KK-15 cells, inducing no DNA damage and less than 20% cell loss. Cotreating KK-15 cells with Dexra prevented acute DXR-induced dsDNA damage. Similarly, Dexra attenuated the DXR-induced 40%–65% increase in dsDNA breaks in primary murine granulosa cells and cells from in vitro cultured murine ovaries. DXR can cause DNA damage either through a topoisomerase II-mediated pathway, based on DXR intercalation into DNA, or through oxidative stress. Cotreating KK-15 cells with 2 μM Dexra was sufficient to prevent DXR-induced, but not H2O2-induced, DNA damage. These data indicated the protective effects are likely due to Dexra's inhibition of topoisomerase II catalytic activity. This putative protective agent attenuated downstream cellular responses to DXR, preventing H2AFX activation in KK-15 cells and increasing viability as demonstrated by increasing the DXR lethal dose in KK-15 cells 5- to 8-fold (LD20) and primary murine granulosa cells 1.5- to 2-fold (LD50). These data demonstrate Dexra protects ovarian cells from DXR insult and suggest that it is a promising tool to limit DXR ovarian toxicity in vivo.
The numbers of people surviving cancer are progressively rising with advances in early detection and treatment, making unintended, long-term consequences of chemotherapy an immediate challenge for the health care community. According to the American Cancer Society, there will be roughly 740000 new female cancer cases nationwide this year. Breast cancer is the most prevalent among these cases, and up to 50% of breast cancer survivors will develop premature ovarian insufficiency as a result of their chemotherapy treatment [1]. In addition, approximately 1 in 800 female adults will be a survivor of childhood cancer by the year 2020 [2], roughly 7% of whom will experience ovarian insufficiency [3]. Ovarian insufficiency in turn increases the survivor's risk for infertility, osteoporosis, and heart disease. It is therefore imperative to find ways to preserve ovarian function for cancer survivors and thereby enable a better quality of life.
The American Society of Clinical Oncology recommends physicians offer fertility preservation options to female cancer patients of reproductive age. The options currently available include embryo, oocyte, and ovarian tissue cryopreservation, and ovarian suppression [4]. The recommended therapies, however, are expensive with no guaranteed success, delay cancer therapy, and are not available for prepubescent patients. In addition, oocyte and embryo cryopreservation provide limited future fertility options, but they do not protect ovarian endocrine function and prevent premature menopause or osteoporosis. New chemotherapy-shielding approaches must be developed to protect the function of the ovary as a whole.
Doxorubicin (DXR), an anthracycline, was first used in clinical trials in the 1960s and is still a cornerstone agent in chemotherapy regiments for breast and childhood cancers [5]. Although DXR treatment causes infertility in cancer patients due to follicular attrition [4], the mechanism(s) of DXR-induced cell death in the ovary are undefined. We and others have shown DXR induces acute apoptosis (within 12 h) in the mouse ovary [6–8] (Roti Roti, Leisman, Salih, personal communication); this acute cell death occurs primarily in the granulosa cells of growing follicles as opposed to stroma cells and primordial follicles [6–8].
DXR can induce cellular toxicity via two distinct mechanisms, depending upon cell type and growth rates. This intercalating drug kills rapidly dividing cancer cells by preventing resealing of topoisomerase II (TOP2)-mediated double-strand (ds) DNA breaks that occur during normal DNA replication [9, 10]. Cells respond to unrepaired DNA damage by committing to apoptotic death. In the heart, where DXR causes dose-limiting toxicity, the drug's primary mode of insult occurs when DXR interacts with iron to induce oxidative stress [11–15]. Blocking oxidative stress is sufficient to prevent acute DXR insult in the heart but is not enough to prevent long-term DXR cardiotoxicity, which requires TOP2 inhibition as well [16]. Whether one or both of these mechanisms functions in the ovary is not well-defined.
Dexrazoxane (Dexra) (also known as ICRF-187) is a chemoprotectant currently used to protect the heart and skin from DXR-induced extravasation and cardiotoxicity [17–21]. Dexra can protect cells via two mechanisms, both of which correspond to the known modes of DXR-induced toxicity. Dexra, a member of the bisdioxopiperazine family [22, 23], specifically inhibits the closed-clamp conformation of TOP2, keeping TOP2 bound to the DNA after resealing the strand breaks, thereby preventing the next enzymatic cycle of TOP2-mediated dsDNA breaks [16, 23–28]. Cells cleave Dexra during normal metabolism, creating an ethylenediaminetetraacetic acid (EDTA) derivative that chelates iron to reduce oxidative stress, providing the mechanism by which it protects the heart from acute DXR injury [29, 30]. Importantly, Dexra does not prevent DXR antitumor activity in breast cancer nor pediatric leukemia cases, and does not increase the risk for secondary malignant neoplasm in leukemia cases [17, 31–41].
This study is the first to test Dexra as an ovarian chemoprotectant agent and demonstrates that Dexra prevents DXR-induced DNA damage in KK-15 granulosa cells at doses that do not limit H2O2-induced DNA damage, suggesting that the mechanism of DXR insult in these cells is largely based on TOP2 activity. The putative protective agent also blocks DXR-induced H2AFX activation and attenuates DXR toxicity, right-shifting the kill curve 5- to 8-fold. Similarly, Dexra attenuated the DNA damage response to DXR for cells from in vitro murine ovary culture and primary murine granulosa cells, where Dexra right-shifted the DXR kill curve ~2-fold. The data suggest Dexra is a promising drug to develop as a protective agent to attenuate DXR injury in the ovary. This approach has the advantage over current fertility preservation methods in that it may be applicable to prepubescent patients, limits downstream genetic consequences following chemotherapy, and circumvents the prohibitive time and expense involved in traditional fertility preservation options and hormone replacement therapy.
Complete protease inhibitors were obtained from Roche. All the other chemicals were obtained from Fisher. DXR was obtained as a gift from the UW-Madison Chemotherapy Pharmacy as a 2 mg/ml aqueous solution. Dexra (Sigma) was solubilized in dimethyl sulfoxide (DMSO) (stock = 80 mM).
KK-15 (mouse immortalized granulosa-derived cell line) cells were cultured in 50/50 Dulbecco modified Eagle medium (DMEM)/F12 (Cellgro) supplemented with 2.5 mM l-glutamine, 15 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 10% heat-inactivated fetal bovine serum, and penicillin 1000 units/ml; Cellgro and streptomycin 1000 μg/ml; (Cellgro) at 37°C with 5% CO2.
This study was conducted in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act and its subsequent amendments. All the animal procedures were reviewed and approved by the Graduate School Animal Care and Use Committee of the University of Wisconsin-Madison. The University of Wisconsin Animal Care Facility is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care as part of the University of Wisconsin-Madison Graduate School. Animals were housed in the University of Wisconsin Animal Care Facility and provided standard care with free access to food and water. Female CD1 mice were purchased from Charles River Laboratories through the University of Wisconsin Animal Care Facility. Ovaries were harvested from 4-wk-old female CD1 mice euthanized with CO2 per approved animal protocol. Ovaries were cleansed of bursa and attached fat in minimal essential media (minus phenol red). One ovary from each mouse was transferred to a filter basket (Millipore) in a well containing ovary culture media (Ham F12/DMEM minus phenol red, 0.01 mg/ml bovine serum albumin [BSA], 1 mg/ml albumin, 0.05 mg/ml ascorbic acid, 5 units/ml penicillin, 5 μg/ml streptomycin, and 0.0275 mg/ml transferrin) plus Dexra or DMSO (vehicle control) and incubated for 1 h at 37°C. Ovaries were then transferred to baskets in new wells containing DXR or DXR plus Dexra at the concentrations given in the figures. Ovaries were incubated an additional 3 h at 37°C and then processed for the neutral comet assay (NCA; see below). Granulosa cells and oocytes were released by gently puncturing the follicles. Stroma cells were isolated by 30-min treatment with 0.25% collagenase at 37°C followed by cell dispersion using a 23-gauge needle. While this cell-separation technique does not provide pure cell populations, it is expected to provide two populations that are enriched in granulosa and theca/stroma cells, respectively. We will refer to these enriched populations as granulosa cells and stroma/theca cells throughout.
The second ovary from each mouse (above) was incubated for 30 minutes at 37°C in dissociation media (DMEM/F12, 0.5 M sucrose, and 10 mM ethylene glycol tetraacetic acid). Granulosa cells were released by gently puncturing the follicles and dispersed into single-cell suspensions using a 23-gauge needle. Viable cells were counted using trypan blue exclusion, and for the NCA, cells were plated in 6-well dishes at 2 × 105 cells/well and cultured overnight at 37°C in 5% CO2. The cells were then pretreated with DMSO (carrier control) or 20 μM Dexra for 1 h at 37°C. DXR was then added at the given concentrations to the media containing either DMSO or Dexra as indicated in the figures. After a 3-h incubation with DXR, the cells were processed for the NCA.
KK-15 cells at 50% confluency were treated with drugs (see the figure legends). The cells were pipetted to achieve single-cell suspensions in PBS (137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, and 2 mM KH2PO4), and blind samples were subsequently used. The cells were diluted 1:10 in 1% low-melting agarose/PBS and plated onto microscope slides (precoated with 1% agarose in double-distilled [dd] H2O) with coverslips and incubated 10 min on ice. Coverslips were removed, and the slides were incubated for 1 h at 4°C in the NCA lysis buffer (2.5 M NaCl, 100 mM EDTA, 10 mM Tris, pH 10.0, 1% Triton X-100, and 10% DMSO). The slides were then equilibrated 30 min at 4°C in 90 mM Tris base, 90 mM boric acid, and 2 mM EDTA, and subjected to 30 min electrophoresis at 25 volts. The slides were rinsed twice with ddH2O and dried overnight at room temperature. Nuclei were stained by incubating the slides for 20 min in 2 μg/ml propidium iodide in PBS. The slides were washed twice with ddH2O and imaged on an Olympus microscope fit with a 20× objective and a live charge-coupled device camera (University of Wisconsin-Madison Flow Cytometry Facility). Images were collected using Spot Advanced Plus software. Olive moments [42] were measured using CometScore software (Autocomet.com), collecting at least 50 cells per condition. Postanalysis, the samples were unblinded. One-way ANOVA analysis with a Bonferroni means comparison was carried out using OriginLab.
KK-15 cells were plated at 1 × 106 cells per 100 mm dish 24 h prior to drug treatment. Following drug treatment, the cells were washed twice with PBS, scraped into 1 ml PBS, and collected in microcentrifuge tubes. All the steps for nuclear lysate preparation were conducted at 4°C. Cells were harvested by centrifugation for 5 min at 900 × g. Pelleted cells were resuspended in 250 μl hypotonic solution—10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 1.5 mM MgCl2, 10 mM KCl, 0.5 mM dithiothreitol, and 1× complete protease inhibitors (PIs) (Roche)—and incubated 15 min on ice. Cells were physically disrupted using 40 strokes of a size B Dounce homogenizer. Lysates were centrifuged 5 min at 230 × g to pellet the nuclei and membranes. The nuclear pellet was resuspended in 200 μl of 0.25 M sucrose, 10 mM MgCl2, 1× PIs, and 1 mM sodium orthovanadate; layered over 200 μl 0.88 M sucrose, 0.5 mM MgCl2, 1× PIs, and 1 mM sodium orthovanadate; and centrifuged 10 min at 2800 × g with no brake to enrich for nuclei. Nuclear pellet was solubilized in 100 μl of radioimmunoprecipitation assay buffer (100 mM Tris, pH 7.3, 500 mM NaCl, 1% Triton X-100, 0.5% deoxycholate, 0.2% sodium dodecyl sulfate, 1 mM sodium orthovanadate, 100 mM NaF, and 1× PIs). Samples were sonicated five times for 10 sec on ice with a 5-sec rest between each burst. Lysates were stored on ice overnight at 4°C and then analyzed via Western blots.
Protein quantification was determined using the BioRad DC Protein Assay per the manufacturer's instructions. Lysates were prepared in Laemmli sample buffer (63 mM Tris HCl, 10% glycerol, 2% sodium dodecyl sulfate, 0.0025% bromophenol blue, and 50 μM dithiothreitol, pH 6.8) and heated for 5 min at 95°C. Approximately 10 μg total protein was loaded per lane and samples were size separated on a 4%–20% gradient gel (BioRad) under reducing conditions. Proteins were transferred to polyvinylidene fluoride membranes optimized for fluorescence (Millipore) where the membranes were preblocked in TBS-T (20 mM Tris base, 137 mM NaCl, and 1M HCl) plus 5% BSA for 1 h at room temperature. Blots were probed with rabbit anti-phospho γH2AFX antibody (1:500; Abcam) and mouse anti-β actin (1:1000; Sigma) in TBS-T plus 5% BSA overnight at 4°C. Blots were washed with TBS-T and then probed with donkey anti-rabbit Alexa 680 (1:15000; Molecular Probes) and donkey anti-mouse IRdye 800 (1:15000; LiCor) in TBS-T for 1 h at room temperature. Blots were washed with TBS-T, dried, and scanned using the LiCor Odyssey System (University of Wisconsin Small Molecule Screening Facility). Density measurements were taken using the Odyssey software.
KK-15 cells were plated in a 96-well dish, 5000 cells/well, 24 h prior to drug treatments. Primary granulosa cells were plated in a 96-well dish at 1.5 × 104 cells/well 24 h prior to drug treatments. Triplicate samples were processed using the CellTiter-Glo kit (Promega) per the manufacturer's protocol, and the luminescence was read on a Synergy plate reader (Typhoon, University of Wisconsin Small Molecule Screening Facility). Graphs were generated in Origin. Two-way ANOVA was done using OriginLab.
Testing Dexra as a putative protective agent required defining the onset of DXR-induced DNA damage in our murine granulosa-derived cell line model, KK-15. We used the NCA to quantify acute DXR-induced DNA damage in KK-15 cells. This is a sensitive single-cell assay of DNA damage where ds breaks are measured as the OM [42]. Time-course experiments revealed that 3 h was the earliest time at which 500 nM DXR exposure induced measurable DNA damage (OM), with no further significant increase at 6 h (Fig. 1A). The 3-h point was therefore utilized in subsequent experiments. Treating for 3 h with either 50 or 500 nM DXR, to encompass the range of circulating blood serum concentrations in patients (100–400 nM) [43], induced a 40%–55% increase in the extent of DNA damage in KK-15 cells (Fig. 1B).
A 3-h pulse with DXR was also sufficient to cause dose-dependent KK-15 cell death as demonstrated by cytotoxicity curves. Cells were treated with DXR at the indicated doses either continuously for the entire duration of the experiment or for only 3 h; the media was then replaced with drug-free media. The percentage of viable KK-15 cells 48-h postdrug treatment was quantified using the ATP-based CellTiter-Glo kit. The cytotoxicity curve generated from a 3-h pulse of DXR paralleled that from continuous exposure (Fig. 1C), indicating that DNA damage measured after 3 h (Fig. 1B) is sufficient to induce dose-dependent cell death.
KK-15 cells were treated with Dexra alone to determine whether the putative protective agent caused any measurable DNA damage or cytotoxicity. Cells were treated for 3 h with indicated Dexra concentrations, and DNA damage was measured using the NCA. Summary data demonstrated the OM never rose above baseline levels (Fig. 1D), indicating that Dexra did not cause any dsDNA damage. In addition, treating KK-15 cells for 24 h with a 100-fold range of Dexra doses induced less than 20% cell loss as measured by the ATP-based viability assay (Fig. 1E). A 3-h pulse exposure caused less than 5% cell loss (Fig. 1E). These data indicate that Dexra causes minimal toxicity in KK-15 granulosa cells.
To test the hypothesis that Dexra protects KK-15 cells from DXR-induced DNA damage, dsDNA breaks in cells exposed to DXR for 3 h, with or without a 1-h Dexra preincubation and continued cotreatment, were measured using the NCA. OM measurements quantified in Figure 2A demonstrated that cotreatment with 20 or 200 μM Dexra prevented DNA damage induced by 500 nM DXR. In addition, Dexra (0.2–200 μM) reduced dsDNA breaks resulting from 50 nM DXR treatment to at or below control levels (Fig. 2B). Dexra pretreatment is required to afford protection from DXR in KK-15 cells because adding Dexra and DXR to the cells simultaneously did not provide protection (data not shown). These data demonstrate that cotreating KK-15 cells with a 1000-fold range of Dexra concentrations prevented the onset of DXR-induced DNA damage in a dose-independent manner.
We tested the hypothesis that Dexra also attenuated DXR-induced H2AFX activation, the earliest cellular reporter of DNA damage. KK-15 cells were exposed to 500 or 50 nM DXR for 3 h (Fig. 2, C and D, respectively) with or without a 1-h, 2−200 μM pre- and cotreatment with Dexra. Nucleus-enriched lysate fractions were analyzed on Western blots probed for S139-phosphorylated (activated) H2AFX and β-actin (loading control) (Fig. 2, C and D). Dexra attenuated H2AFX phosphorylation in response to DXR at every dose tested, consistent with the DNA-damage protection afforded by Dexra in the NCA.
Dexra is an inhibitor of TOP2 catalytic activity, but it is also an EDTA derivative and can limit oxidative stress. To help determine which mechanism plays the primary role in preventing DXR insult in granulosa cells, we assessed Dexra's ability to prevent oxidative stress-induced DNA damage in our model system. KK-15 cells were treated with H2O2 (an oxidative stress-inducing agent) in the presence or absence of Dexra. The DNA damage response to the H2O2 treatment appeared greater than the 3-h DXR response, but the two were not significantly different. OM measurements revealed that a 1-h pre- and cotreatment with Dexra attenuated H2O2-induced DNA damage in a dose-dependent manner (Fig. 3). While 200 μM Dexra prevented and 20 μM Dexra diminished the DNA damage response to H2O2, 2 μM Dexra had no effect (Fig. 3). In contrast, both 2 and 20 μM Dexra completely eliminated DXR-induced DNA damage (Fig. 2B), suggesting that at these doses, the anti-oxidant effect is not sufficient to account for Dexra-mediated protection from DXR-induced DNA damage and that the protection may predominantly occur through inhibition of TOP2 catalytic activity. We attempted to copurify Dexra bound to TOP2 from the treated KK-15 cells to measure the extent of inhibition achieved in the cells during the Dexra treatments. Dexra does not bind covalently to TOP2, however, and is washed out during the stringent protein purification process required to purify and assay TOP2 activity (Brian Hasinoff, personal communication). Because we were unable to copurify Dexra-TOP2 complexes from KK-15 cells, we cannot rule out the involvement of undefined ovarian-specific mechanisms for Dexra-mediated protection in these cells.
To determine whether attenuating acute DNA damage translated into increased cell viability, we assessed changes in DXR's cytotoxicity dose-response curve in the presence or absence of Dexra. KK-15 cells were pretreated for 1 h with Dexra or DMSO (carrier control) followed by continuous exposure to DXR with or without Dexra as indicated in Figure 4. At 24 h post-DXR treatment, every Dexra dose examined right shifted the cytotoxicity curve, resulting in a 5- to 8-fold increase in the LD20 (Fig. 4). The LD50 would not have been an accurate measurement because 50% cell loss was reached only at the highest DXR dose with 24-h treatment, and the LD50 was therefore not calculated. Treatment with 10 μM Dexra afforded the best protection, inducing the largest LD20 shift. These data demonstrate Dexra preserves KK-15 cell viability in the presence of DXR.
The ovary is an organ with a complex structure, consisting of multiple cell types. To determine whether Dexra could protect ovarian cells from DXR insult in a more nativelike environment, murine ovaries were cultured in vitro and treated with DXR with and without Dexra. Both stroma/theca and granulosa cell populations exhibited a 40%–65% increase in dsDNA breaks, measured by the NCA, in response to a 3-h exposure to a range of DXR doses as summarized in Figure 5, A and B. In contrast, oocytes did not exhibit DXR-induced damage in response to the 3-h treatment with DXR (Fig. 5C). Cotreatment with 20 μM Dexra (1-h pretreatment and maintained in the media with DXR) prevented or significantly decreased DXR-induced dsDNA breaks in stroma/theca (Fig. 5A) and granulosa cells (Fig. 5B) at doses up to 10 μM DXR. Dexra had no protective effect on the oocytes because of the inherent absence of DXR-induced DNA damage (Fig. 5C). Cotreatment with 20 μM Dexra also prevented the DXR-induced 20%–40% increase in DNA damage across the same range of doses in primary murine granulosa cells (Fig. 5D). These data suggest that Dexra can protect the ovary as a whole from DXR insult.
To determine whether Dexra could increase the viability of primary granulosa cells to the same level as that seen with KK-15 cells, we assessed changes in DXR's cytotoxicity dose-response curve in the presence or absence of Dexra. Primary granulosa cells were pretreated for 1 h with Dexra or DMSO (carrier control) followed by continuous exposure to DXR with or without Dexra as indicated in Figure 6. After 24-h continuous DXR treatment, 20 and 200 μM Dexra right shifted the cytotoxicity curve for DXR, resulting in a ≥2-fold increase in the LD20 and 1.5- to 2-fold increase in the LD50 (Fig. 6), respectively. Treatment with 2 μM Dexra did not significantly shift the cytotoxicity curve (Fig. 6). These data demonstrate Dexra doses ranging from 20 to 200 μM preserve primary murine granulosa cell viability in the face of DXR insult.
This study is the first to identify Dexra as a drug-based protection mechanism to prevent anthracycline toxicity in the ovary and to implicate Dexra as a promising candidate for continued in vivo experiments to prevent DXR-induced ovarian insult. In the mouse model granulosa cell line, a wide range of Dexra doses eliminated acute DNA damage and H2AFX activation in response to DXR. Similar reductions in DNA damage were obtained using Dexra to protect mouse primary granulosa cells and in vitro mouse ovary cultures from DXR insult. The putative protective agent also significantly increased cell viability following DXR treatment.
This study is also the first to identify an ovarian protective agent that prevents both the primary DNA insult and ensuing toxicity, rather than inhibiting only apoptosis that occurs subsequent to the initial insult. In the ovary, an organ dedicated to supplying, protecting, and maturing oocytes for reproduction, genetic fidelity is critical. Oocytes have extraordinary DNA repair machinery, and simply blocking apoptosis in response to radiation or cisplatin is sufficient to preserve follicles and viable oocytes [44, 45]. Oocytes exposed in vitro, however, cannot repair DNA damage after premature removal from DXR treatment [46], so preventing the initial insult is critical to maintaining their genetic fidelity. Over the time course of our 3-h in vitro ovary treatment, oocytes did not exhibit DXR-induced DNA damage (Fig. 5). This is consistent with a TOP2-mediated damage model because a vast majority of oocytes in the ovary are meiotically quiescent. Whether oocytes would exhibit DXR-induced DNA damage, however, if followed over a longer period and as they mature remains to be seen. Future studies will determine whether Dexra protects oocyte DNA integrity in vivo in the face of DXR insult and whether the protection can be maintained to preserve development and maturation prior to ovulation and meiotic competence through to fertilization.
Maintaining the integrity of the other cell types comprising the ovary is also of paramount importance in preserving oocyte health. Granulosa cells sustain the oocyte; they are the primary site of DXR-induced apoptosis [6] and therefore must also be protected to preserve follicular and oocyte integrity. Furthermore, granulosa cells produce estrogen that promotes endometrial proliferation for embryo implantation and have a role in protecting from osteoporosis and urogenital atrophy [47]. Likewise, stroma/theca cells are integral to preserving ovarian structure and function, playing a key role in steroidogenesis and hormone synthesis. Data presented here show that Dexra prevented DXR insult in primary cultured murine granulosa cells and granulosa and stroma/theca cells from in vitro ovarian culture; future studies will determine whether Dexra also protects each ovarian cell type from DXR insult in vivo, thereby preserving follicular health and oocyte viability. The lack of Dexra protection of the oocytes in this study was due to the inherent lack of DXR toxicity on the oocyte in our model of ex vivo ovarian culture. While others have shown denuded oocytes cultured in vitro with DXR exhibit DNA damage [46], we did not observe induced DNA damage in our ex vivo ovarian culture, suggesting the surrounding follicular cells and stromal tissue may play a role in protecting the oocyte from DXR toxicity. The potential to protect the ovary as a whole from chemotherapy, regardless of cell type, makes Dexra a promising tool as an ovarian shield.
DXR can cause cellular toxicity via two main mechanisms: oxidative stress and TOP2-mediated dsDNA breaks following DXR intercalation into DNA. If DNA damage occurs via the TOP2-dependent mechanism, we predict that Dexra-afforded protection will be solely dependent upon Dexra's inhibitory constant for TOP2 and therefore independent of DXR concentration. In agreement with this prediction, we found that DNA damage caused by 50 or 500 nM DXR was prevented by Dexra under identical pretreatment conditions (Figs. 2 and and5).5). If the tested Dexra dose is sufficient to completely inhibit TOP2 activity, the observed protection will also be independent of Dexra concentration. While we could not copurify TOP2-Dexra complexes from treated KK-15 cells, studies from multiple groups have demonstrated that Dexra and other members of the bisdioxopiperazine family inhibit the enzymatic activity of purified TOP2 [48, 49] and have identified residues in the N-terminus of TOP2 critical for Dexra binding through mutation and crystallography studies [25, 26]. Our data fit the model of TOP2 dependency for dsDNA breaks because every tested Dexra concentration afforded similar protection from DXR-induced DNA damage (Fig. 2). In contrast, Dexra prevented oxidative stress-induced DNA damage in a dose-dependent manner. In addition, doses of 2 and 20 μM Dexra were sufficient to completely prevent DXR-induced DNA damage in KK-15 and murine granulosa cells, but either failed or only partially decreased H2O2-induced DNA damage. We therefore propose a model in which DXR causes acute DNA damage in granulosa cells primarily in a TOP2-dependent manner and KK-15 cells are protected from that insult mechanism by Dexra pretreatment. Dexra-afforded protection from DXR-induced cytotoxicity, however, may be more complicated. In primary murine granulosa cells, 20 and 200 μM Dexra increased cell viability in response to DXR, where 2 μM Dexra did not. This dose dependence suggests that DXR cell demise may include an oxidative stress response or other unknown ovarian-specific mechanisms. In addition, Dexra did not completely prevent DXR-induced cell demise at DXR concentrations above 100 nM, consistent with the possible role of multiple DXR-toxicity mechanisms or indicating that higher doses of Dexra may be required to completely eliminate DXR-induced cytotoxicity.
Dexra pretreatment is required to afford protection from DXR in our cell system, just as in the heart and skin; adding Dexra and DXR to the cells simultaneously did not provide protection. While DXR is labeled a TOP2 poison, Dexra is an inhibitor of TOP2 catalytic activity, and the two drugs act at different points in the enzymatic cycle of TOP2 as illustrated in steps 1 and 2 of the model (Fig. 7). DXR, and other TOP2 poisons, act early in the enzymatic cycle, preventing resealing of TOP2 dsDNA breaks based on the drug's presence in the DNA strands (step 1 of the model, Fig. 7) [16, 27, 28, 50]. During normal DNA processing, in the absence of TOP2 poisons, TOP2 seals the strand breaks and then releases the DNA (step 2 of the model, Fig. 7). Dexra acts by stabilizing the closed-clamp conformation in which TOP2 holds the DNA after resealing breaks [16, 23, 27, 28, 50]. In this model, pretreating cells with Dexra locks TOP2 in the closed-clamp conformation, preventing DNA release from the TOP2 complex and making the enzyme unavailable to cleave the DNA when cells are subsequently treated with DXR (step 3 of the model, Fig. 7). We hypothesize that this allows the cells to clear DXR, providing long-term increase in cell viability. The effects of Dexra are reversible, making it well-tolerated in slow- or nondividing cells.
Whether only one of both of the DXR-insult mechanisms occurs in the intact ovary in vivo remains to be seen. The ovary is a unique, heterogeneous organ within which follicles reside in various developmental stages ranging from rapidly growing antral follicles to quiescent primordial follicles. It is possible that these distinct follicle populations respond differently to DXR based on cell division rates and metabolic activity. One model is that primordial follicles may respond to DXR via the oxidative stress pathway, in a manner similar to nondividing heart cells, while growing follicles may succumb to TOP2-mediated DXR insult. Given this inherent heterogeneity of the organ, however, our data indicate that Dexra may still be effective in protecting the ovary as a whole. Dexra similarly protected granulosa and stroma/theca cells with no evidence for separate populations exhibiting differential responses. These data therefore suggest Dexra provides a unique tool that may be well-suited to protecting a heterogeneous organ like the ovary because it can prevent both mechanisms of DXR toxicity and appears effective across granulosa and stroma/theca cell types. Future studies may also determine whether other members of the bisdioxopiperazine family can similarly protect the ovary from chemotherapy insult.
Dexra may provide a time- and cost-efficient way to attenuate DXR insult in the ovary and prevent premature menopause and associated health risks without decreasing the effectiveness of cancer therapy as evidenced by its clinical application to prevent both DXR-induced cardiotoxicity and extravasation [17–21]. Dexra does not diminish DXR antitumor activity in pediatric leukemia cases; while it may slow the response, it does not diminish survival in breast cancer cases; and nor does Dexra increase the risk for secondary malignant neoplasm in leukemia cases [17, 31–41]. One possible explanation for this dichotomy, protecting healthy tissue but not cancer cells, was provided in a mechanistic study by Yan et al. [51]. Their work demonstrated that while Dexra blocked DXR-induced dsDNA breaks in a human fibrosarcoma cell line, it did not prevent DXR-induced apoptosis that occurred via glutathione depletion in a TOP2-independent manner. Dexra can have synergistic effects when combined with other chemotherapy agents in cancer treatment. Dexra impairs the development of DXR resistance in the leukemia cell line K562 [52] and is synergistic with docetaxel or docetaxel plus DXR in treating MCF7 wild-type or resistant breast cancer cells and BT474 breast cancer cells [53]. Combined therapy incorporating Dexra with DXR allows an increase in the maximal DXR dosage used [40]. This may be beneficial for patients with triple-negative breast cancer, whose cancer is aggressive and DXR is part of the frontline chemotherapy regime [38, 41, 54]. Similarly, Dexra pretreatment allows increased doses of etoposide in a mouse model by preventing not only cadiotoxicity, but preventing etoposide-induced decreases in white blood cell, platelet, and absolute neutrophil cell counts [55], suggesting that Dexra has the potential to prevent insult across a range of TOP2 poisons.
Utilizing a chemical ovarian shield like Dexra presents a clear advantage over traditional hormone replacement therapy and current fertility preservation approaches. Traditional fertility preservation options are both time and cost prohibitive. While they can provide the option for a female cancer survivor to have biologically related children in the future, they do not protect endocrine function of the ovary. This leaves survivors susceptible to premature ovarian insufficiency and associated health complications, including osteoporosis and cardiovascular disease. Ovarian hyperstimulation and in vitro fertilization cycles required for oocyte and embryo banking for cancer patients can delay cancer therapy and promote the growth of tumors that are hormone responsive. In addition, oocyte and embryo cryopreservation are not treatment options for prepubescent patients. Pretreating patients with Dexra prior to DXR may provide a time- and cost-effective way to preserve not only fertility, but endocrine function as a whole. It is a therapy that should be equally effective in pediatric as well as adult cancer patients and bypass the pitfalls of hormone stimulation. This therapy therefore has the potential to increase the quality of life for female cancer patients without compromising their cancer treatment.
The authors are extremely grateful to Dr. David Abbott for ongoing mentorship and aid with statistical analysis, manuscript review, and scientific input; Scott Leisman for scientific input; Trever Greene, Polly Godfrey, Abby Forss, and Lydia Weyenberg for technical assistance; and Sharon Moses for providing doxorubicin from the University of Wisconsin-Pharmacy.
1Supported by startup funds from the University of Wisconsin-Madison and NIH training grant K12HD0558941 to S.M.S., and by the UW-Madison Comprehensive Cancer Center grant NIH/NCI P30 CA014520.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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We welcome you to the Broomfield Democrats. We are a progressive grass roots organization that acts on the principles of equality among all people, individual liberty, belief in a transparent democracy, and the value of public service. We welcome all interested persons, and hope that if you are not already an active member, you will find in our policies and actions a like-mindedness that resonates with you. We invite you to see for yourself by attending a monthly meeting.
All registered Democrats who reside in Broomfield County are considered bona fide members of the Democratic Party of Broomfield. We encourage members to become active and participate in Party functions, and to seek decision-making positions within the Party.
Mission Statement
The mission of the Broomfield County Democrats is to be the leading political organization in Broomfield as measured by respect, political knowledge of the county, turnout for Democratic candidates and success of the Democratic agenda.
- News from OFA's Truth Team - May 23, 2015
- CDP Statement on the Affordable Care Act in Colorado - December 4, 2013
- Broomfield Democrats Attend Officers' Summit - June 22, 2013
- Statement from Rick Palacio, Chairman of the Colorado Democratic Party on HB 1303 Voter Access & Modernized Elections Signed Into Law - May 10, 2013
- Announced Democratic Candidates for 2014 State Election
Stay tuned for breaking news as it occurs!


text:
Outraged Members of Congress Move to Halt US Funding of Secret Armies in the Andes
Congressional outrage over the killing of civilians by the Peruvian Air Force has spurred increased opposition to US privatization of the drug war.
Congressperson Jan Schakowsky, an Illinois Democrat and one of the most progressive voices in Congress, has just introduced legislation–the Andean Region Contractor Accountability Act (ARCAA)–to end US funding of secret armies in the Andes.
- Congresswoman Jan Schakowsky (D-IL-9)
This is a rush transcript. Copy may not be in its final form.
AMY GOODMAN: We continue on the issue of secret wars in Latin America and mercenary forces. Congressional outrage over the killing of innocent civilians, the missionary and her infant, by the Peruvian Air Force, having been targeted by a CIA crew on a plane, has spurred increased opposition to U.S. privatization of the drug war.
Congressperson Jan Schakowsky, a Democrat of Illinois, one of the leading progressive voices in Congress, has just introduced a bill to end U.S. funding of secret armies in the Andean region, and she joins us on the phone from Congress right now. Welcome to Democracy Now!
REP. JAN SCHAKOWSKY: Thank you. I'm glad to be with you.
AMY GOODMAN: Well, can you explain the bill that you've just introduced?
REP. JAN SCHAKOWSKY: I've introduced legislation that would prohibit the United States government from entering into any contract with private organizations or individuals, quote, "to carry out military, law enforcement, armed rescue, or other related operations in the countries of the Andean region, including any operations relating to narcotics control efforts." Essentially, this says we can't enter into these kind of private contracts that lead us into secret wars.
AMY GOODMAN: We just finished a half-hour conversation with Juan Tamayo, who is Miami Herald Andean correspondent in Bogota, Colombia, going through Dyncorp and MPRI and the other private companies. Do you call these "mercenaries"?
REP. JAN SCHAKOWSKY: I would say "mercenaries" is exactly the right word to use. It's interesting that, actually, Juan has more information than members of Congress are able to get. I talked to the CIA, and they wouldn't even tell me — they wouldn't neither confirm nor deny that private contractors were involved in the Peruvian shoot down, that how much money is being spent. It's all top secret. They won't tell us anything, which has — your lead-in was congressional outrage. This was on both sides of the aisle, from either end of the political spectrum. The most conservative to the most progressive of members are just furious about the lack of information.
AMY GOODMAN: So what kind of support do you have?
REP. JAN SCHAKOWSKY: Well, how this is going to eventually play out is unclear, but I know that Dan Burton, who chairs the Government Reform Committee, is pretty determined to get at the bottom of it. He doesn't understand why that would be classified information. If we're using taxpayer dollars to fund these activities, if in fact they're legitimate activities, then shouldn't the American people know about it? So I'm hoping at least disclosure will be the end of it.
In terms of support, I have a number of co-sponsors on the Democratic side of the aisle and intend to continue to push this legislation.
AMY GOODMAN: You're talking about so many ex-CIA operatives; former military men, like MPRI being headed by retired General Carl Vuono, who commanded the Army during Desert Storm; ambassadors; former CIA officials. Can you really talk about these as separate from the government? Is it just a way of providing deniability for the U.S. government in these military actions abroad?
REP. JAN SCHAKOWSKY: Well, I think that it may be that. That's one of the questions that I asked, if it was to provide deniability. Are we trying to avoid public scrutiny, controversy, embarrassment? Do we want to end up hiding body bags from the media and shielding them from public opinion? I think these are all important questions that need to be answered. But to me it's pretty obvious on its face. We're already spending $300 billion a year to fund the world's most powerful military. How much more are taxpayers paying, and why?
AMY GOODMAN: The name of the bill you've introduced, if people are interested and getting in touch with their Congress members?
REP. JAN SCHAKOWSKY: Yeah, the name of the legislation is the Andean Region Contractor Accountability Act, and the number is HR1591.
AMY GOODMAN: That's the Andean Region Contractor Accountability Act or ARCAA, legislation that would prohibit the federal government from funding private armies in the Andean region.
Jan Schakowsky, I want to thank you for being with us. I know you're just in the midst of caucus meetings and other congressional activities. Jan Schakowsky is a Congress member from Illinois, a Democrat.
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Apple incompetence could save the world
Three malwares could wipe out all things Apple
Apple's faith based security system could end up smashing every iPhone and IPad in the world and thus saving the world.
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text: So determined was I to get to my appointment, that I skipped a funeral. I went to the wake the night before, so maybe I'm not a completely horrible person. Anyway, I got there, peed in a cup, filled out a bunch of paperwork and waited. I was finally called, went in, got weighed (way more than I thought) and got my blood pressure taken (111/51, good for me). I was escorted to the room, where a nurse introduced herself, congratulated me (pee test came back positive, obviously) and told me I'd be seeing a lot of her in the next 9 months. I nodded but managed to keep the "we'll see" inside. She left after telling me to strip down and put on one of those horrid gowns. I did as I was told, sat on the table and waited. The doctor finally came in, made some small talk, then proceeded to feel me up. Once the breast exam was over, she did an internal and then that horrible beginning of pregnancy feeling the uterus thing that I am always sure is going to unlodge my very fragile pregnancy. I was told all was looking well and then we discussed my past medical history, which was quick since there were no changes since the miscarriage last May. She told me she was going to send me for blood work and an ultrasound to see how this pregnancy was going. She gave me a prescription for more progesterone and for prenatal vitamins and then told me to go see the receptionist to make my next appointment. I got dressed and went to the window where I was told I was to make my appointment for two weeks. I was confused, but took the appointment. The doctor came out to tell me to make another appointment for the ultrasound. Apparently, the new health insurance allows me to have it in the office instead of going to the women's imaging place. They make the appointment for the 30th and I'm to come back and see the doctor on the 31st. After that I am going to rotate between all of the doctors in the practice. So I leave, all happy because the doctor seems to be taking my past miscarriages seriously. This lasts until I get to the car and wonder whether perhaps my uterus seemed small or she saw something during the internal that she didn't mention. Maybe that's why I need to come back in two weeks. I fight the urge to go back in and ask, and instead return home. I worry about cramping (which I didn't really have) all day, blaming the uterus measurements. I refuse to go to LabCorps to get blood work because it's noon and I have no desire to sit and wait for two hours. I went and got my blood taken this morning. My veins dislike needles and it usually takes at least 4 tries to get blood. The lady managed to get all 4 vials of blood in one stab and I happily return home. I have spent the rest of my day today wonder whether my doctor is concerned (because of previous miscarriages) or concerned (imminent miscarriage). My mom thinks she's just concerned (better insurance equals better care). If I don't get a phone call about my blood work, all is well. If I make it until the 30th, I'll have the ultrasound and maybe that will make me feel better. I never really had a good ultrasound in the last three pregnancies. Weak, or nonexistent heartbeats, hemorrhages, etc. So I sit and wait some more.


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text:
A sample of folders in my web application is as follows:
--> MasterPages/MasterPage1.aspx
--> Reports/Clients/ARReports.aspx
--> AboutUs/CompanyInfo.aspx
--> Javascript/General.js
I have added Print ImageButton to Master page MasterPage1.aspx. It has a JavaScript function onClientClick event:
<asp:ImageButton ID="imgbtnPrint" runat="server"
AlternateText="Print" OnClientClick='javascript:PrintContent("printable");this.blur();return false;' />
The PrintContent function is in General.js file.
CompanyInfo.aspx and ARReports.aspx both have Masterpagefile = MasterPage1. Now the issue is that the Print ImageButton in CompanyInfo.aspx is able to call the JavaScript function when clicked. However, in ARReports.aspx no JavaScript function is fired when clicked.
What could be the problem? The ImageButton is in Master page which refers to the JavaScript file which has the JS function. It is working for CompanyInfo.aspx, but if we go deep inside the folders, it is not working.