Selected works of art are currently on display at Homer High Schools old music building for the Imagination Celebration, an art show for Cortland County K-6 students. The opening reception was Thursday, March 21, and the artwork is available for viewing through Sunday, March 31. Twenty McGraw elementary students were selected to have artwork showcased in this county wide art show! It was extremely difficult to choose pieces to enter the show, since Mrs. Rickards is proud of all of the artwork being produced in the art room! Keep up the great work!


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Peter Sermanni	Player Profile
Peter Sermanni (b. 1971)
Full Name: Peter Hugh Sermanni
Born: July 9th, 1971 (Glasgow)
Signed: August 31st, 1990
Career Totals: 35 appearances, 4 goals
1991-92 First Division 4 0 - 0 0 50.0% 0.0% 50.0%
1990-91 First Division 21 (10) 4 0.13 4 0 29.0% 25.8% 45.2%
Totals: 25 (10)	 4
Dec 8th, 1990 08/12/90 League Division 1 vs. Meadowbank Th (A) 3 - 0
Dec 1st, 1990 01/12/90 League Division 1 vs. Airdrie (H) 5 - 2
Nov 24th, 1990 24/11/90 League Division 1 vs. Forfar (A) 3 - 0
Sep 8th, 1990 08/09/90 League Division 1 vs. Dundee (H) 1 - 3
Dec 8th, 1990 08/12/90 League Division 1 vs. Meadowbank Th (A) 3 - 0 (67')
Dec 1st, 1990 01/12/90 League Division 1 vs. Airdrie (H) 5 - 2 (65')
Nov 24th, 1990 24/11/90 League Division 1 vs. Forfar (A) 3 - 0 (72')
Sep 8th, 1990 08/09/90 League Division 1 vs. Dundee (H) 1 - 3 (43')
May 4th, 1991 04/05/91 League Division 1 vs. Raith Rovers (A) 2 - 1 (sub)
Apr 2nd, 1991 02/04/91 League Division 1 vs. Morton (A) 2 - 2 (sub)
Mar 30th, 1991 30/03/91 League Division 1 vs. Dundee (H) 1 - 1 (sub)
Mar 23rd, 1991 23/03/91 League Division 1 vs. Forfar (A) 2 - 2 (sub)
Mar 16th, 1991 16/03/91 League Division 1 vs. Brechin City (H) 1 - 0 (sub)
Jan 26th, 1991 26/01/91 Scottish Cup 3rd Round vs. Ayr Utd (H) 0 - 1
Jan 19th, 1991 19/01/91 League Division 1 vs. Partick Th (H) 2 - 3 (sub)
Jan 5th, 1991 05/01/91 League Division 1 vs. Hamilton Accies (A) 0 - 2
Jan 2nd, 1991 02/01/91 League Division 1 vs. Morton (H) 2 - 4 (sub)
Dec 22nd, 1990 22/12/90 League Division 1 vs. Ayr Utd (H) 0 - 2
Dec 15th, 1990 15/12/90 League Division 1 vs. Raith Rovers (H) 1 - 1
Nov 17th, 1990 17/11/90 League Division 1 vs. Clyde (H) 2 - 1
Nov 10th, 1990 10/11/90 League Division 1 vs. Falkirk (A) 1 - 5
Nov 3rd, 1990 03/11/90 League Division 1 vs. Brechin City (H) 3 - 4 (sub)
Oct 27th, 1990 27/10/90 League Division 1 vs. Ayr Utd (A) 1 - 1 (sub)
Oct 13th, 1990 13/10/90 League Division 1 vs. Morton (A) 0 - 2
Oct 6th, 1990 06/10/90 League Division 1 vs. Airdrie (A) 2 - 2
Oct 2nd, 1990 02/10/90 Challenge Cup 1st Round vs. East Fife (H) 1 - 2
Sep 29th, 1990 29/09/90 League Division 1 vs. Meadowbank Th (H) 2 - 2 (sub)
Sep 22nd, 1990 22/09/90 League Division 1 vs. Raith Rovers (A) 0 - 2
Sep 18th, 1990 18/09/90 League Division 1 vs. Kilmarnock (H) 1 - 3
Sep 15th, 1990 15/09/90 League Division 1 vs. Partick Th (A) 1 - 0
Sep 1st, 1990 01/09/90 League Division 1 vs. Falkirk (H) 3 - 1
Clydebank 3 - 1 Falkirk
Peter was born on this date in Glasgow.
Friday, August 31st, 1990
Debut - Clydebank 3 - 1 Falkirk
Saturday, September 1st, 1990
First Goal - Clydebank 1 - 3 Dundee
Saturday, September 8th, 1990
Last Goal - Meadowbank Th 0 - 3 Clydebank
Saturday, December 8th, 1990
Last Appearance - Clydebank 1 - 3 Hamilton Accies

redpajama_set_name: RedPajamaCommonCrawl


In part one of this two-part series, we examined the Canada Pension Plan's (CPP) investment in drones, computerized soldiers, land occupation and an infamous prison scandal. Part two is dedicated to the many potential conflicts of interest — yours, mine, the executives' and the PMO's. Some might be moral. Some might be something more.
If you look at the CPP Investment Board of Directors, you will find that all but one executive was appointed since the determined change in strategy under the Harper government. These board members are skilled leaders from different industries, but no matter their background, most of them share something in common.
Bourne is also the Director of Canadian Oil Sands Limited, which has a large stake in the Syncrude project — the project at the heart of a lawsuit involving Greenpeace and the death of wildlife. Syncrude was convicted and fined more than half a million dollars. Our CPP investments in this company total $80 million.
David Suzuki continues to educate about the misnomers of "ethical oil" and points to other companies in business with the Alberta oil sands. Exxon Mobil has a history of major oil spills. CPP gave them $553 million. Exxon funded a lobby against the Kyoto Protocol, and Canada eventually cancelled our commitment to the international community.
BP is responsible for the tragic Gulf Coast oil spill that may cost more than $7 billion in legal settlements to cover the damage. And if we look in our CPP foreign column, we'll find $347 million invested in BP.
Nexen is another curious entry with $62 million in CPP investments. It's unclear what will happen to this particular investment, since Harper made waves by allowing the company to be purchased by China. The deal was embroiled in controversy regarding national security. CSIS raised concerns about compromising Canadian intelligence, while the United States rebuked the purchaser's energy partnership with Iran. Still, it went unreported that the Securities and Exchange Commission (SEC) had to freeze assets to investigate cases of Nexen insider trading that resulted from our sell-off.
CPP also has $218 million invested in TransCanada Corp. They're the ones fighting for the Keystone XL pipeline that was met with public backlash across the continent. We have another $201 million socked away in Enbridge, which has challenged Native land rights in preparation for the Northern Gateway pipeline.
Moving along in our Board of Directors, we arrive at Pierre Choquette was the CEO of Methanex. Douglas W. Mahaffy is the current director of Methanex. This company is the world's largest producer of methanol for petrochemical use. It received $38 million from CPP. Choquette further served as a director at TELUS, which received $116 million from CPP. TELUS employs two former consultants linked to the E-Health scandal that rocked Ontario.
Heather Monroe-Blum sits on the Board of Directors for the Royal Bank of Canada. RBC received $707 million from CPP and is the Plan's largest domestic holding. That's putting a lot of our eggs in one basket, which seems unwise, especially when that one company has been implicated in the LIBOR scandal .
Karen Sheriff heads Bell Aliant as the CEO and president. CPP invested $21 million with that company. Joe Mark Zurel is listed as the Director of Major Drilling Group, which also received $12 million from CPP. Nancy Hopkins is the Director of Cameco Corporation. CPP invested $43 million there. Robert Brooks was the Vice Chair of Scotiabank. CPP invested $537 million in the company. Brooks also headed Dundee Wealth and CPP invested $20 million with Dundee's parent company.
In addition to these revelations, the CPP is a substantial partner of Onex. The Onex Corporation purchased Raytheon's air division in 2006. Raytheon is a defence contractor. It's the world's largest producer of guided missiles and nuclear warheads. These weapons are involved in conflicts from Iraq to Afghanistan, from Libya to Syria and everywhere the U.S. military sets foot. The acquisition of Raytheon's flight technology created the Hawker Beechcraft company, putting Onex in the business of peddling combat planes to governments.
The managing director of Onex was Nigel Wright. He took leave from the position to become our Prime Minister's chief of staff, exactly two months after CPP entered a multi-billion dollar partnership with his company. While the Conservatives called this "great news for Canada's economic policy," the NDP's Charlie Angus cautioned Wright to "follow the rules" regarding conflict interest.
Wright was recently cleared in an ethics probe about the same issue with Barrick Gold (in which CPP holds a $330 million stake). The founding family of Barrick sat on the Onex board of directors and there were questions about personal lobbying that could have led to the PMO.
Despite the investigation's positive outcome for Wright, MP Angus took issue with the commissioner's process. When additional conflict issues were raised by OMERS, they were dismissed as mistakes in a hasty response from the Prime Minister on Wright's behalf.
As we've seen, Harper's chief of staff is also connected to Lockheed Martin (incidentally CPP holds $78 million in that company as well). Nigel Wright's duties as director of Onex included oversight of Hawker Beechcraft, the partner to Lockheed Martin, which produced the fighter jets at the centre of F-35 debacle. This places the CPP in a bizarre love triangle with Onex and Lockheed, well beyond anything we purchased in stock.
Hawker Beechcraft's Onex deals with Lockheed include supplying the US Air Force and Homeland Security with cannon equipped fighter jets. They produce a handful of warplanes with rocket capability and their accounts include the Canadian, American, Greek, Israeli, Iraqi, Moroccan and Mexican military. One of the shared executives (PDF) managed the Lockheed F-35 file before coming to head government relations at Onex's Hawker Beechcraft.
So that introduces our business partner.
In July 2010, CPP and Onex purchased Tomkins PLC together, for $4.5 billion (£2.9 billion) with our retirement dollars. We are equally listed owners and our acquisition provides hydraulics to the oil, gas and mining industries. Tomkins was also the previous owner of Smith and Wesson guns before we bought them out.
In November 2012 CPP deepened its relationship with Onex to acquire Tomkins Air Distribution for an additional $1.1 billion (PDF); meaning when Nigel Wright leaves his position with the Prime Minister's Office, he'll presumably return to managing our CPP partnership from the private industry end.
With the 2012 expansion, Onex and the CPP came to own all subsidiaries under the parent heading. One of those spinoffs is Titus, a company that provides data security to the military in Canada, the U.S., Australia, Belgium and Denmark. Titus provides services to the whole of government, aerospace, police and financial industries.
The moral of the story is we've got to come clean about the unethical use of our retirement funds. There isn't enough money to expand CPP because the surplus was earmarked to boost the military-industrial complex. When our hard-earned money isn't being used to cause bloodshed, it's going to companies affiliated with the CPP's own CEOs and the Alberta oil sands.


Below you will find a listing of selected Artscape research, including key works for full download.
In February of 2011, Artscape released a report – Advancing Toronto's Centre for Creative Sector Entrepreneurship – that presents the findings of a 12-month-long research and sector engagement study that sought to understand the macro-market challenges facing the creative and cultural sector in Toronto.
The report calls for the creation of centre that will cultivate the entrepreneurial capacity and business skills of self-employed individuals and micro-businesses across a spectrum of creative and cultural sector enterprises. The centre would support the development of a resilient, sustainable, innovative and successful sector that makes a growing contribution to the prosperity of the city.
The report recommends that GTA needs a place that acts as a portal to what is available, while at the same time clustering and coordinating the efforts of those providing services.
Work on the study was guided by an Advisory Committee consisting of representatives from the City of Toronto Economic Development Office, Cultural Careers Council Ontario, Toronto Fashion Incubator, Toronto Business Development Centre and Ontario Ministry of Culture. The study was funded in part by The Ontario Trillium Foundation Future Fund and the City of Toronto Economic Development & Culture Division.
Toronto's identity has been re-energized over the past five years through cultural, political and community leadership. The city's Cultural Renaissance began with new iconic museums, galleries and training institutions then gained further momentum through Nuit Blanche, Luminato and a host of other programs and events. On the heels of this great adventure, a new wave of energy is building in the city's cultural and creative sector. It could be said that the first wave of the Cultural Renaissance helped put "creativity on display" with greater panache than ever. The second wave, in contrast, is about putting "creativity to work" to build our city and grow our prosperity.
The Convergence Centres: Building Capacity for Innovation report is intended to contribute to Toronto's progress in generating a more sophisticated understanding and advancing a more strategic approach to growing the cultural and creative sector. The impetus for the report grew out of the Strategies for a Creative City study in 2005/06. Through this study, a group of directors from Toronto's creative institutions realized that there was a groundswell of new infrastructure development that was happening below the radar and formed the Creative Convergence Project Consortium. It included more than a dozen major new projects that shared an interesting characteristic – they were purposefully designed to optimize creative work by providing a platform for collaboration. The Convergence Centres: Building Capacity for Innovation report reveals new ways that talent, space and collaboration are being combined and leveraged to fuel our capacity for innovation. It has already been successful in generating numerous collaborations, partnerships, and networks. We hope this work will also provide helpful insight for governments at all levels that are looking for new ways to stimulate the economy, create jobs and build infrastructure for the future.
Artscape played a leadership role in developing a strategic framework for supporting and nurturing Toronto's creative economy. Informed through an international best practices study, the framework profiles the city's creative assets, highlights challenges to supporting the creative economy and identifies opportunities to strengthen four key pillars of creativity and innovation – people, enterprise, space and connectivity.
Artscape partnered with Ryerson University and the City of Vancouver to explore the spin off effects of investing in cultural facilities at a local level. The research offers cultural institutions a means of demonstrating a range of social, environmental and economic impacts in their communities.
On Wednesday, January 26, 2011, a community meeting was held to present the research and final recommendations of Artscape's feasibility study on a cultural/creative hub in Weston Mount Dennis that was commissioned by the City of Toronto. The full report was submitted to the City in March 2011.
In July 2010, the City of Toronto issued a Request for Quotations (RFQ) for a feasibility study for a cultural/creative hub in Weston Mount Dennis. The purpose of the RFQ was to identify and retain a team of researchers who could create a model for a cultural/creative hub that could be used in Toronto's Priority Neighbourhoods, and to apply that model to the Weston Mount Dennis area.
To ensure that the model was grounded and well researched, a survey of best practices among cultural/creative hubs in Toronto and internationally was mandated as was substantial primary and secondary research into the state of the cultural and creative sector in the study area. The public's involvement and input was to be solicited through an information meeting with key local organizations and networks, a Community Open House and a presentation to the community of the report findings.
The report investigates the feasibility of cultural/creative hubs in socially, economically and culturally disadvantaged areas. This report hopes to offer some answers as to how cultural/creative hubs may be one tool that can be used to stimulate economic growth and the broader benefits of culture-led regeneration in Toronto's Priority neighbourhoods.
Artscape was retained by the City of Toronto to explore the conditions for the successful development of cultural /creative hubs in Toronto's "priority neighbourhoods"; to develop a model for sustainable cultural/creative hubs in these economically and socially challenged communities and to explore the feasibility of developing a project in the Weston Mount Dennis areas of Toronto's west end.
Artscape was retained by the Toronto Economic Development Company (TEDCO) to explore the potential for the development of a "centre for creative enterprise" in Toronto's Liberty Village. The report explored place and space based conditions for the emergence of dense creative districts and international models designed to support and grow the creative sector as a key economic driver of growth and transformation.
Artscape was retained as part of a consultant team led by Canadian Urban Institute to develop the City of Mississauga's first Culture Master Plan. The plan, which supports the City's Strategic Plan, provides a framework and long term vision, and identifies key opportunities and strategies for implementation over a five year period.
Artscape was retained by the City of Vancouver to research and develop a Cultural Facilities Priorities Plan that articulated cultural space and place priorities for the City for the next 15 years along with recommendations on strategies for how the city, working with the community, government and private partners, could realize these priorities. The plan is a key aspect of the city's Culture Plan implementation.
The City of Ottawa selected Artscape and LORD Cultural Resources as part of a consultant team to develop a building program and business plan for the transformation of an existing multi-tenant arts facility. Artscape developed a comprehensive sector engagement strategy and business plan that provided the foundation for a renewed civic role for the heritage site as a leading centre of innovative and multi-disciplinary performing and visual arts.
Artscape was engaged by the Toronto District School Board to undertake a preliminary feasibility study of transforming the former 1915 Givins-Shaw Public School into a community-based arts and cultural centre. Artscape's community engagement strategy established a strong vision based on the intersection of community, creativity and learning. This study provided the clients with a successful pilot process to addressing the repurposing of surplus school properties.
As a key initiative of the City of Kitchener's Downtown Strategic Plan, Artscape was selected to identify local creative assets, evaluate development opportunities for cultural infrastructure in the core area and to articulate key strategies for the municipality as a key stakeholder in the regeneration process. The framework provided a blue-print that reinforces the role of the creative sector in downtown's emergence as the City's civic, entertainment and cultural centre.
Artscape was selected as part of a U.S.-based consultant team to identify and connect the cultural assets of three business improvement districts into a more cohesive strategic framework. As a key initiative of the City of Saskatoon's Cultural Capital Program, Artscape developed an integrated strategy for the Cultural Crescent areas focused on festival programming, cultural infrastructure development, independent retail attraction initiatives and governance models.
As part of a broader master planning process, Artscape teamed with LORD Cultural Resources to develop a vision and preliminary strategy for attracting and sustaining a broad range of cultural activity throughout Toronto's East Bayfront Precinct. Strategies focused on affordable infrastructure provision, infusing artists in the development process, accommodating mixed-uses, and developing high-quality public spaces.
Artscape prepared a feasibility analysis for a downtown, multi-tenant arts facility for the St. Catharines and Area Arts Council . Artscape's engagement process brought together a range of public, private and non-profit interests to create a vision and implementation framework for the shared facility. The Arts Cluster model provided a new catalyst for arts activity in the downtown area and provided affordable programming space for non-profit arts organizations.
Artscape was retained by the City of Kingston to undertake a multi-phase feasibility and business planning process for the redevelopment of a 57,000 ft2 former distillery on Kingston's waterfront. The proposed development model integrated plans for a Queens University concert hall and black box theatre with community-based performance, programming and office space to create a new cultural learning hub for the region. The concept and business plan provided a successful foundation for the integration of institutional expansion needs and an existing cultural community.


Manchester City are coming off a big win and will have high hopes that they can continue this good form as they travel to London where they will face West Ham in what is set to be a good game. Both teams are exciting to watch and it should be a game filled with plenty of goals and entertainment.
West Ham are a team in good form and although they lost to Newcastle last week, they will be confident that they can turn things around with the help of their superstar player, Dmitri Payet. This team is so much better with the French superstar around and now that he is back from injury, Hammers supporters are starting to believe again. That being said, they will be facing some tough opposition this weekend and I think it will be a little too much for the Hammers.
Manchester City, as we all know, are filled with superstars all throughout the park. They will go into this match confident and that will be good for the Sky Blues as they look to take first place. I think that they will cruise home here but statistics show that they will concede. Kompany is still out and without him, that backline is not very steady so I expect a few goals to be leaked at the back.
As far as betting is concerned, betting on the result is not a good play since City will win but we are not getting good odds and taking a handicap with the team on the road is not profitable. That is why taking both teams to score is the best option here. Kompany is out so City will probably not keep a clean sheet and I am almost certain that City will score so that is a good bet in my opinion.


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Sleepless Knights of the Milky Way
There is an argument to be made, especially after the expansion of Fantasyland was completed, that the Magic Kingdom is the most complete park in all of Walt Disney World. Making a quick check of the circuit, Epcot has needs both in Future World and around the lagoon of World Showcase, Disney's Animal Kingdom continues to plus its experiences, but could definitely expand, and Disney's Hollywood Studios, in the midst of a massive renovation, has been in need of targeted growth and development for years. Looking around the Magic Kingdom, there is a lot of good to be seen. Great dining, wonderful classic and modern attractions, and stories can be found around every corner. If there is one area that could be pointed to as a blight on an otherwise stellar park, however, it would be Tomorrowland.
In fact, the problem with Tomorrowland might actually be terminal because it can't answer the founding principle upon which it was built. That is to say that if you were to ask for a definition of Tomorrowland, there has never been a clear cut answer. The land has an identity crisis that isn't easy to solve. There have been some brave attempts to do so over the years, not the least of which was the land's complete overhaul in 1994, but nothing has ever stuck.
The inherent issue stems from how fast technology moves. While sixty years ago it was believed we'd have flying cars by now, the lack of flying cars doesn't mean that things have sat still. Things we could only have dream of a decade ago are now commonplace in society today. Defining what tomorrow looks like means that there is a finite amount of time that you have before that image becomes one of two things, either it becomes true in the here and now or it begins to look like a farcical daydream. In terms of it becoming true, you've now turned at least some portion of your vision of tomorrow into a look at today. Remember the gag in Meet the Robinsons where they flew by the amusement park called Todayland? That's what can happen with a realistic view of tomorrow.
The other idea is to look at the world of tomorrow through the lens of science fiction. Creating a world that could never be, or one that relies upon another theme to get us there. Some of the golden age of this futuristic imagery has a lot in common with steampunk aesthetics. Utilizing this pair of themes you can come up with some pretty far out ideas that would likely never come to pass in any way, shape or form. Of course, by blending two possible ideas, or finding a point at which they intersect, it means that you'll have to cast aside some other clean and clear ideas or visions that could lend you credibility.
Creating this intersection of reality and daydream is just what Tomorrowland received as refurbishment infusion in 1994. There was a community of tomorrow, utilizing pieces of what we knew could be with fantastical visions of what could never be. To give Tomorrowland a sense of place and time, everything revolved around this idyllic community. Transportation lines, a lighting and power company, museum exhibits, and convention centers were all part of the world that guests could visit as part of the land's attractions. There were even signs for restaurants, civic organizations, and housing options that were created solely to give Tomorrowland a lived-in, larger than life vibe.
Over time, however, much of these components have lost their sheen or been cast aside completely. There are out of place characters, I'm looking at you Monsters Inc., and even some of the aesthetics have begun to be shuffled off. The cornucopia of gears and robots for all occasions that once permeated the land have started disappearing. Tomorrowland has become a melting pot of various visions of future, and I don't mean that in a good way. It no longer has a dedicated mission or vision that guides it and all of the components that live within its borders, but it is high time Tomorrowland did some strategic planning.
I'm not saying that it should all fall under one banner or a single IP. Let me pause here and say that as much as I love Star Wars, I am certainly glad that the land dedicated to it is going to be housed in a park more befitting the property than in the Magic Kingdom where each land should be filled with different stories. There are, however, plenty of stories to gleam attractions and theme from. Everything from Lilo and Stitch to TRON, 20,000 Leagues Under the Sea to WALL-E, there are places where each of these could find a home alongside the PeopleMover and Space Mountain or assist in defining the style and setting of Tomorrowland.
There isn't an answer to how to define Tomorrowland, there are a number of answers. All of them could be right, but it takes guidance and a clear vision. It should look out of this world, but it shouldn't be populated by the toys under our beds. It should be a place where ideas are exchanged, but not with yesterday's news. Tomorrowland should always be reaching for our wildest dreams, both real and fanciful. With all that lies ahead for Walt Disney World, we are likely years away from ever seeing the land shine like the beacon of tomorrow it should be and deserves to be.
Labels: Perspective
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Home Actor Sammy Azero
Sammy Azero
Sammy Azero is a Canadian actor, director, writer and producer born and raised in Toronto, Ontario, Canada . He studied medical science at the University of Western Ontario.
His career in acting began with a recurring role on CBS television series In The Dark, executive produced by Ben Stiller and Micheal Showalter, portraying the character Wesley Monroe for 8 episodes. He has since played the supporting character Arman in the feature film Easy Land, written and directed by Sanja Zivkovic, and worked alongside Ed Skrien in the feature Midway directed by Roland Emmerich. He most recently landed the leading role in the feature film Once Upon A Time in Tehranto, written and directed by Faran Moradi, and spent time shooting motion capture in Montreal as a co-star in an upcoming video game for Supermassive Games.


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Lacklustre Leeds mauled by the Lions
A pretty forgettable first half gave way to a lacklustre second half Leeds United fans will want to forget quickly. as the Whites fell to a fourth straight defeat against a distinctly average Millwall side.
There's little to sugar-coat what was a poor showing from Leeds, Millwall found space far too easily in the second 45 and Leeds were perhaps lucky to only lose by two.
Both the goals Leeds conceded were a failure of the team as a whole, particularly the midfield who left far too much space between themselves and the defence which Millwall effortlessly exploited.
The second goal was particularly bad from a Leeds United point of view because of the amount of opportunities we had to close Millwall's players down. Malone and Trotter played five passes between themselves which went unchallenged as they advanced into Leeds United's half, Malone ultimately finding himself in acres of space from which he dealt the deciding blow.
Millwall had already struck the post in the first half before Paddy Kenny attempted to head an attempted lob (when it looked easy enough to catch), missing it completely but saved once again by the woodwork. Another chance was crossed between Leeds United's line of defenders and Kenny, with neither making any contact, but their blushes were spared by Millwall's failure to connect.
If this game had ended four or five nil, Leeds United could have no complaints. A better team would have walked us off the park, but Millwall are a pretty average Championship side and that's what makes this particular defeat so difficult to stomach.
Had Leeds United posed any kind of attacking threat themselves, this could have been a different game. Ross McCormack went closest for Leeds, trying to glance Alex Mowatt's cross into the far corner, only to see his effort go wide. It was the best chance Leeds United had created and a poor miss from eight yards out.
To underline just how average Millwall are, a defensive blunder almost gave Leeds United a goal. I've no idea what it was their defender was attempting to do, but he hit the ball towards his own goal, then scrambled back to save the shot he'd taken, desperately hitting the ball against his own woodwork (more luck than judgement) to make the save.
But it doesn't matter what class of opposition you face when there are so many holes in your formation. The space between midfield and defence was big enough to house Piers Morgan's ego; Stoke City could look like Barcelona playing with that much space around them.
At times, Millwall looked like they were on the training ground. Cutting through Leeds United's midfield and defence was far too easy, so easy in fact, they're probably a little disappointed to have not scored more.
Overall, a dreadful performance from Leeds.
FT Millwall 2-0 Leeds United
All the talk of reinforcements has centred on a striker this last week or so, but I don't think that'll solve the problems Leeds United have. For me, it still comes down to wingers. I've been repeating that line for so long now that I'm starting to bore myself, but we only created one and a half good chances today (McCormack's that I mentioned above and Rodolph Austin late on). Millwall were able to pile players forward because they didn't fear Leeds United's counter attack, nor should they have.
Furthermore, the addition of wingers allows us to address the cause of all our problems – the easily exploited formation which leaves acres of space for opposition players to dance around in while doing absolutely nothing for us in an attacking sense. I agree with McDermott that you have to play a formation that fits the players, but the one we're using is so narrow that we're easily broken down by the opposition congesting the area we're playing in, then, as soon as they take control of the ball they break away into the acres of space we leave all over the pitch. It's pretty amateurish at times.
From an attacking sense, the biggest issue is that we can't stretch teams and drag players out of position. Key to our attacking prowess under Grayson was the unpredictability of Gradel and Snodgrass, who constantly moved around the pitch dragging opposition players with them. Early doors, we were hugely over-reliant on McCormack doing just that, but the opposition have grown wise to that approach and we lack an alternative.
There's a quality issue too. Take Michael Tonge for example. He's very good at tying things together and bringing a bit of composure to the centre of midfield, but he offers very little defensively and is nowhere near quick enough to cover the distance required of a central midfielder playing in a box-to-box role. Here we need a Jonny Howson, who was much better in that role than many fans give him credit for.
Another problem is Rodolph Austin who was a bit careless at times today and didn't do enough to fill the gap between midfield and defence. Paul Green did well at DM early in the season and while I don't wish to start second-guessing the manager already, I think Austin is better off in Tonge's position with Green playing behind him.
The only midfielder who came out of this fixture with any credit is Alex Mowatt, who at times, looks a class above those around him. It"ll take time for him to fully command any fixture, but he's quickly growing into his first team role and should retain his place for the visit of Bournemouth.
On and on…
featuredLeeds UnitedMillwall
Misfiring Leeds scrape three points against ten men Bournemouth


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A superb HVAC system can maintain your own home snug, irrespective of how hot or how chilly it could be outdoors. Nonetheless, it can be laborious to seek out the perfect system for your wants. There is so much that it's worthwhile to keep in mind. The tips you've gotten learn here will likely be very helpful to you. Whenever doable, try to shade the compressor unit outside. The air that's in a spot that is shaded is often 5 to six levels cooler than the encompassing air. Your air-con unit can be up to ten percent extra efficient whether it is properly shaded in the course of the summer season months.
Ensure you ask for an estimate in writing before selecting a specific HVAC vendor. There are a lot of moving items in relation to purchasing these big items. You will want to compare not solely the price of the gear, but in addition the set up and the overall vitality prices. Outer coils can be cleaned with a daily outdoor hose earlier than you flip the unit on for the season. That mentioned, inside coils ought to be taken care of by a professional so that you don't do any injury as you try to scrub them. Bring someone in to finish a test up.
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Cover 4: Broncos' defense stymies Tua Tagovailoa, holds on late in 20-13 win
Aric DiLalla
Lead writer
DENVER — Tua Tagovailoa made national headlines during a 3-0 start to his career.
After Sunday's game in Denver, perhaps the Broncos' defense will get some of the attention.
The Broncos held the Dolphins to 223 total yards and just three second-half points as Denver earned its second home win of the season and snapped a two-game skid.
Tagovailoa entered Sunday's game with a chance to become the first rookie quarterback since Ben Roethlisberger to win his first four starts. Instead, Head Coach Vic Fangio improved his record against rookie quarterbacks as a head coach or defensive coordinator to 18-8. Ryan Fitzpatrick nearly brought the Dolphins back after replacing Tagovailoa in the fourth quarter, but Denver held on for the win.
Drew Lock, meanwhile, recovered from a poor start to finish 18-of-30 for 270 yards. Only a late Melvin Gordon III goal-line fumble prevented the Broncos winning by multiple scores.
Justin Simmons secured a late interception in the end zone to save the win.
These were the players and plays that mattered in a 20-13 win over the previously 6-3 Miami Dolphins:
Game-changing moment
The Broncos didn't secure the win until late in the game on Simmons' interception, but the game swung on Denver's third possession of the game. To that point, Denver had tallied just one yard, and Drew Lock was 0-for-5 with an interception that set up a Miami touchdown.
On the team's third possession, that changed. On third-and-10 from Denver's 27-yard line, Lock found Hamler down the seam for a 15-yard gain that moved the chains for the first time and kick-started the Broncos' offense. Denver pieced together an 11-play, 73-yard touchdown drive on the possession, and Lock rebounded from a tough start.
After starting 0-for-6, he completed 18 of his next 24 passes for 270 yards and no interceptions. There were questions about Lock's ability to bounce back from a few bad performances. On that first-quarter third down, he showed his ability to keep the Broncos alive.
Defining statistic
After failing to record a sack in a blowout loss to the Raiders, the Broncos offered Tua Tagovailoa his welcome-to-the-NFL moment. Tagovailoa was sacked six times, including twice apiece by Malik Reed and DeShawn Williams. The Broncos' defensive efforts were aided by their ability to consistently keep the Dolphins in third-and-long scenarios, and they forced five three-and-outs in Sunday's game. The Dolphins totaled just 82 yards in the first half, and they were held to three points in the second half.
Memorable highlight
Melvin Gordon III recorded a pair of rushing touchdowns on Sunday as he reached seven total touchdowns on the season, and his 20-yard score to push the Broncos' lead to 20-10 was the more impressive of the two. Gordon cut through an open hole, and there was no defender within several yards of him as he bounded into the end zone to extend the Broncos' margin.
Malik Reed recorded 1.5 sacks, three quarterback hits and two tackles for loss while DeShawn Williams posted two sacks of his own.
Melvin Gordon III carried the ball 15 times for 84 yards and two touchdowns, and his day was hampered only by a goal-line fumble. Phillip Lindsay added 82 yards on 16 carries.
Drew Lock responded from an early interception to finish 18-of-30 for 270 yards.
Justin Simmons saved the game with an end-zone interception with 1:03 to play in the game.
Cover 4: Broncos dominate on ground, rack up interceptions in 24-15 win over Cardinals
These are the players and plays that led to the Broncos' Week 15 win over the Cardinals.
Cover 4: Broncos rally in fourth quarter to earn 21-17 win in London vs. Jaguars
These are the players and plays that led to the Broncos' Week 8 win in London.
Cover 4: Broncos earn 11-10 come-from-behind prime-time win over 49ers
These are the players and plays that led to the Broncos' Week 3 win over the 49ers.
Cover 4: Broncos' defense stands strong, offense scores late as Denver rallies to earn 16-9 win over Texans
These are the players and plays that led to the Broncos' season-opening win.
Cover 4: Broncos honor Demaryius Thomas, earn 38-10 win over Lions to stay in playoff race
These were the players and plays that made a difference in the Broncos' win over the Detroit Lions.
Cover 4: Broncos' defense swarms Chargers, Teddy Bridgewater battles in 28-13 win
These were the players and plays that made a difference in the Broncos' division win over the Chargers.
Cover 4: Broncos parlay stifling defense, timely offense into dominant 30-16 win over Cowboys
The Broncos went into Dallas and earned their best win of the season as they knocked off the previously 6-1 Cowboys.
Cover 4: Broncos' fourth-quarter touchdown, late defensive stands key 17-10 win over Washington
On the day that former quarterback Peyton Manning was honored as one of the franchise's all-time greats, the Broncos got back in the win column.
Cover 4: Broncos lose Teddy Bridgewater, fall 23-7 to Ravens for first loss
The Broncos' defense only allowed three points in the second half prior to the final moments, but Denver ultimately didn't have enough offensive firepower to overcome their largest deficit of the season.
Cover 4: Broncos' defense dominant in 26-0 shutout win over Jets
The Broncos got after rookie Zach Wilson, and the Denver offense did enough in the team's home opener.
Cover 4: Broncos rebound from slow start to wrap up second straight win
The Broncos earned a 23-13 win to improve to 2-0 on the season.
Cover 4: Teddy Bridgewater dazzles as Broncos earn 27-13 season-opening win
In his first start with the Broncos, Bridgewater completed 28-of-36 passes for 264 yards and two touchdowns as Denver overcame a first-half deficit to earn the win.


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In the Cienega Watershed, adaptive management is collaborative, science-based management in tandem with stakeholder, public, and partnership involvement. The watershed is already experiencing changing vegetation communities, higher temperatures, and ecological change associated with climate change. Because the ecological processes and components that define this landscape are not stagnant, the decisions, policies, and practices that guide living in and managing the watershed cannot stand still.
In the field at Las Cienegas National Conservation Area: researchers discuss the impact of climate change, including invasive species.
Adaptive management responds to uncertainty, change, and challenges. Current efforts to assess the watershed conditions and annual monitoring of key indicators are meant to define trends and changes and to determine whether management decisions and practices are working. One picture coming clear is that climate change adds to the stress already on the land.
A critical element in adaptive management is participation by managers, scientists, stakeholders, and the public. Cienega Watershed Partnership plays a key role in bringing together partners to practice larger land-scale, adaptive, science-based management and to plan for a future in which climate change is a major challenge.
Scenario planning session at a recent State of the Watershed workshop.
Related climate change scenario planning work is ongoing. To participate, please contact us.
The Science on the Sonoita Plain Symposium is held annually to share results of scientific investigations and land management activities that are occurring within the upper watersheds of Cienega Creek, Sonoita Creek, and the Babocomari River.
Over the past two years, CWP has convened a series of workshops, conducted an electronic survey, and held several smaller working group sessions to gauge the state of the Cienega Watershed, including the development of watershed indicators and assessment tools.
CWP partners with the Bureau of Land Management's Tucson Office on biological planning semi-annual field days at Las Cienegas National Conservation Area. The field days provide an ongoing opportunity for researchers and administrators to come together in the field to discuss issues related to the watershed, as well as solutions incorporating adaptive management.
For additional information, or to participate in CWP's adaptive management and climate change activities, please contact us.


Tarra - Name Meaning, What does Tarra mean?
Tarra as a name for girls means "hill; star". Tarra is an alternate spelling of Tara (Gaelic, Sanskrit).
Popular variation forms of Tarra listed in the Top 2000 are Tara (#1002 A YEAR AGO) and Tarah. Adoption of these relations of Tarra was widespread in the 1970s (MEDIAN #957) and is now much less.
Tarra is alike in pronunciation to Taree, Taura, Teara, Tera▼, Teree, Teri▼, Terie, Terra▼, Terrey, Terry▼, Terrya, Tiairra, Tiara▼, Tiarah, Tierra▼, Tierrea, Tora, Tori▼, Toria, Torrey, Torry, Torrye, Tory, Tyra▼ and Tyria. Other suggested similar-sounding names are Amarra, Barra, Caera, Cara▼, Cearra, Darra, Fabra (see Fabia), Farra, Hajra, Iara, Jadra, Karra, Kerra, Larra, Lawra, Mahra, Maira, Marra, Mavra, Mirra, Sabra, Saira, Sarra, Tacia, Tahira, Tahna, Talea, Talia▲, Talma, Talya, Tama, Tamarra, Tamera▼, Tamra▼, Tamrah, Tanea, Tania▼, Tanya▼, Taran, Taren, Tarina, Tarnya, Tasa, Tedra, Tersa, Thora, Thyra, Trea, Yaira and Zayra. These names tend to be less frequently used than Tarra.


Will Android Be the One Operating System to Rule Them All?
Why Now for Tablets and Phablets, Nokia?
Tech Europe covers Europe's technology leaders, their companies, and the people and industries that support them — and their ideas. The blog is edited by Ben Rooney, with contributions from The Wall Street Journal and Dow Jones Newswires.


Left to right areWillie Smith, representing Alleghany Mountain Radio and Alan Hicks, WestRock communications analyst.
Covington, VA (April 3, 2019) - April 3, 2019– The Covington mill recently presented a donation to Alleghany Mountain Radio in support of the Bluegrass Jamboree, which is scheduled for April 6, at Bath County High School from 6 – 9 pm. The concert will feature David Parmley and Cardinal Tradition, Southern Rail Express, and Mountain Highway.
Food and drink will be available starting at 4:30 pm, and the doors will open at 5 pm. Tickets are $12 for adults, $5 for youth age 13 – 18, and $1 for age 12 and under.


"When you want something done right, do it yourself." You've probably heard this many times. Probably in situations involving everything from straightening displays to cleaning the floors. Or from negotiating with suppliers to obtaining startup capital. Taking the initiative and getting things done on your own can be smart. But this isn't true when it comes to filing your taxes. When it comes to business tax accounting services, you probably want to hire professionals. Otherwise, you may experience problems with mistakes, procrastination and loss of time efficiency. Of course, that leads to penalties and interest with the IRS.
I know. You hate taxes. Get at the end of a very long line. You can relieve some of the tax burden by maintaining accurate bookkeeping. Proper tax planning and a strong tax accounting team is essential. Use professional services to make the filing process easier. More importantly, it is less costly. Besides, it appears that most folks do not like to fill out reams of paperwork, only to finally discover how much money they are really giving to the IRS. Business & Financial Solutions works hard to make this process as painless as possible. And we want ensure that you keep all the money you deserve, legally and ethically, under the current tax code.
Business & Financial Solutions has been servicing the needs businesses for 14 years. We provide bookkeeping, accounting and tax services all over the United States. All business in the United States are required to file income tax returns. And they are also required to pay their taxes. It doesn't matter the size of the business.
Small business owners are required to follow specific tax laws. And there are different tax laws governing the business preparation of taxes depending on the size of the business. Further, each business must prepare its tax returns, based on the formation of its entity.
Our services are rendered at a reasonable cost. Moreover our clients consider us a value to their companies. There may be other low cost business tax services available on the market But be careful to shop for the value in the service you require. We stand by our services and our offices are open year-round. And we have three convenient locations.
Choose your tax preparer well. As this is an important step. You'll want to choose wisely because you are legally and financially responsible for everything on the return. Although most tax preparers are honest professionals, unscrupulous ones do exist. And even some honest preparers may lack the knowledge required to get the best result.
Our clients are encouraged to participate in tax planning meetings. And they are encouraged to identify opportunities that can minimize taxes. They are also well informed and this takes away any element of surprise. Lastly, we don't believe tax day needs to be the day you find out what your tax consequence is.


1) It is the trait of those who are rebellious to the laws of Allah, that they are always under stress. Suffering from anxiety and sorrows, always complaining and moaning. Allah (swt) says all the hardships and trails that come our ways is in the knowledge of Allah. In islam we believe that nothing happens in coincidence.
Since hardships and trails that we face is in the knowledge of Allah. He (swt) tells us why we face them on the life of dunya aswell. The reason is so that we return to Allah. Many people despite having everything are in stress and turmoil. This is a example of how Allah (swt) wants people to turn to him. However we tend to do the opposite. We complain and move more away from Allah. When it should make us turn to Allah more.
People continually ask for guidance. Allah (swt) wants to guide us. However we are far away despite asking Allah for guidance.
-Revelation is only revealed upon the prophets. no one else receives revelations. This brings the question, how does Allah then communicate with normal humans. – in relation to giving us lessons, to turn to him and not be deluded by the dunya? He (swt) does so by the tests and trails he sends our way. With these Allah (swt) is telling us to turn to him. All the stress of the dunya, bills, financial, social, economical problems etc are small trails Allah sends us. Before we receive the great trail and hardship of the hell fire.
2) secondly, one of the reasons why we face hardships is also because, when someone turns him/herself away from Allah and his prophet (saw) then the mashaykh and ulema say Allah (swt) attaches a jinn with the individual. This is why we face hardships and go under stress and hardships.
Some people came to imam Ahmad Ibn hanbal (ra) and said such ad such a woman is affected by jinn. He (imam Ahmad Ibn hanbal) said take my sandals and say to the jinn that is affecting the woman to leave otherwise it will be hit by this sandals. The jinn replied I do not care if I get hit by the sandals. But I have immense respect for the shaykh. Because of him I will leave this woman and not only that but leave the whole country of iraq. – This is a example of how Allah give respect and honour to his friends, in the hearts of all the other creations.
When hardships come instead of turning to Allah. We tend to turn away from him. This is what Allah tells us. We do not correct our actions, and instead shaitan tells us and glorifies our actions to us, in the sense of it being correct. So, when hardships as illness comes our way we need to turn to ourselves and see what we are doing wrong and correct our selves. If we do we will not need to turn to doctors and nurses for our cures. We will receive the divine cures and successes of Allah (swt).
Previous PostHow good deeds are acceptedNext PostLoving the prophet (saw) according to Allah.


text:
import dash
from dash.dependencies import Input, Output
import dash_core_components as dcc
import dash_html_components as html
import plotly.graph_objs as go
import click

@click.command()
def cli():
    pass

if __name__ == "__main__":
    cli()

redpajama_set_name: RedPajamaGithub


I've had the opportunity to be on interview loops for the last six months or so at Microsoft. I had previously done interviews as part of my job at Terralever as well, and at least for the technical part of the job, it hasn't really changed. This post isn't really about interviewing specifically at Microsoft. I'm a Program Manager, but on a programming language team, which means that my job is much more technical than most PM jobs on, for example, Office products. My expectations as a technical interviewer for PM are probably more in line with a developer's job in other parts of the company. As such, I'd also expect that they're in line for other development jobs throughout the industry.
Basic problem-solving skills. If I give you a simple problem statement, can you talk through how you would solve the problem and then turn it into code? Can you do it on a whiteboard without a code editor? What level of detail do I need to provide? What levels of detail are you going to ask me for?
Performance analysis and trade-offs. While approaching your basic problems, almost always, the problems have multiple possible solutions. I hope you're identifying the alternatives as we go, but if you don't, can you discuss them when I ask you about them?
Data structures and algorithms. Do you understand LIFO/FIFO, linked lists vs. arrays, hash tables, etc.? If you're a junior candidate and are unfamiliar altogether with the data structures, do you understand what I'm talking about if I explain them to you?
Debugging. What are the tools you could use to debug a problem that might crop up? Do you know the sequence of steps to diagnose a bug that I might have introduced, or that you introduced?
Testing. Do you know how to test and validate your code? What are the ranges of inputs you might want to test?
Over the next few posts, I'm going to talk through some common interview problems, what a candidate's answers might be, and then what the interviewer might try to discuss about the answers and questions. This isn't a comprehensive guide, and you shouldn't expect to get these questions if you actually interview with me. The purpose is really to give you the mindset for an interview. What will make you successful? What do you need to know? How can you build up your skills to be ready?
Up next: testing for a palindrome. (Yes, it's super-common).


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Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib
Lokesh Jain1,2,
Tristan M Sissung1,3,
Romano Danesi4,
Elise C Kohn3,
William L Dahut3,
Shivaani Kummar3,
David Venzon5,
David Liewehr5,
Bevin C English6,
Caitlin E Baum6,
Robert Yarchoan7,
Giuseppe Giaccone3,
Jürgen Venitz2,
Douglas K Price3,6 &
William D Figg1,3,6
Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.
Toxicities (≥ grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.
Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136).
This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.
The process of angiogenesis is crucial for carcinogenesis, invasiveness and metastasis in several tumor types including prostate, ovary, kidney, non-small cell lung and colorectal cancer [1–3]. This process is governed by an array of growth factors; however, vascular endothelial growth factor (VEGF) and its major receptor in the endothelium, VEGFR2, are predominant regulators of this process [2]. Rising interest in angiogenic modulators has led to the design and synthesis of several new molecules that target the VEGF signaling pathway, such as sorafenib, bevacizumab and sunitinib, which are currently approved for various solid tumors. There is wide inter-individual variation in toxicity and clinical outcome following treatment with agents targeted at the VEGF pathway suggesting that predictive markers of these outcomes could be clinically useful.
Sorafenib and bevacizumab have some common toxicities, such as hypertension (HT), diarrhea, and gastrointestinal perforation [4, 5]. However, sorafenib confers frequent cutaneous side effects, including hand-foot skin reaction (HFSR; palmar-plantar dysesthesia; acral erythema) and rash in many individuals while bevacizumab confers HFSR in a limited number of individuals. Both in-vitro and in-vivo evidence support that HT, results directly from the pharmacologic activity of VEGF inhibitors [6]. Recently, we demonstrated that sorafenib-induced HFSR was directly related to cumulative sorafenib dose, that HT and HFSR development coincided, and that HFSR is more prevalent in individuals being treated with a combination of sorafenib and bevacizumab targeting the VEGF receptor and the VEGF growth factor, respectively. A pharmacokinetic interaction was not observed [7]. Taken together, these results suggest that HFSR and HT may both be related to the activity of anti-VEGF and anti-VEGFR therapy; thus, HT and HFSR may also be markers for a greater degree of response in patients treated with sorafenib and bevacizumab. Inter-individual genetic variation in the VEGF pathway may also alter both the toxicity and response to these agents.
The VEGFR2 gene contains two SNPs that are located in exons 7 and 11 and result in nonsynonymous amino acid changes at residues 297 Val>Ile and 472 His>Gln in the third and fifth immunoglobulin like (Ig-like) domains of VEGFR2 receptor, respectively. The Ig-like domain 3 is critical for binding to the VEGF ligand [8], while domains 4-7 contain structural features that inhibit VEGFR2 signaling in the absence of VEGF [9]. HEK293 s cells that were transfected with VEGFR2 V297I SNP had significantly low VEGF binding efficiency regardless of VEGFR2 H472Q genotype, while variant VEGFR2 H472Q allele had minimal effect on VEGF binding efficiency [10].
We hypothesize that 1) the development of HT and HFSR following anti-VEGF therapy with bevacizumab and sorafenib is a marker for response to these drugs; 2) that since both toxicities are related to the activity of these agents, the development of a single toxicity (i.e. HT) would increase the risk of developing the other toxicity (i.e. HFSR); and 3) that functional SNPs in VEGFR2 could alter antiangiogenesis treatment response or outcome by affecting the VEGF signalling pathways. To this end, we determined if HT and HFSR were associated with progression free survival or overall survival, and if development of HT increased the risk of developing HFSR in patients with various solid tumors being treated with sorafenib and/or bevacizumab. We also determined if genetic polymorphisms in the VEGFR2 gene modified the relationship between toxicity and survival endpoints as well as the relationship between coincidence of HT and HFSR.
Patients and treatment
The analyses were performed on genomic DNA from 178 patients (143 males and 35 females) with solid tumors who received sorafenib (VEGFR2 inhibitor) and/or bevacizumab (anti-VEGF) with or without other agents. These patients were enrolled in six phase I or II clinical trials at the National Cancer Institute (Table 1). Two phase II trials (BAY-CRPC and APC-CRPC; NCT00093431 and NCT00091364 respectively on clinicaltrials.gov) in patients with castrate resistant prostate cancer (CRPC) administered sorafenib 400 mg bid and a combination of thalidomide (200 mg qhs), bevacizumab and docetaxel (15 mg/kg plus 75 mg/m2 day 1, q 21 days), respectively [11, 12]. Two other phase II trials (BAY-NSCLC and BAY-CRC; NCT00100763 and NCT00343772 respectively) treated patients with non-small cell lung cancer (NSCLC) [13] and colorectal cancer (CRC), respectively with sorafenib 400 mg bid and a combination of sorafenib (400 mg bid) and cetuximab (400 mg/m2 loading dose in week 1 + 250 mg/m2 i.v. week). Two phase I trials (BAY-BEV and BAY-KS; NCT00098592 and NCT00304122 respectively) administered sorafenib plus bevacizumab (200 mg bid + 5 mg/m2 i.v. q15 days) [14] and sorafenib with or without a protease inhibitor (starting dose of 200 mg qd/bid ± starting dose of 200 mg qd) respectively to patients with solid tumors and Kaposi's sarcoma.
Table 1 Summary of patients included in analysis
The most severe grades of common, sorafenib treatment associated toxicities, namely rash, desquamation, diarrhea, HFSR, HT and fatigue were used for analysis. Toxicities were graded based on the National Cancer Institute common toxicity criteria version 3.0. This retrospective genotyping analysis was approved by the National Cancer Institute Institutional Review Board.
DNA was extracted from plasma or whole blood using QiaBlood extraction kit (Qiagen, Valencia, CA). Genotyping for two VEGFR2 loci was performed by single/nested PCR using the following primers at an annealing temperature of 60°C: rs1870377 (T/A) F1:5'-CAGAATCACCCTACACAGATGC-3', R1: 5'-TTCCCAGAATAGCTGCTTCC-3', F2: 5'-TGGTACTGCTAAAAGTCAATGG-3', R2:5'-GGCTGCGTTGGAAGTTATTT-3'; and rs2305948 (C/T) F4: 5'-GGTTTGAACCCAAGTTCCTG-3', R4: 5'-CACTTTCACCACGTGAGGTTT-3', F5: 5'-TGGCCTCCCTAACAAGAAAA-3', R5: 5'-TGGTGTCCCTGTTTTTAGCA-3'. The details of the genotyping procedure are described elsewhere [15]. The sequencing PCR was carried out with Big Dye (v3.1, Applied Biosystems, Foster City, CA) using the following PCR primers: rs1870377 (T/A) F3: 5'-CCTGGAAGTCCTCCACACTT-3', R3: 5'-AACCAAAGTCTGAATCTTTTCCTT-3'; and rs2305948 (C/T) F6: 5'-CCCTGACAAATGTGCTGTTC-3', R6: 5'-TGCTGTGCTTTGGAAGTTCA-3'. The PCR products were then sequenced on an ABI Prism 3130xl Genetic Analyzer (Applied Biosystems) as per the instructions from the manufacturer.
Statistical considerations
The progression free or overall survival based on genotype or toxicity groups (grade ≥ 2/grade < 2) was estimated by the Kaplan-Meier method [16] and compared by the exact log-rank test. Deviation from Hardy-Weinberg equilibrium was tested separately for different ethnic groups, using the Chi-squared test. The impact of genotypes on treatment-associated toxicities and the association between toxicities were assessed by Fisher's exact test. All statistical analyses were two-tailed at a pre-specified significance level of < 0.05. In view of the exploratory nature of analysis, P-values were not formally corrected for multiple testing. SAS for Windows version 9.1.3 was used for these statistical analyses.
Genotyping data
The genotype and allele frequencies of studied VEGFR2 SNPs are shown in Table 2. Both VEGFR2 SNPs were in Hardy-Weinberg equilibrium (P ≥ 0.77) when evaluated in Caucasian patients (n = 140) and African American patients (n = 17). Hardy-Weinberg equilibrium was not assessed in Hispanics and Asians (n = 13). There was no linkage between the two VEGFR2 SNPs (P > 0.05) in any of the studied populations.
Table 2 Genotype and allele frequencies for SNP in VEGFR2 loci for patients treated with sorafenib and/or bevacizumab, with or without other agents
HT and HFSR as phenotypic markers for PFS and OS
Because drug-induced toxicities may be directly related to the activity of bevacizumab and sorafenib, we hypothesized that these toxicities may also predict the progression free survival (PFS) and overall survival (OS) following anti-VEGF therapy. Patients on BAY-KS were not included in the survival analysis since this cohort was small with limited survival data. When the other 5 clinical trials presented in Table 1 were examined individually, we determined that HT was associated with prolonged PFS in patients treated with bevacizumab on the APC-CRPC and BAY-BEV trials (P = 0.0009, and P = 0.052 respectively). The median PFS difference was 14.9 (HT < grade 2, n = 45) versus 31.5 months (HT ≥ grade 2, n = 15) in patients participating on the APC-CRPC trial (Figure 1A), and 3.7 (HT < grade 2, n = 12) versus 11.9 months (HT ≥ grade 2, n = 15) for those on BAY-BEV (Figure 1B). Development of HT was not related to survival following sorafenib without bevacizumab (BAY-NSCLC and BAY-CRC; P > 0.19), with a single exception where patients on BAY-CRPC with < grade 2 HT (n = 37) actually had marginally non-significantly prolonged survival when compared to those individuals with HT ≥ grade 2 (n = 9; 1.8 versus 3.6 months respectively; P = 0.067).
Kaplan-Meier curve of progression-free survival following treatment with bevacizumab in combination with docetaxel and thalidomide, n = 60 (A) , or bevacizumab in combination with sorafenib, n = 27 (B) , or sorafenib alone or in combination with bevacizumab, or cetuximab in patients with prostate cancer, various solid tumors, colon cancer, or NSCLC n = 113 (C) , or overall survival following treatment with bevacizumab in combination with sorafenib, n = 26 (D) versus development of ≥ Grade 2 toxicity - - or < Grade 2 toxicity ------ as indicated on each respective figure. Respective P = 0.0009, P = 0.052, P = 0.0003, and P = 0.0068 by a two-tailed log-rank test.
As is indicated in Table 1, incidence of ≥ grade 2 HFSR was also associated with PFS in patients with colon cancer treated with sorafenib (P = 0.0065) with those patients having HFSR (n = 2) having a significantly longer response to sorafenib (8.7 months) than those without HFSR (4.7 months, n = 16). HFSR and PFS were either marginally not associated in patients on BAY-BEV (P = 0.094), or were not associated on BAY-NSCLC and BAY-CRPC (P ≥ 0.29). However, since each group treated with sorafenib had a similar trend (i.e. patients with HFSR always had a longer median PFS) with a small number of patients in each group (n ≤ 46), we pooled survival data obtained from the above trials to analyze the relationship between HFSR and PFS with greater statistical power. The pooled analysis significantly improved the relationship between PFS and HFSR with patients who developed HFSR following treatment with sorafenib, either as single agent or in combination with bevacizumab or cetuximab (n = 32), having a median PFS of 6.1 months compared with 3.6 months in patients without these toxicities (n = 81; P = 0.0003, Figure 1C). However, this pooled analysis should be interpreted with caution given that it is present only when heterogeneous groups of data obtained from patients are combined together. Association of these toxicities with OS was not significant with a single striking exception where those patients receiving the BAY-BEV combination had a significantly longer survival (P = 0.0093) if they developed hypertension during therapy (29 months, n = 14) when compared to those that did not develop hypertension (5.7 months, n = 12; Figure 1D). No other toxicity (i.e., rash/desquamation, diarrhea, or fatigue) was related to PFS (P > 0.05) for either drug.
Increased risk of developing HFSR along with HT
We next hypothesized that since HT and HFSR originate from the activity of bevacizumab and sorafenib, the development of a single toxicity (i.e. HT) would increase the risk of developing the other (i.e. HFSR). Analysis of association between toxicities revealed that individuals with HT grades < 2 had a lower risk of developing HFSR grades ≥ 2 (19 of 126 patients, 15.1%) than those patients with HT grades ≥ 2 (19 of 52 patients, 36.5%, OR (95%CI) = 3.2 (1.5-6.8), P = 0.0024). Therefore, increased HT grade conferred a significantly increased risk of also developing HFSR.
VEGFR2 H472Q and V297I genotypes vs. treatment associated toxicities and survival following sorafenib and/or bevacizumab therapy
The associations of HT and HFSR with the VEGFR2 H472Q polymorphism were significant when all trials were pooled (see Table 3). Frequencies of HT and HFSR for patients carrying the variant VEGFR2 H472Q polymorphism was almost double the HT/HFSR frequency of wild-type allele carriers who recieved therapies against VEGF pathway (HT: variants, 39% vs. wild-type, 21%, OR (95%CI) = 2.3 (1.2 - 4.6), P = 0.0154; HFSR: 33% vs. 16%, OR (95%CI) = 2.7 (1.3 - 5.6), P = 0.0136). Similar results were obtained for following subgroups: patients treated with only sorafenib (HT: 32% vs. 18%, P = 0.25; HFSR: 39% vs. 16%, P = 0.045) and patients treated with sorafenib as at least one of the therapies (with or without bevacizumab; HT: 42% vs. 21%, P = 0.0210; HFSR: 44% vs. 20%, P = 0.0063). These results must also be interpreted with caution given that multiple clinical trials with different toxicity incidence were pooled together. VEGFR2 genotype was not related to other toxicities (i.e., rash/desquamation, diarrhea, or fatigue; P > 0.05).
Table 3 Comparison of toxicities between wild type and variant allele groups for VEGFR2 SNPs
To determine whether the aforementioned association between HT and HFSR is confounded by VEGFR2 H472Q, the association between any two of the factors (i.e., HT, HFSR and VEGFR2 H472Q) with stratification by the remaining factor were tested. The results were consistent with the hypothesis that the associations are independent of each other. Genotype-toxicity relationships for other toxicities and studied VEGFR2 SNPs were not significant (Table 3). The VEGFR2 V297I SNP was not related to toxicity, and neither VEGFR2 genotype was related to any survival endpoint in any of the individual clinical trials in spite of the relationship with toxicity.
We hypothesized that 1) increased HT and HFSR were markers for increased response duration in individuals treated with bevacizumab and/or sorafenib; 2) that since these toxicities are likely derived from the activity of bevacizumab and sorafenib, the development of HT would increase the risk of also developing HFSR; and 3) that VEGFR2 genotypic variation may be responsible for alterations in the activity of bevacizumab and/or sorafenib therapy that would manifest in associations with toxicity or clinical outcome following treatment with these agents. The results of the present study confirm a previously published study where HFSR development was noted to be related to PFS in patients with various solid tumors receiving doses of sorafenib between 300-600 mg bid [17], and a small study that HT is related to bevacizumab response [18]. Moreover, those receiving combination therapy with bevacizumab and sorafenib that developed hypertension enjoyed a greater than 5-fold increase in overall survival following therapy initiation. Consistent with our previous results [7], the development of HT was also directly related to the incidence of HFSR, further suggesting that these two toxicities are markers for the activity of anti-VEGF therapy. This study is the first to evaluate VEGFR2 H472Q status; carriers of 472Q alleles were more likely to experience HT and HFSR, although the relationship between genotype and toxicity was independent of the relationship between the two types of toxicity, and was not related to any of the studied survival endpoints.
The physiological basis for bevacizumab- and sorafenib-induced HT and HFSR is currently unknown although they most likely originate from the activity of these drugs altering signaling through several targets (i.e., VEGF, Raf-1, wild-type B-Raf, mutant b-raf V599E, VEGFR2, VEGFR3, PDGFR-β, Flt3, c-KIT and p38) [19, 20]; recent data suggests that the VEGF pathway directly contributes [6, 7]. Once these pathways are altered, HT may develop because of decrease in vascular surface area [6], and HFSR may develop due to inefficiency of the repair of microtrauma originating from use of the hands and feet [21]. In spite of the unknown origin of these toxicities, our data are consistent with the hypothesis that HT and HFSR are related to the activity of these drugs. The data also suggest that these toxicities are markers for prolonged response, and in the case of sorafenib and bevacizumab coadministration, prolonged survival benefit from these therapies. Others have also observed that the severity of rash in patients with NSCLC is directly related to EGF-RTK inhibition by tyrosine kinase inhibitors, and that this cutaneous toxicity is also a marker for increased survival [17, 22]. Moreover, it has also been suggested that rash brought on by EGF-pathway inhibitors could be useful for optimal dose titration [17]. Therefore, future studies directly evaluating the development of HT and HFSR as markers for effective dosing of these bevacizumab and sorafenib are warranted in order to decrease the incidence of toxicity and improve response.
Interestingly, VEGFR2 genotype may also be related to the incidence of both HT and HFSR independently, but does not confound the relationship between the two toxicities. These data suggest that the development of these toxicities is related to signaling through the VEGF pathway, at least in part, although the polymorphism in VEGFR2 is not the sole factor responsible for the relationship between HT and HFSR. Given the heterogeneity of the clinical trials under study, the lack of a relationship between VEGFR2 genotype and PFS may be due to low statistical power and it is hoped that future studies in homogeneous populations will validate the relationship between VEGFR2 polymorphism and survival.
The present analysis is inconsistent with a previous report where it was determined that patients with breast cancer reported significantly longer OS for patients who developed HT on bevacizumab and paclitaxel combination than patients without this toxicity [23]. The present data were obtained retrospectively from clinical studies that were not designed to retain patients on the basis that toxicity was a marker for efficacy. Indeed, a greater proportion of patients carrying the 472H/Q substitutions were removed from the trials due to toxicity (14%) than those carrying wild-type or variant genotypes (9%), although this was not statistically significant (data not shown). This is not surprising given the association of VEGFR2 variants and toxicity. However, since those carrying this genotype also had a better response in general, it is possible that the desirable long-term benefit of the treatment may not have been enjoyed in patients being removed from therapy prior to tumor progression due to toxicity.
In conclusion, our data indicate that HT and HFSR are markers for prolonged progression free survival in patients treated with bevacizumab and/or sorafenib, patients receiving a combination of both agents that develop HT have a large increase in treatment-related survival, and that the development of HT on these agents increases the risk of also developing HFSR. The association with toxicity was not significant with respect to overall survival. When VEGFR2 genotypes were considered, the present data suggest that those carrying 472Q alleles at H472Q are at an increased risk of developing both HT and HFSR following bevacizumab, although the SNP is not related to either progression free survival or overall survival. Given the exploratory pilot nature of this study, it is hoped that future studies will validate these results and provide a mechanism by which toxicity is related to PFS and VEGFR2 genotypic variation is related to toxicity.
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Azad NS, Aragon-Ching JB, Dahut WL, Gutierrez M, Figg WD, Jain L, Steinberg SM, Turner ML, Kohn EC, Kong HH: Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy. Clin Cancer Res. 2009, 15: 1411-1416. 10.1158/1078-0432.CCR-08-1141.
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This study was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD. We thank our data managers Cynthia Graves, Sonja Crandon, Qinghua Ge (Roger), Shveta Tiwari, and Kathleen Wyvill, and most of all, our patients who participated in these trials. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.
Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, 20892, USA
Lokesh Jain
, Tristan M Sissung
& William D Figg
Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 N 12th Street, Richmond, 23298, USA
& Jürgen Venitz
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, 20892, USA
Tristan M Sissung
, Elise C Kohn
, William L Dahut
, Shivaani Kummar
, Giuseppe Giaccone
, Douglas K Price
Department of Internal Medicine, University of Pisa, 55 Via Roma, Pisa, 56126, Italy
Romano Danesi
Biostatistics and Data Management Section, National Cancer Institute, 6116 Executive Boulevard, Bethesda, 20852, USA
David Venzon
& David Liewehr
Molecular Pharmacology Section, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, 20892, USA
Bevin C English
, Caitlin E Baum
HIV and AIDS Malignancy Branch, National Cancer Institute, 9000 Rockville Pike, Bethesda, 20892, USA
Robert Yarchoan
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Correspondence to William D Figg.
LJ, TMS, BCE, CEB, and DKP carried out experiments; ECK, WLD, SK, RY, and GG treated the patients and collected the data for the study; LJ, TMS, DV, and DL conducted final statistical analysis; Study was conceived by TMS, RD, JV, and WDF; WDF provided financial support. All authors have read and approved the final manuscript.
Lokesh Jain, Tristan M Sissung contributed equally to this work.
Jain, L., Sissung, T.M., Danesi, R. et al. Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib. J Exp Clin Cancer Res 29, 95 (2010) doi:10.1186/1756-9966-29-95
Bevacizumab
Progression Free Survival


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Trailer Debut of The Broken Ones: A Drama About Romance and Depression
By Chris Gore	| June 14, 2018
The Broken Ones is a romantic drama based on a true story from writer Cece King. One woman struggles to cope with the loss of her father in the 9/11 attacks. Two troubled strangers meet and help each other overcome personal fears and tragedies. Directed by Elyse Niblett-Russell, the film was written and produced by Cece King and stars King, Charlie Bewley, Margaret Colin, Constance Schulman, and James Russo.
Multicom Entertainment Group has acquired worldwide rights to The Broken Ones, which is set for release on VOD and DVD on July 10th. More about the film and filmmakers on FaceBook here. Enjoy the trailer below, an exclusive Film Threat debut.
HALSTAN WILLIAMS says:
Nice trailer I'm looking forward to seen your beautiful film. It's so nice to see my fellow friends finish projects.
SCREENWRITER'S LAB AND ISCRAMBLE AT SIDEWALK
Sidewalk Screenwriter's Lab, Sidewalk's second in a series of workshops designed to encourage and inspire independent filmmaking in Alabama will soon be...
And now for a film that I'm sure no one is seriously looking forward to, Shakespeare's Hamlet starring Ethan Hawke. I guess Johnny Depp was busy, so they...
THE 2001 TEXAS FILM FESTIVAL
You think 2001 is a long way away? Well, you're wrong, and The 2001 Texas Film Festival knows that. The Festival, which begins on February 15th and...


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The Alzheimer's Association International Research Grant Program lies at the heart of our commitment to advance Alzheimer's research. Since awarding our first grants in 1982, the Association has grown into the largest private, nonprofit funder of Alzheimer's research, investing over $440 million in more than 2,900 scientific investigations.
The Alzheimer's Association International Research Grant Program funds investigations that advance our understanding of Alzheimer's disease, help identify new treatment strategies, provide information to improve care for people with dementia, and further our knowledge of brain health and disease prevention. Our awards support investigators at every professional stage and always include categories specifically designed to help talented young scientists establish careers in Alzheimer's research. Our entire grant portfolio is structured to meet the needs of the field and to nurture fresh ideas. Learn more about the types of grants we fund.
The Association works to identify and fund a wide range of the most promising projects, from basic discovery science to studies addressing social and behavioral aspects of Alzheimer's - and related dementias. The studies we've invested have enabled significant advances across the research spectrum in such areas as diagnosis, genetics, treatments, prevention, early detection and enhancing quality of life.
For people living with Alzheimer's, every discovery offers new hope. Our grants program is a vital source of support for the worldwide scientific effort to build our knowledge base and conquer this complex disease.
Our grants program has funded some of the most important research threads in Alzheimer's science. These areas move the field forward by contributing to knowledge about Alzheimer's, refining research questions, and yielding clues to causes and treatments.
Foster a diverse, inclusive scientific community that meets the needs of researchers at every career stage, with an emphasis on engaging and supporting early career investigators and those new to Alzheimer's and related dementia research.
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Phyllis Schlafly Praises Jeff Sessions, Trump & Cruz, Warns GOP 'Kingmakers'
By Peter Montgomery | February 29, 2016 3:35 pm
In her February newsletter, which came out just after Sen. Jeff Sessions' endorsement of Donald Trump, Eagle Forum founder Phyllis Schlafly reproduced a column she wrote earlier in the month gushing about a round of interviews Sessions had given in which he said 2016 "is the last chance for the American people to take back control of their government." Sessions helped Trump craft his immigration platform and previously backed his call for a ban on Muslims entering the U.S.
Here's Schlafly:
"To win, Republicans need to demonstrate that they care about the average person who goes to work every day," he added. Average Americans are tired of paying billions in welfare handouts to immigrants who are undermining U.S. wages. "People should have total confidence and a clear commitment on those issues. If they don't, then they don't have my vote," he said…
Our immigration policy has been anti-American, decade after decade, and the voters need to know that 2016 might be our last chance to elect a president who can reduce this tide of illegals crossing our borders. The interests of working Americans must "be put first," Sessions urged. "We need a president with the credibility to tell the world that the time of illegality is over. Do not come to this country unlawfully," he said.
In the same column, Schlafly praised "outsider" candidates like Trump and Ted Cruz, and warned against "the Washington-based Republican Establishment" who she said are plotting to "take back control of the party from the outsiders and grassroots." Among those she names as would-be "kingmakers" are House Speaker Paul Ryan – "who is openly contemptuous of Trump and has little use for Cruz" – and South Carolina Gov. Nikki Haley, who offended Schlafly by using her response to the State of the Union Address "to slam the 'angriest voices' in the presidential campaign and disavow the Republican front-runner's popular call for a temporary pause in Muslim immigration."
Schlafly vows that the Republican platform will be written by GOP delegates who are disappointed with the ineffectiveness of congressional Republicans and who "will have no use for Ryan's open-borders ideology, which holds that anyone who can find a low-wage job should be allowed to settle in the United States." Schlafly warns that a deadlocked convention could make someone like Ryan the nominee. "Such an outcome," she writes, "could destroy the Republican Party and guarantee a Democratic victory by causing disheartened grassroots voters to stay home and tempting an aggrieved candidate to mount a third-party or independent presidential campaign."
In January, Schlafly declared that Donald Trump was "the only hope" to defeat the GOP's "Kingmakers."
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Member of Parliament for North Swindon, Justin Tomlinson, and Adrian Griffiths, CEO, Recycling Technologies, today opened Recycling Technologies' new headquarters and manufacturing facility in Stirling Court, Swindon.
Recycling Technologies has developed and patented a plastics recycling machine, the RT7000 that converts plastic waste back into an oil called Plaxx® from which new plastics can be made. The machine heats up the plastic in the absence of oxygen to break the waste plastic down into Plaxx®. This process allows the RT7000 to recycle plastics currently considered unrecyclable such as plastic film, laminated food pouches and crisp packets and even black plastics. These unrecyclable plastics are currently exported, incinerated or buried. The RT7000 machines are relatively small scale, allowing them to be located within existing waste management facilities, reducing the financial and environmental costs of transporting residual plastic waste.
At the opening, Recycling Technologies was also joined by Swindon and Wiltshire Local Enterprise Partnership, staff, suppliers, councillors, neighbours and organisations from the plastics and waste sectors.