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Archive for the ‘Population Health Management, Genetics & Pharmaceutical’ Category

Science Budget FY’14: Stakeholders’ Reactions on Selective Budget Drops and Priorities Shift

Reporter: Aviva Lev-Ari, PhD, RN

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Reactions to Obama’s Science Budget

by Science News Staff on 12 April 2013, 12:00 PM

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Credit: Francisco Diez

The words are flowing. Reactions are starting to trickle in to the research-related portions of President Barack Obama’s 2014 budget request, which was delivered to Congress. ScienceInsider will be tracking what groups are saying as they release statements.

Statement by the Task Force on American Innovation on the president’s FY ’14 budget (12:00 p.m. on 12 April):

Members of the Task Force on American Innovation—a coalition of industry, universities, and scientific societies—believe it is essential that the federal government maintain a robust investment in scientific research. We believe that Congress and the President can and must commit to such spending even as they work to reduce budget deficits.

In that context, the Task Force supports President Obama’s proposed increases in funding for the National Science Foundation, the Department of Energy Office of Science, Department of Defense basic research, and the National Institute of Standards and Technology.

The federal investment in scientific research is vital to the nation’s long-term economic growth and national security. Indeed, one of the reasons that deficit reduction is so important is to ensure that the government can afford this and other critical investments. We recognize that there are strong differences over how to reduce budget deficits. But we believe there should be bipartisan support for the research that is the foundation of innovation and economic competitiveness.

With both the House and Senate having approved budgets, and the President now having submitted his own, we continue to urge the nation’s leaders to come together and negotiate a major long-term budget agreement that not only protects coming generations from unsustainable debt but also ensures our ability to invest in their future.

The American Chemical Society responds (4:00 p.m. on 11 April):

WASHINGTON, April 11, 2013 — The American Chemical Society (ACS) applauds the release of the President’s FY14 budget and his continued recognition of the importance of science and technology as the fuel for economic growth and job creation.

The ACS sees the President’s budget, and those prepared by Congress, as excellent starting points toward enactment of a balanced and bipartisan FY14 budget for the country,” said ACS President Marinda Wu, Ph.D. “We fully appreciate that this has been, and will be, a challenging budget season. We encourage our national leaders to make a bipartisan effort to focus on achieving a balanced budget that helps put the U.S. economic house in order, while also putting forth a road map that fosters innovation and leads to economic growth and job creation.”

ACS believes strongly that economic growth in the U.S. is based on three foundations: sustained support for scientific and medical research that leads to technological innovations, a strong science education enterprise that prepares a world-class workforce and a robust business climate that will make American companies competitive with our international competitors. To accomplish this we need our nation’s leadership to prioritize continued and predictable investment in scientific research to identify and enable new opportunities for innovation.”

The three-part ACS public policy agenda is outlined in U.S. Innovation and Entrepreneurship, and specific policy recommendations are contained in positions on enhancing research and technology development,science education and the empowerment of U.S. businesses.

As scientists and engineers, we are confident in recommending that the FY 14 budget should — indeed, must — emphasize innovation. In the last sixty years, more than half of all growth in GDP has directly resulted from scientific research and subsequent commercialization of new products and processes. Our American roots lie in pioneering innovation! This is what we do best.

Representative Lamar Smith (R-TX), the chair of the Science, Space, and Technology Committee of the U.S. House of Representatives released the following (5:00 p.m. on 10 April):

Even after a two-month delay, the President’s budget still gets a failing grade. Filled with new spending and over one trillion dollars in tax increases, his proposal once again fails to balance the budget and continues to borrow 25 cents for every dollar the federal government spends. Hardworking taxpayers are tired of watching the government borrow and spend money it doesn’t have.

While getting points for creativity, a proposed NASA mission to ‘lasso’ an asteroid and drag it to the Moon’s orbit will require serious deliberation. Seemingly out of the blue, this mission has never been evaluated or recommended by the scientific community and has not received the scrutiny that a normal program would undergo.

I am also concerned that the Administration continues to favor subsidies associated with its green energy agenda over basic research that helps keep America competitive. The bankruptcies of Solyndra, Abound Solar and Beacon Power have demonstrated a lack of accountability within the President’s green energy initiatives. The President now wants more money to fund more pet projects, when it is clear that his administration has not been responsible with the taxpayer dollars that have already been spent.”

The Science Committee will hold hearings in the coming weeks to receive testimony on the President’s budget priorities.

The following is a statement from the LIVESTRONG Foundation (4:50 p.m. on 10 April):

The LIVESTRONG Foundation applauds President Obama’s budget proposal to increase funding for lifesaving cancer research at the National Institutes of Health and the National Cancer Institute. We are also encouraged that the Administration, through funding for the Department of State and the U.S. Agency for International Development, continues to make strengthening health systems globally a priority. These essential investments will fuel the discovery of new treatments and cures for the leading cause of death worldwide.

The Foundation is pleased the President’s budget aims to significantly reduce smoking’s deadly toll through a 94-cent increase in the federal tax on tobacco products. Tobacco taxes are a proven method of reducing smoking rates, especially among youth, and associated health care costs. With a tobacco tax increase also generating billions of dollars in revenue, it is a win-win for the health and economic vitality of our country.

Additionally, the Foundation is encouraged by the Administration’s proposal to put the necessary funding increases in place to support the advancement of electronic health records technology. The LIVESTRONG Foundation advocates for the rights of cancer patients to have the increased control of their records that electronic technology would bring, including the potential to improve and enhance many areas of medical care.

Our work is focused solely on addressing the needs of those facing cancer today, improving their quality of life and health outcomes through free support services, programs, tools, resources and advocacy efforts. Since our founding 16 years ago, we have mobilized more than $500 million to help 2.5 million individuals facing cancer. On behalf of the millions living with cancer today, the Foundation looks forward to working with the Administration and Congress to make these budget increases and priorities a reality.

Association of Public and Land-grant Universities (APLU) President Peter McPherson today released the following statement (4:40 p.m. on 10 April):

President Obama’s Fiscal Year 2014 budget proposal reflects a strong commitment to supporting research at our public universities while also providing financial assistance to help students pay for school. While we continue to review the administration’s budget documents in more detail, the overall figures reflect an understanding that continued investments in basic research and higher education will more than pay for themselves through the innovations and subsequent economic growth they generate. Research at our universities has led to the development of everything from the Internet, GPS and treatments for cancer and other devastating diseases. I greatly appreciate the President’s understanding that despite having more limited funding to allocate, we must continue to devote additional resources to the research that will lead to future economic gains.

Investments in student aid and research, the majority of which is conducted at our nation’s universities, did not cause our budget deficits. In fact, those deficits would be even higher had we not made those past investments. Along with other leaders in the research university community, I have repeatedly called for a balanced approach of entitlement reform that yields savings and tax reform that produces new revenue as a path toward reining in budget deficits. While details certainly need to be worked out, the President’s budget proposal provides the framework for such an approach and I hope Congress works with the White House to get a much-needed big deal done this year.

APLU has been working very hard to transform STEM education and teacher training through our Science and Mathematics Teacher Imperative (SMTI). We are very pleased to see the President continue his focus on training 100,000 new STEM teachers and producing 1 million new STEM graduates. This effort is incredibly important for increasing science literacy among all Americans and for producing the next generation of researchers and engineers who will discover and develop new technologies that will improve lives and power our economy for decades.

In recent years we’ve seen states cut funding for public universities at the same time those schools are taking on additional students, which has furthered the need for federal financial assistance to offset this shift in costs. To that end, I’m pleased that the President maintained investments in the Pell, Work Study, and other student aid programs. We also appreciate that the President’s budget seeks to prevent interest rates on federal student loans from doubling on July 1 as scheduled, and look forward to learning more about how the proposed fixed-variable rate would be funded.

Statement from Research!America President and CEO Mary Woolley (3:30 p.m. on 10 April):

The president’s FY14 budget proposal offers a lifeline for medical research to replace sequestration’s damaging footprints. The budget includes $31.3 billion for the National Institutes of Health, as well as increases for the Food and Drug Administration and National Science Foundation. These increases would take our nation in the right direction, but we’re concerned that budget proposals from Congress—one from each of the House and Senate—unlike the president, fail to reverse sequestration. Sequestration, 10 years of across-the-board spending cuts, will drag our nation down from its leadership position in research and development as other countries aggressively ramp up investments, attracting American businesses and young scientists concerned that federal funding is on the decline, that the U.S. no longer prioritizes research. Our nation has the most sophisticated medical research ecosystem in the world; yet our elected officials have ignored the short- and long-term consequences of dismantling it via sequestration—more deaths from preventable diseases, increased joblessness and soaring health care costs as more Baby boomers become afflicted with Alzheimer’s, cancer, heart disease and other life-threatening, costly illnesses. Policy makers must start acting in the best interests of this nation and tackle tax and entitlement reform to end sequestration. Without bold action by Congress and the administration, our nation’s research enterprise will sputter as other countries fuel their competitive edge.

Following is a statement by Hunter Rawlings, president of the Association of American Universities (AAU) (1:50 p.m. on 10 April):

AAU and its member research universities have frequently expressed our view that the nation can and should reduce budget deficits but maintain strong investments in research and education. Such spending is critical to the nation’s long-term economic growth, health, and national security.

We are pleased to see this approach reflected in the President’s FY14 budget. The President’s budget offers hope that the nation will continue to make science and education investments a top national priority while taking serious steps to reduce budget deficits. We strongly support the President’s proposals to eliminate the ill-considered across-the-board sequester and to increase funding for the National Institutes of Health, the National Science Foundation, the Department of Energy Office of Science, Department of Defense basic research, the National Endowment for the Humanities, and some key student financial aid programs.

While we have concerns about some of the specifics, we also appreciate that the Administration proposes taking steps to address entitlement programs, which are the most serious driver of spending increases, and to raise additional revenues, which also are essential to serious, balanced deficit reduction.

We do not agree with everything in this budget. But it is a strong start, and we will work with the Administration and with Republicans and Democrats in Congress to support balanced deficit reduction, elimination of the sequester, and strong and sustained investments in the nation’s future.

The following is a statement from United for Medical Research (UMR) in reaction to President Obama’s FY ’14 budget (1:50 p.m. on 10 April):

United for Medical Research applauds President Obama’s proposal to increase funding for the National Institutes of Health (NIH) in FY 2014. As the centerpiece of the medical innovation ecosystem, NIH not only supports the research that leads to treatments and cures for our most devastating diseases, but drives the life sciences economic engine, annually sustaining over 400,000 jobs and nearly $60 billion in economic activity nationwide. The President’s NIH budget proposal is an important step forward in restoring the crippling $1.6 billion cut the agency received as a result of the sequester.

We look forward to working with the Administration and Congress in making this increase in NIH funding a reality. Following a decade of decline in purchasing power, even as scientific opportunities have grown exponentially, increasing the NIH budget should be a critical national priority. In these perilous economic times, we cannot afford to underinvest in our nation’s most talented scientists. Their work, undertaken in all 50 states, has enabled the U.S. to lead the world in life science innovation.

Every year, NIH research on cancer, heart disease, stroke, and diabetes alone averts up to 1.35 million deaths annually while providing hope to millions of patients and their families. Funding roughly one-third of all U.S. medical research, NIH supports more than 300,000 research positions at over 2,500 research universities and institutions in all 50 states.

http://news.sciencemag.org/scienceinsider/2013/04/reactions-to-obamas-science-budg.html

Obama’s 2014 Science Budget: At CDC, Budget Drops and Priorities Shift

by Science News Staff on 11 April 2013, 4:00 PM 

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Talking money. White House science adviser John Holdren (left) discusses the research-related parts of President Barack Obama’s 2014 budget request to Congress at briefing at the Washington, D.C., headquarters of AAAS (publisher ofScienceInsider).
Credit: David Malakoff

On 10 April, President Barack Obama submitted to Congress his spending plan for the 2014 fiscal year that begins on 1 October. The document can be found at www.fdsys.govScienceInsider is following the story closely, with regular updates on the requests of particular agencies and what those requests say about the president’s vision for science. Plus, reactions from the research community and around the web.

Laser Fusion Facility Faces Dimmer Spending

David Malakoff, 4:00 p.m. on 11 April

A controversial and perpetually troubled laser fusion project would get a hefty funding reduction under the president’s 2014 budget request for the Department of Energy (DOE). The cuts to the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory in California appear to be a direct consequence of the project’s failure to create a burning fusion plasma by its 2012 goal.

NIF has long had critics, who contended even before the multibillion-dollar machine was built that it would never work. After numerous delays and cost overruns, NIF finally began operations in 2009, and managers set a 30 September 2012 goal of achieving “ignition” by using its 192 lasers to crush a tiny capsule of hydrogen fuel. But the device fell substantially short of that goal, and late last year officials told Congress that they weren’t sure NIF would ever be able create a burning plasma.

NIF advocates have argued that the project, even if it didn’t achieve ignition, is useful for conducting experiments that would help engineers understand and maintain the nation’s stockpile of nuclear weapons. That is now NIF’s focus, although some outside experts and members of Congress are skeptical of that use. They also question the wisdom of giving NIF any more time or money to achieve ignition.

The budget request appears to reflect some of that skepticism. To help pay for maintaining the nuclear stockpile during a time of austerity, “the Budget proposes to achieve savings by reducing investments in the National Ignition Facility, which failed to achieve ignition in 2012 as scheduled, and by implementing several management efficiencies,” it states. In particular, the budget calls for ending NIF accounting practices that allowed Livermore officials to charge some of the project’s costs to other programs—a practice that critics said effectively obscured NIF’s true cost.

It’s not clear exactly how big the proposed NIF cuts are, because the project receives funding from several programs within DOE’s National Nuclear Security Administration, which oversees the nation’s nuclear weapons program. A Livermore spokesperson tells ScienceInsider that NIF’s operating budget request is $329 million for 2014, down 20% from 2012.

Other NIF-affiliated budget lines also appear to take a hit, but it’s hard to calculate exact numbers, says Marylia Kelley, executive director of Tri-Valley CAREs, a watchdog group in Livermore that has been critical of the laser project. But NIF “is taking a smaller hit that I had anticipated; these are very modest cuts considering NIF’s abject failure to achieve ignition,” she says. Her group wants NIF to be managed by DOE’s Office of Science for civilian research. “We should run it as an unclassified user facility for 5 years, and then do an analysis of what kind of science the nation is getting for its money, and then decide whether to pull the plug,” she says.

At CDC, Budget Drops and Priorities Shift

Jennifer Couzin-Frankel, 3:25 p.m. on 11 April

For the Centers for Disease Control and Prevention (CDC), the 2014 budget request offers a mixed picture. CDC’s budget continues to trend downward, as it has over the last several years. President Barack Obama is requesting $6.6 billion for CDC, a drop of $270 million from 2012. But not every program will suffer: In particular, the administration touted extra money for emerging and zoonotic infectious disease initiatives, with a respectable increase of $70 million to $432 million. Forty million dollars would go to an “Advanced Molecular Detection Initiative,” which aims to do a better and quicker job of detecting and responding to threatening pathogens.

An increase of $35 million for injury prevention and control includes money for gun violence prevention research, which was touted by Obama in January.

None of these dollars are new, however. “If you’re putting additional money into one category, you’re taking it from the other,” says Richard Hamburg, deputy director of the Trust for America’s Health, an advocacy group in Washington, D.C., that focuses on public health. Losers in CDC’s budget include chronic disease prevention efforts and public health preparedness and response. The preparedness cuts would reduce funding to local and state health departments.

In a sense, the mix of increases and cuts suggests tension in how best to allocate resources when it comes to new infectious diseases, such as a novel coronavirus or worrying avian influenza cases in China. On the one hand, says Laura Kahn, an internist at Princeton University who works in public health, we need to quickly be able to identify new viruses and develop vaccines against them. She welcomes CDC’s proposed additional funding for emerging infectious diseases, although wonders how exactly the funds will be allocated.

“Now on the other hand, of course,” Kahn writes to Science in an e-mail, “is how to disseminate a new vaccine to a public without a well-funded public health infrastructure. That’s the downside to the budget cuts.”

NSF Basks in Double-Digit Increase

Jeffrey Mervis, 11:15 a.m. on 11 April

With enough money, many things are possible.

That’s the happy position in which the National Science Foundation (NSF) finds itself after the president proposed giving the agency an increase of $741 million in 2014, to $7.62 billion. That amount is 10.8% more than NSF’s current budget of $6.88 billion, although the administration describes it as an 8.4% boost over NSF’s 2012 budget. No matter how it’s painted, the request sets NSF apart from most federal agencies that are being asked to make do with level or reduced funding.

The double-digit increase, if endorsed by Congress, would allow NSF to expand activities across the foundation. The request would provide a 9.2% boost over 2012 levels for NSF’s core disciplinary research activities, to $6.21 billion. That includes a doubling of its investment in cyberinfrastructure, to $155 million, reflecting NSF’s lead role in a joint program on Big Data with the National Institutes of Health.

The 2014 request would also increase funding for several initiatives begun by Subra Suresh, who stepped down last month as NSF director to become president of Carnegie Mellon University. In particular, the Innovation Corps program to train would-be entrepreneurs would grow in size and geographic scope, and the INSPIRE program would be able to fund more unorthodox approaches to multidisciplinary research questions. A bigger budget would also let NSF start construction of the Large Synoptic Survey Telescope, a $665 million facility in Cerro Pachon, Chile, to which the Department of Energy has committed $160 million. And it would allow NSF to grow its prestigious graduate research fellowship program by one-third, boosting the next class to 2700.

In addition to having friends in the White House, NSF received strong support this year from Capitol Hill to lessen the blow of the mandatory, across-the-board 5% sequester that took effect in March at every civilian agency. (National security funding was cut by 7.2%.) Last-minute increases from a Senate funding panel left NSF’s 2013 budget only 2.1%, or $150 million, below its 2012 funding levels.

NSF’s operating plan for 2013, which spells out how much money each activity will receive, isn’t due to the White House until 22 April. So NSF officials aren’t able to predict how the sequester would affect the number of grants to be awarded in 2013 and the overall success rate of proposals. But, given the additional funding it has received, the agency’s original projection of 1000 fewer grants and a 3% dip in success rates is almost certainly too pessimistic.

NIST Manufactures Some Big Spending Dreams

David Malakoff, 6:20 p.m. on 10 April

The Department of Commerce’s National Institute of Standards and Technology (NIST) was one of the big research winners in today’s 2014 budget request rollout, with the White House requesting a 23%, $177.5 million increase over its 2012 spending, to $928.3 million.

Within that total, NIST’s intramural laboratories would get a 21% hike to $754 million.

The increases are in line with a 2010 law that endorsed a doubling of NIST’s budget over a decade, but Congress hasn’t always come up with the money to stay on track with that goal.

“The FY 2014 budget increases will allow NIST to address high-priority scientific and technical issues that are critical to U.S. economic competitiveness and innovative capacity,” said NIST Director Patrick Gallagher in a statement. In all, he said, the proposal includes some $127 million in new research funding.

The administration is also proposing that NIST help coordinate a one-time $1 billion initiative to create a network of up to 15 manufacturing innovation institutes around the country. The National Network of Manufacturing Innovation would join companies, academic institutions, and government agencies in efforts to develop cutting-edge manufacturing technologies. The Obama administration has already set up one pilot center in an effort to demonstrate the value of the idea .

Smithsonian Outreach Gets a Boost

Elizabeth Pennisi, 6:15 p.m. on 10 April

President Barak Obama wants to tap the Smithsonian Institution’s expertise in informal science education as part of his plan to streamline STEM (science, technology, engineering, and mathematics) education. As part of his 2014 budget request, Obama is proposing a $25 million boost to the institution’s education efforts. “From Day 1, I knew that we could play a much bigger role in science education,” says Wayne Clough, secretary of the Smithsonian. “We have attributes and resources that other agencies don’t have.”

The Smithsonian, which is home to 19 museums, a zoo, and six science research centers, would receive $869 million from the federal government under the 2014 request, a $93 million, 12% increase over $776 million in 2013.

For 2013, the continuing resolution that Congress approved in March added $5 million dollars to staff the African American museum that is under construction and $2 million for roof repairs from Hurricane Sandy to its 2012 allocation of $810 million. But as part of the sequester, the Smithsonian had to come up with $41 million in cuts to that amount.

Those belt-tightening measures included taking all new major science instrumentation projects off the table. But the proposed 2014 budget includes $500,000 to begin to modify a 12-meter radio antenna telescope and move it from Arizona to Greenland. The telescope, which is expected to be operational in 2017, will be used in conjunction with Smithsonian telescopes in Chile and Hawaii to study black holes.

Otherwise, any increases for science programs are primarily for covering salary, rent, and other expenses, such as providing parity in salaries for Panamanians working at the Smithsonian Tropical Research Institute in Panama, says Smithsonian senior budget analyst George Thomas.

Thus, the big win for Smithsonian science is for STEM education. President Obama’s plan would shift $180 million from 90 STEM programs at 11 agencies to the U.S. Department of Education, the National Science Foundation, and the Smithsonian. The first two agencies would work to improve K-12 and undergraduate and graduate education. With its $25 million, the Smithsonian would improve informal education as it relates to the classroom. “The boundary between informal and formal education is breaking down,” Clough says.

The newly named Center for Learning and Digital Access will be expanding its efforts to provide teachers easy access to Smithsonian materials that are geared toward meeting education standards requirements. Already it has a database of 2000 documents, photos, podcasts, videos, and other material, says Michelle Smith, editorial director of the center.

Eventually that database will be expanded to include material from all over the federal government. “We would serve as the agent for other agencies,” Clough says. When Clough first came to the Smithsonian in 2008, the Smithsonian was just starting to reach out to students and teachers online and there was not much coordination among its 250 educators. Now the education effort is much more coordinated, Clough says, and he expects that a similar transformation can happen across the federal government. “We can deliver education to anybody in any place at any time,” he says.

Rock On! Asteroid Spending Hot Item for NASA

Yudhijit Bhattacharjee, 5:50 p.m. on 10 April

Asteroids are hot in the president’s 2014 budget for NASA. He wants the space agency to find them, move them, excavate them, and eventually dispatch astronauts to walk on them.

If NASA’s budget proposal for the next fiscal year contains one shiny new initiative, it is the science fiction-y plan to capture an approximately 454-tonne asteroid with a giant bag and drag it close to the moon where it can be studied in detail. After it has accomplished that feat, the agency will send astronauts to visit the rock, traveling in an Orion space capsule that is now under development. If the plan succeeds by an anticipated date of 2021, President Barack Obama may be able to tweet out a humble brag that might read thus: #Woohoo! Realized promise made at #KennedySpaceCenter.

The promise—made in a speech in April 2010, in which Obama laid out his vision for space—was to land humans on an asteroid by 2025. For 2 years, lawmakers questioned NASA officials on the specifics of how it would be done. Lawmakers have slammed the agency for not having a clear sense of direction. Finally, the agency seems to have come up with an answer that kills both birds with one stone.

“This mission raises the bar for human exploration and discovery,” NASA Administrator Charles Bolden said this afternoon in a media telecon about the budget. The idea, which will be kicked off in 2014 with a total funding of $105 million divided between NASA’s exploration, aeronautics, and science directorates, appears to have gained traction after the crash-landing of a meteorite over Russia in February. That event set off frenzied calls from lawmakers that asteroid detection and deflection should be a high priority for NASA.

The first step in the proposed capture and maneuver mission would be to find the right-sized asteroid. That’s why the administration wants to double the current level of funding for asteroid detection to $40 million. This piece of the new initiative will likely please lawmakers who have already conducted hearings on what NASA and private companies should be doing to tackle the asteroid threat.

The second step of the mission would involve developing new technologies to achieve the task, which dovetails with NASA’s stated goal of inspiring technological breakthroughs. And the final step would involve sending astronauts to the asteroid aboard the Orion space capsule, the development of which is another high priority. In other words, the mission helps tie together several disparate items on NASA’s agenda.

The agency has a number of other programs that have to do with asteroids. One is a mission to return a sample from a known carbonaceous asteroid by 2023. That mission, called OSIRIS-REx, is planned for a 2016 launch.

More Love for USDA’s Competitive Research

Erik Stokstad, 5:30 p.m. on 10 April

It’s no secret that the White House likes competitively awarded, peer-reviewed funding for research. For 2013, the administration asked for a 23% boost to the Agriculture and Food Research Initiative (AFRI) while keeping its requests for other research funding levels at the U.S. Department of Agriculture (USDA) relatively flat. But Congress didn’t deliver, instead keeping AFRI’s budget nearly constant at $266 million.

This year, the White House has doubled down and asked for a 44% boost to AFRI over 2013 levels, to $383 million.

“Great news!” extolled Karl Glasener, who directs science policy for the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America. Whether Congress will go along remains to be seen.

AFRI is part of the National Institute of Food and Agriculture, USDA’s extramural funding division. Existing programs at AFRI focus on food security, water and nutrient management, nutrition, food safety, biofuels, and climate change. They plan to add programs on agricultural education and outreach. While AFRI would see a big boost relative to its estimated FY 2013 budget, so-called formula funds, which are given to land-grant universities, would decline by 1% to $657 million.

As with previous years, the administration is asking for a small increase to R&D at the intramural Agricultural Research Service. As part of its request for a 1.6% increase over 2013 to $1.08 billion, USDA would boost efforts on food safety, human nutrition, and environmental stewardship while decreasing funding for agronomic research. In addition, USDA is asking for $155 million to fully renovate its Southeast Poultry Research Laboratory in Athens, Georgia. The aging facility has a biosafety level 2 lab and three agricultural labs and was identified as the top priority for modernization in a 2012 review of ARS labs.

*Correction, 11:30 a.m. on 11 April: The administration is asking for a small increase to R&D at the intramural Agricultural Research Service for a 1.6% increase over 2013, not a 15% increase as originally reported.

NIH Gets Slight Relief From Sequester Pain

Jocelyn Kaiser, 5:10 p.m. on 10 April

The president’s fiscal year 2014 budget offers the National Institutes of Health (NIH) only a modest 1.5% increase, to $31.3 billion, over 2012 levels. But that small boost would provide welcome relief from the staggering 5% cut that the agency received this year because of the mandatory across-the-board cuts known as sequestration.

“Everything’s relative,” said NIH Director Francis Collins after a press briefing today. “Considering what we’ve been going through in FY ’13, what’s being proposed here is really gratifying.” (Compared with NIH’s final 2013 budget of $29.3 billion, the increase would be 6.8%.) NIH would fund 10,269 new and competing grants, an increase of 351 compared with 2012.

The $471 million in new funding includes $40 million for the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, a brain mapping project that the administration rolled out last week. (Other agencies are contributing about $70 million.) NIH also wants to spend $41 million on a “Big Data” initiative to improve ways to use and share large datasets, Collins said. Another $32 million would go toward anew program that would to attempt to bring more diversity to the biomedical workforce by encouraging minorities to pursue biomedical research careers.

Another favored area is Alzheimer’s research, which would receive $80 million in new grants for drug development at the National Institute on Aging—accounting for the entire increase that the institute is slated to receive.

The Cures Acceleration Network, a program aimed at supporting drug development within NIH’s National Center for Advancing Translational Sciences, would receive $50 million, a $40 million increase.

Biomedical research groups cautiously praised the increase for NIH. “We don’t want to sound unappreciative, but this continues the pattern of failing to keep pace with inflation” for a decade at NIH, said Dave Moore of the Association of American Medical Colleges. The budget also assumes that Congress finds a way out of the sequestration cuts mandated for the next 10 years, he adds. “It’s a little bit of good news, but I think it’s still very worrisome as to where this is all headed,” Moore said.

USGS Sees Budget Boost as Vote for Expanding Mission

Erik Stokstad, 5:05 p.m. on 10 April

The U.S. Geological Survey (USGS) patted itself on the back today for a proposed 8% increase in the president’s budget request, compared with its FY 2012-enacted budget. The $98.8 million boost would lift theagency’s budget to about $1.2 billion.

“This is a really significant increase,” said acting Director Suzette Kimball in a teleconference. “It’s largely due to USGS being recognized among the large science agencies as part of the larger R&D effort” and not just a mission agency to the Department of the Interior, in which it exists.

A request of an 8% increase is exceptional for USGS, which last year was slated for an overall 3% increase in the president’s request. Typically, the agency has seen increases on the order of 1% to 2%. The proposed budget would include a $13 million boost for research on hydraulic fracking, to $18.6 million. It would also raise the funding for stream gages, which monitor water levels and collect other data, by $7.2 million. That would buy about 400 new gages to supplement the existing network of some 3130. USGS has said that the budget cuts known as the sequester threaten the operation of about 350 existing gages. Other proposed increases include a 22% increase for climate change science, to $72 million. A3D-elevation mapping program would get started as well. Research into mineral deposits and the Water Resource Research Institutes would be cut, but details were not immediately available.

A Fundamental Shift at the Pentagon

Eliot Marshall, 4:35 p.m. on 10 April

To sustain an edge in military technology, the White House aims to spend more on key military research programs—particularly fundamental basic research—even as it trims the overall Pentagon budget next year.

The plan calls for a total of $526.6 billion in discretionary funding for the U.S. military in 2014, about 0.7% less than in 2012 and 2013. The administration foresees a sharp decline in the account that pays for weapons testing and evaluation, from $72 billion in 2012 to $68 billion next year. At the same time, it gives a boost to the blue-sky innovation agency known as DARPA (Defense Advanced Research Projects Agency); its budget would increase by 1.8%, to $2.9 billion. Funding for basic science and technology accounts would remain steady at around $11.9 billion, with a shift of about $200 million inside this category to emphasize fundamental work—including the kind of research carried out at universities.

This is a good sign, says Matthew Owens, an analyst at the Association of American Universities, the lobby for major research institutions based in Washington, D.C. He believes the administration is sticking with a theme articulated by the previous two secretaries of defense—investing in research not just to acquire advanced technology but also to draw talented people into the field of national security.

EPA Loses Out in R&D Budget

Erik Stokstad, 4:25 p.m. on 10 April

If you don’t have much nice to say, don’t say much. That pretty much sums up the Environmental Protection Agency’s (EPA’s) discussion of research when it rolled out its proposed budget for FY 2014, which includes a cut to the agency’s science program.

The request “reflects the Obama Administration’s commitment to drive strong economic growth by supporting innovative research” on pollution, climate change, and clean energy, the agency said in a statement. The agency’s more detailed “EPA Budget in Brief,” released today, stated that the R&D program “leverages expertise” to meet its challenges.

The agency overall would see a 4% whack from its funding under the 2013 continuing resolution to $8.2 billion, continuing its slide in recent years. The research program, which was funded at $568 million in FY 2012, would drop by 1.9% from that level in 2014. About $16 million would be taken from the popular STAR fellowships as part of an administration proposal to reorganize STEM programs across the government.

Research on drinking water would decline by $2.3 million, endocrine disruptors by $1.2 million, and four other programs by $1 million each. EPA would expand its cooperative research with the U.S. Geological Survey and DOE on the environmental impact of hydraulic fracking, and increase its funding on minimizing chemical hazards by $4.1 million and climate change by $3.2 million. Baseline funding for these programs was not immediately available.

Outside the science division, EPA’s Greenhouse Gas Reporting Program would get a $2.4 million boost. And the Air, Climate, and Energy Research program would see a 7.9% increase to $105 million over FY 2012 levels for research on environmental and health impacts from air pollution, climate change, and biofuels.

Nanotechnology Initiative Would Get Smaller

David Malakoff, 4:05 p.m. on 10 April

A 13-year-old nanotechnology research initiative would take a cut of $159 million, or 8.5%, to $1.7 billion under the president’s budget request to Congress.

The National Nanotechnology Initiative (NNI), launched in 2001, coordinates an array of nanoscale science projects across about 15 federal departments and agencies. In 2013, the Obama administration requested a 4.1% increase for NNI, to $1.77 billion. This year’s budget documents offer no explanation for the turnabout.

Historically, about two-thirds of NNI funding has gone to academic research, with the remainder supporting science at government and industry laboratories.

Climate Change Research Gets a Warm Reception

David Malakoff, 2:35 p.m. on 10 April

Spending on climate change research at 13 federal agencies would rise by a total of 6%, to $2.65 billion, over 2012 levels under the president’s 2014 budget request to Congress.

The biggest winner would be NASA, which would get a $71 million, 5% increase to $1.49 billion. In contrast, the National Science Foundation would see a decrease of $7 million, or 2.1%, to $326 million.

The 13 agencies are part of the U.S. Global Change Research Program (USGCRP), an initiative that cuts across the U.S. government.

More details on the USGCRP request can be found on this White House fact sheet.

Big Bump-Up for Department of Energy Research

Adrian Cho, 2:10 p.m. on 10 April

The details have not yet been released, but the proposed 2014 budget for the Department of Energy (DOE) appears to be a researcher’s dream. DOE’s basic research arm, the Office of Science would get a 5.7% increase from the level enacted for fiscal 2012—the last budget that Congress passed—to $5.15 billion. (Last month, Congress essentially extended the 2012 budget through the rest of fiscal year 2013, which ends on 30 September.)

Even more impressive, the Advanced Research Projects Agency-Energy (ARPA-E) would see its budget climb 38% from the 2012 level to $379 million. ARPA-E aims to cherry-pick the most promising ideas from energy-related basic research and quickly develop them into commercially viable technologies.

Within the Office of Science, the biggest winner by far is the fusion energy science program, which would see its budget soar 14% to $458 million. Such a boost is desperately needed, researchers say, as the U.S. contributions to the international fusion experiment ITER, under construction in Cadarache, France, threaten to consume much of the United States’ domestic fusion research.

Otherwise, the trend toward research that is more applicable to clean energy continues. Funding would increase by 10.3% from the 2012 level to $1.862 billion for the basic energy science program—which funds materials science, condensed matter physics, chemistry, and related fields and runs many of DOE’s x-ray sources and other “user facilities.” Advanced scientific computing research would jump 5.7% to $466 million. Biological and environmental research would edge up 2.6% to $625 million. And nuclear physics would climb 4.2%, to $570 million.

In contrast, DOE’s high-energy physics program, which funds work in elementary particle physics, would see its budget fall 1.7% from the 2012 level to $777 million.

All of this ignores the effects of the automatic budget cuts known as sequestration, which are required by the Budget Control Act of 2011. Unless it is reversed, sequestration would knock DOE budget levels for 2014 down 7.2%, leaving the Office of Science a net loser instead of a winner.

Homeland Security Would Move Ahead With Controversial Agrosecurity Laboratory

David Malakoff, 1:45 p.m. on 10 April

The Department of Homeland Security’s (DHS’s) science and technology directorate would see its current budget roughly double, to $1.4 billion, if the president’s request is enacted. Essentially all of the increase, $714 million, would go to building the National Bio and Agro-Defense Facility (NBAF), a controversial high-security laboratory slated for Manhattan, Kansas, that would study diseases that threaten humans and livestock. NBAF is supposed to replace the Plum Island Animal Disease Center in New York, which the budget request says “will soon reach the end of its useful life.”

Last year, the White House surprised many by omitting funding for NBAF in its 2013 request. Officials said that they needed to take a fresh look at the project in light of safety and budget concerns, as well as opposition from some well-placed members of Congress. Several generally positive outside reviews conducted by the U.S. National Academies, however, appear to have helped persuade the White House to fully back the effort.

There is certain to be congressional opposition to building NBAF. Representatives Tim Bishop (D-NY) and Joe Courtney (D-CT) have vowed to block NBAF funding, saying the money would be better spent upgrading Plum Island in New York. Senator Jon Tester (D-MT) has also expressed concern about NBAF, reflecting fears among the livestock industry that disease could escape from the facility and threaten U.S. livestock herds.

The new budget requests $467 million for the directorate’s primary research account, extending the program’s recent rebound. In 2012, Congress slashed that account by 52%, to $265 million, as a result of an unrelated battle over disaster assistance spending and concerns about the program’s effectiveness. If Congress approves the 2014 request, the account would return to 2011 levels. But that number would be more than $130 million below where spending stood in 2010.

NASA Budget Includes Money to Send New Rover to Mars, Capture Asteroid

Yudhijit Bhattacharjee, 12:55 p.m. on 10 April

The administration wants to hold NASA’s overall budget line for 2014 at nearly the same level as what the agency is getting this year. But it wants to make some key changes in how some of that $17.7 billion would be spent.

It wants the agency to launch a robotic mission to capture a small asteroid in space and drag it close to the moon. “Astronauts would later visit the asteroid and return samples to Earth,” according to NASA budget highlights posted on the White House’s Web site this morning. The budget provides $78 million to develop technologies for the mission.

The budget also provides money for “multiple missions focused on Mars exploration, including a new large rover to be launched in 2020.” NASA has been considering various ideas for exploring Mars after last year’s pullout from the European-led ExoMars program, and sending another rover to the Red Planet seems to be what the administration has settled on.

Another key change that the administration wants to make is to shrink the agency’s budget for education and outreach by $47.5 million, which would be redirected to other agencies. “NASA’s assets will be used more effectively through coordination with the National Science Foundation, the Department of Education and the Smithsonian Institution to achieve the Administration’s wider STEM [science, technology, engineering, and mathematics] education goals,” according to the White House’s summary of highlights.

Most Civilian Agencies Get a Boost

Jeffrey Mervis, 12:40 p.m. on 10 April

President Obama today proposed a significant increase in federal spending on civilian research for 2014. His support for science comes as part of an otherwise flat budget that aims to shrink the federal deficit through clamping down on entitlement programs and raising money by altering the tax code.

The president has requested a total of $143 billion in 2014 for research and development. That’s level with current spending and up 1% from 2012. But within that total, civilian research spending would jump by 9% over 2012.

The increases for research, if approved by Congress, would allow most research agencies to recover from the cuts to their current budgets under the across-the-board sequester that went into effect last month. But that’s a huge if. And there are also some caveats in what the president has proposed.

As in past years, the National Science Foundation (NSF), the Department of Energy’s Office of Science, and the National Institute of Standards and Technology would receive hefty boosts in line with a 2010 law that endorses a doubling of their budgets over a decade. NSF’s budget would jump by 8.4%, for example, to $7.6 billion, and the Office of Science would rise by 5.7%, to $5.1 billion. In contrast, the budget for the National Institutes of Health would inch up by 1.6%, to $31.3 billion.

All of those numbers are based on a comparison with 2012 spending levels. That’s because Congress didn’t complete work on the 2013 spending bill until 21 March, too late to be included in the president’s request. The proposed increases would be considerably larger if compared with 2013, because sequestration sliced 5% off every civilian agency’s budget.

The president’s budget also fails to take into account how much agencies would lose in 2014 under sequestration, the 2011 budget law that requires across-the-board cuts to lower the federal deficit over the next decade. For 2014, civilian agencies would suffer a cut of 7.9%. But the White House maintains that sequestration is bad policy and has urged Congress to repeal the law. Hence, it is not a factor in the president’s request.

As the day goes on, we’ll bring you more details on the president’s science budget.

http://news.sciencemag.org/scienceinsider/2013/04/obamas-2014-science-budget.html

#FY2014: Scientific Community Responds to President’s Spending Plan

http://news.sciencemag.org/scienceinsider/budget_2014/react.html

As White House Embraces BRAIN Initiative, Questions Linger

by Emily Underwood on 3 April 2013, 5:00 PM 

si-brain_whitehouse.jpg

A lot of nerves. President Barack Obama is introduced by Francis Collins, director of the National Institutes of Health, at the BRAIN Initiative event in the East Room of the White House on 2 April.
Credit: Official White House Photo by Chuck Kennedy

For neuroscientist Rafael Yuste, sitting in an ornate White House chamber yesterday listening to President Barack Obama heap praise—and some $100 million—on a brain-mapping initiative that he helped hatch was a “luminous” experience. “It felt like history,” says the researcher, who works at Columbia University.

“There is this enormous mystery waiting to be unlocked,” Obama told the East Room crowd packed with leaders of American neuroscience during a 12-minute paean to brain research (likely the most expansive yet delivered by an American president). By “giving scientists the tools they need to get a dynamic picture of the brain in action,” he said, the new initiative will help scientists find a cure for complex brain processes such as traumatic brain injury and Parkinson’s, and create jobs that “we haven’t even dreamt up yet.”

For all the lofty rhetoric, however, the White House didn’t provide many details about how the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative will accomplish its mission. And the lack of detail is worrying not only BRAIN skeptics—who argue that it targets the wrong goal and could detract from other research efforts—but also even some staunch advocates such as Yuste. The way that the White House has packaged and plans to fund and coordinate the initiative, they say, is creating some unease.

“As the proposal stands, it’s still awfully vague, so it’s hard not to have some reservations,” says biophysicist Jeremy Berg of the University of Pittsburgh in Pennsylvania, who is a former director of the National Institute of General Medical Sciences at the National Institutes of Health (NIH).

Several years ago, Yuste and other scientists originally pitched BRAIN to U.S. government officials as the Brain Activity Map, a 10-year, $3 billion effort to develop tools in nanotechnology, optogenetics, and synthetic biology that could measure “every spike from every neuron” in a neural circuit. In a 2012 paper in Neuron, based on meetings organized by the Oxnard, California-based Kavli Foundation, Yuste and colleagues laid out a plan to progress gradually from mapping the brain activity of simple model organisms such as the fruit fly to charting the brains of creatures that contain roughly 1 million neurons, such as the Etruscan shrew. Human applications were couched as the ultimate aim, but not an immediate goal.

Since the idea was adopted by the White House, however, it has evolved substantially. The plan that Obama unveiled yesterday calls for BRAIN to be funded by three federal agencies as well as private foundations. Officials say the president’s fiscal year 2014 budget request, to be released on 10 April, will request approximately:

  • $40 million for NIH’s Blueprint for Neuroscience Research, a project which spans 15 institutes and centers
  • $50 million for the Defense Advanced Research Projects Agency, for research that could improve treatment and diagnosis of combat-related conditions such as post-traumatic stress, brain injury, and memory loss
  • $20 million for the National Science Foundation (NSF), to support research into the development of nanoscale probes that can record the activity of neural networks; information processing technology that can handle the flood of data generated by BRAIN research; and better understanding of the neural representation of thoughts, emotions, actions, and memories

Four private groups—the Allen Institute for Brain Science, the Howard Hughes Medical Institute, the Kavli Foundation, and the Salk Institute for Biological Studies—say they will support the project by funding BRAIN related research at their institutions. (See this infographic for more details.)

The initiative will be steered by an NIH-backed working group of 15 neuroscientists, co-chaired by Cornelia Bargmann of Rockefeller University in New York City and William Newsome of Stanford University in Palo Alto, California.

Although that group will not release a detailed research spending plan until later this year, BRAIN is expected to put a greater emphasis on human applications than its original planners envisioned, says neuroscientist John Donoghue of Brown University, one of two researchers from the Kavli-led effort that has been named to the BRAIN steering committee (neuroscientist Terrence Sejnowski of the Salk Institute is the other).Human applications and animal research are now being thought of as “a parallel rather than a serial effort,” he says. And NIH Director Francis Collins confirms that human applications will be of great interest: “We don’t want to waste any time moving to science that has direct human applications,” he said during a press teleconference yesterday.

That shift has created some worries. Yuste, for example, says that keeping human benefits in mind is important, but he wonders whether the project’s original sharp focus on tool development may be diluted if the NIH advisory panel is dominated by traditional neuroscientists, rather than a more interdisciplinary mix of scientists including nanoscientists, optogeneticists, and synthetic biologists. “Neither Bargmann or Newsome are tool builders, so it’s a worry that they are packing the committee with users, rather than tool builders,” Yuste says, adding that he and some allies are asking NIH to add members to the panel. “We are asking for more technologists.”

Just 2 months ago, Bargmann herself expressed skepticism about the project. “Based on my conversations, there is great concern in the neuroscience community that this sounds like a big central planning project that will take resources away from creative work,” she wrote in a February e-mail to Science. “The project needs to make sense to those who care deeply about neurological disease and neuroscience, and we haven’t seen the leaders in those areas involved yet.” (ScienceInsider has not been able to reach Bargmann for comment since she was named co-chair to the working group.)

Although Pittsburgh’s Berg was skeptical of the 10-year, $3 billion Brain Activity Map proposal, “now that it’s been downsized somewhat and focused on technology development I feel much more comfortable with the project,” he says. Based on his experience at NIH, Berg says that the emphasis on technology development is “a very good thing,” because groups within the agency tend to struggle with developing new technologies” because they are “focused on what problem they’re trying to solve rather than the technology development per se.”

Allowing the system to be flexible and adapt over time is crucial, he says. The fact that Bargmann and Newsome are on the advisory group “adds a lot of comfort for me.” While both are “spectacular contributors” to neuroscience, Berg says, they also have a broad view of how to administer both small and large science projects.

Like any big project, the success of BRAIN will ultimately depend on its leadership, Donoghue agrees: “There are a lot of people involved in this who have built independent careers running labs on their own. … The question is whether they will all pull together in the same direction.”

Still unclear is whether BRAIN’s funding will siphon money from other research efforts and if the $100 million will be followed by further investments in coming years. “My understanding is that it’s coming from new money” not previously allocated to neuroscience research, Donoghue says. Yuste’s initial reaction to the figure was that it was “much too low” to accomplish the project’s original goals.

But “that money has to be seen as something that can be built around, from which you can build forward,” says Alan Leshner, CEO of AAAS (publisher of ScienceInsider). “At a time when funding is so tight across the government,” White House support for neuroscience research is a “major opportunity,” says Leshner, a former director of NIH’s National Institute on Drug Abuse and acting director of the National Institute of Mental Health. “If the scientific community doesn’t rise to the moment, shame on us.”

Although there’s no predicting whether Congress will approve the president’s request, “there has historically been and there seems to be today bipartisan interest in this kind of innovative research,” said White House press secretary Jay Carney yesterday during his daily briefing.

One top Republican leader in Congress has already expressed his support. “Mapping the human brain is exactly the type of research we should be funding,” said Representative Eric Cantor (R-VA), the majority leader of the U.S. House of Representatives, in a statement. “It’s great science.”

(Obama, meanwhile, joked during his remarks that “presumably my life would be simpler” if scientists could map the brain. “It could explain all kinds of things that go on in Washington. We could prescribe something.”)

Despite their concerns, many of the researchers who laid the foundation for BRAIN are simply happy to see at least part of their idea being realized. On the evening before the president’s announcement, Yuste and more than a dozen other colleagues involved in the effort met for dinner in downtown Washington, D.C., for what they jokingly described as their “Last Supper.” The feeling of accomplishment was “bittersweet,” Yuste says. They were pleased that the Obama administration has embraced the project, he says, but now “it’s out of our hands.”

http://news.sciencemag.org/scienceinsider/2013/04/as-white-house-embraces-brain-in.html

Read Full Post »

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/29/2018

 

HDL-C: Is It Time to Stop Calling It the ‘Good’ Cholesterol? – Medscape – Jul 27, 2018.

 

In Eli Lilly’s Pipeline: DISCONTINUING Evacetrapib, a CETP inhibitor that’s meant to boost HDL

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/10/12/in-eli-lillys-pipeline-discontinuing-evacetrapib-a-cetp-inhibitor-thats-meant-to-boost-hdl/

 

On April 3, 2012 we published

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

ACP-501, a recombinant human lecithin-cholesterol acyltransferase (LCAT) enzyme.

LCAT, an enzyme in the bloodstream, is a key component in the reverse cholesterol transport (RCT) system, which is thought to play a major role in driving the removal of cholesterol from the body and may be critical in the management of high-density lipoprotein (HDL) cholesterol levels.  The LCAT enzyme could also play a role in a rare, hereditary disorder called familial LCAT deficiency (FLD) in which the LCAT enzyme is absent.

http://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

On April 4, 2013, the next day, a new study was published on a novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects was published on Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Writer’s VIEWS:

    • AstraZeneca acquisition of AlphaCore represents its market entry into the CETP inhibitor segment via an acquisition where the company did not have presence or inhouse research. The results of the second study will position Merck at a superior position upon completion of Phase III Clinical Trials for Anacetrapib
    • If Biologics will help increase HDL in wide market penetration, the market share of Statins will be negatively impacted. Patent expiration and generic market availability of Statin erode future profits
    • Anacetrapib in in Phase III clinical Trial, if successfully completed — will be the FIRST biologics to use CETP inhibition biology of lipid metabolism in the quest to fight atherosclerosis by improving CVD outcomes
    • A connection between this two events and cites in Disclosure, AstraZeneca, Merck, supporting the research of Christopher P Cannon on the study on Anacetrapib.
    • Full Article PDF file was published in Research Reports in Clinical Cardiology, one of the Journals on Beall’s list publisher, where scientists pay to have the article been published, Dove Press, on its Web site says, “There are no limits on the number or size of the papers we can publish.” See reference for Beall’s list publishers http://www.nytimes.com/2013/04/08/health/for-scientists-an-exploding-world-of-pseudo-academia.html?pagewanted=1&_r=0&emc=eta1

Study Goals:

  • testing the hypothesis that CETP inhibition may reduce atherosclerotic outcomes. 
  • answer important questions regarding the role of CETP in the biology of lipid metabolism and atherosclerosis.

Research Reports in Clinical Cardiology, 4 April 2013 Volume 2013:4 Pages 39 – 53

Dylan L Steen,1 Amit V Khera,2 Christopher P Cannon1

1TIMI Study Group, Cardiovascular Division, 2Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Disclosure

Dr Cannon is a member of the advisory boards of and has received grant support from Alnylam, Bristol-Myers Squibb, Pfizer, and CSL Behring; has received grant support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda; and is a clinical advisor to Automated Medical Systems. All other authors have reported that they have no relationships relevant to the contents of this paper.

Abstract: Despite major advances in cardiovascular care in recent decades, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Statins have been shown to reduce cardiovascular events by 25%–40% in a dose-dependent fashion; yet additional therapies are needed to reduce vascular disease progression and acute thrombotic events. In addition to low-density lipoprotein cholesterol (LDL-C) reduction, other lipid risk factors, such as low high-density lipoprotein cholesterol (HDL-C), have created interest as therapeutic targets to lower cardiovascular risk. However, the absence of compelling data for incremental benefit of non-LDL-centric therapies in the statin era has limited their clinical use. A novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects. While in vitro and animal data for CETP inhibition have been encouraging, the initial enthusiasm for the class has been tempered by the failure of two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III trials to reduce cardiovascular outcomes. Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Keywords: anacetrapib, cholesteryl ester transfer protein, cholesteryl ester transfer protein inhibitor, atherosclerosis

  • Niacin, which augments HDL-C by 20%–25%, recently failed to lower atherosclerotic events in both the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH)6 and Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials.7,8
  • Lp(a) lowering has not yet been evaluated in randomized controlled trials, but observational and genetic (including Mendelian randomization) analyses have demonstrated an independent association of increased Lp(a) levels with increased CV events, suggesting Lp(a) lowering may confer benefit.9
  • surprising failure of the first two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III outcomes trials has somewhat tempered this initial excitement and forced a re-evaluation of the complex effects of CETP inhibition on lipid metabolism and vascular biology.
  • Anacetrapib results in near-complete CETP inhibition with more pronounced lipid effects than its predecessors and is currently in a Phase III study for secondary prevention of coronary events. If successful it is likely that anacetrapib will also be considered for statin-intolerant patients and for primary prevention in patients who require LDL-C lowering beyond statin monotherapy
  • Human CETP is a 476-residue, 74 kDa, hydrophobic glycoprotein primarily secreted by the liver and adipose tissue.13 CETP was first cloned in 1987.14 The structure of CETP allows formation of a tunnel with the opening on one end interacting with HDL and the other with a very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), or LDL particle. The hydrophobic central cavity of this tunnel is large enough to allow transfer of neutral lipids (eg, cholesteryl esters [CEs], triglycerides [TGs]) from donor to acceptor particles, but conformational changes may occur to accommodate larger lipoprotein particles. The concave surface of CETP matches the curvature of the HDL particles to which it is primarily bound in the bloodstream.15,16
  • The overall effect of CETP is a net transfer of CE from HDL to these apolipoprotein B (apoB)-containing particles and TG to HDL and LDL
  • An important driver of the transfer of CE from HDL to apoB-containing particles is the production of CE from free cholesterol within HDL by lecithin acetyltransferase (LCAT).17

    The role of CETP in reverse cholesterol transport.

    Beginning in the peripheral tissues, free cholesterol is predominantly taken up by small “immature” HDL particles (eg, pre-β-HDL) via the ABCA1 transporter. Alternatively, it can be taken up by larger “mature” HDL particles (eg, HDL2) via the ABCG1 transporter. LCAT converts free cholesterol into cholesteryl ester, which is then shuttled to apoB-lipoproteins (eg, LDL, VLDL) in exchange for triglycerides. Only a minority of cholesteryl ester is delivered directly to the liver by HDL via the SR-BI; the majority is delivered indirectly to the liver by apoB-lipoproteins via the LDL recepter.

    Abbreviations: CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; LCAT, lecithin acetyltransferase; apoB, apolipoprotein B; LDL, low-density lipoprotein; VLDL, very low density lipoprotein; SR-BI, scavenger receptor-BI; FC, free cholesterol; CE, cholesteryl ester.

  • One of the interesting questions in CETP deficiency is whether the HDL particles produced by potent CETP inhibition are functional. Regardless of whether reverse cholesterol transport is increased, the initial steps of cholesterol efflux from foam cells may be one of the key anti-atherogenic functions of HDL.5
  • This increased efflux is related to the very high content of LCAT and apoE in these large HDL particles, presumably driving net cholesterol efflux by promoting cholesterol esterification.36
  • effect of CETP deficiency on liver uptake of cholesteryl ester, an important downstream step in a reverse cholesterol transport. These studies suggest that there may be increased CE uptake via SR-BI as well as through a high affinity of large apoE-rich HDL for LDL receptors.20
  • meta-analysis established that three CETP genotypes were not only associated with decreased CETP activity and increased HDL but also with a lower risk of myocardial infarction (MI). For example, for each allele inherited, individuals with the TaqIB polymorphism had lower mean CETP activity (−8.6%), higher mean HDL-C (4.5%), higher mean apoA-I (2.4%), and an odds ratio for coronary disease of 0.95 (95% confidence intervals [CI], 0.92, 0.99). Similar associations were found for the other two CETP genotypes.40
  • Subsequent studies have confirmed that genetic variants leading to reduced CETP activity and its corresponding anti-atherogenic lipid profile are associated with reduced atherosclerotic outcomes.41–43
  • In ILLUSTRATE, an inverse association between HDL-C achieved and the primary endpoint of atheroma volume (r = −0.17, P , 0.001) was found. In addition, the highest quartile of HDL-C achieved (.86 mg/dL) demonstrated atheroma regression, suggesting that there may be a “threshold effect” to HDL-C elevation.68
  • Other CETP inhibitors:

Dalcetrapib
was developed by Hoffmann–La Roche until May 2012. It did not raise blood pressure and did raise HDL, but it showed no clinically meaningful efficacy.

Evacetrapib 

is under development by Eli Lilly & Company.
Torcetrapib
was developed by Pfizer until December 2006 but caused unacceptable increases in blood pressure and had net cardiovascular detriment.
Anacetrapib At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in blood pressure in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg. Merck performed a dose-ranging study of anacetrapib, with the results presented in 2009.

Anacetrapib 

Anacetrapib is a 3,5-bis-trifluoromethyl-benzene derivative with similar binding properties to CETP as torcetrapib. The compound was developed when it was found that a substitution modification of the oxazolidinone ring increased its potency for CETP inhibition in a transgenic mouse model.85 In terms of its pharmacokinetics and pharmacodynamics, anacetrapib is rapidly absorbed with a time-to-peak plasma concentration of about 4 hours. The oral bioavailability of anacetrapib is poor, with only about 20% being absorbed; however at this exposure, LDL-C is reduced up to 40% and HDL-C increased up to 140%. It is recommended that anacetrapib be taken with food (ie, low-fat diet) to increase drug exposure (and efficacy) as well as compliance.86

Anacetrapib is highly protein bound (eg, CETP) in the plasma (.99.5%). It is cleared by oxidative metabolism via Cytochrome P450 3A4 (CYP3A4) with excretion of the metabolites via the biliary/fecal route. Only a trace amount is eliminated by urinary excretion.87 Importantly, while anacetrapib is a sensitive CYP3A4 substrate, anacetrapib neither inhibits nor induces CYP3A4 activity. No meaningful interactions have been found between anacetrapib and simvastatin, digoxin, or warfarin.86 Anacetrapib in part to its redistribution to adipose tissue has a long terminal half-life.88

In terms of safety endpoints, anacetrapib demonstrated no increase in side effects (including myalgia), drug-related adverse effects, adverse events leading to drug discontinuation, or other important safety endpoints, such as BP, electrolyte, aldosterone, creatinine kinase, or transaminase levels. A very small increase in C-reactive protein of undetermined significance was seen with anacetrapib, which notably was also reported with torcetrapib and dalcetrapib in their Phase III studies. It is unknown whether this is a class effect as the small sample size in the evacetrapib Phase II study limits evaluation of small C-reactive protein changes.

It is expected that the REVEAL (the Phase III) population will also have lower starting LDL-C levels, both because statin-intolerant subjects will not be enrolled and because of more stringent lipid entry criteria. The final major difference is that the primary endpoint in REVEAL is focused on coronary events, while ACCELERATE has a broader primary endpoint. A broader primary endpoint along with a slightly higher risk population will allow for a shorter follow-up duration and much smaller sample size in ACCELERATE.

Conclusion

  • CETP remains a valid target and that the lipid changes resulting from its inhibition may be protective. The biology of CETP inhibition is complex, and questions remain regarding which lipid changes (eg, reductions in LDL and Lp(a), increases in HDL) are most likely to be important and whether there are still unknown effects that may negate any overall clinical benefit.
  • if potent CETP inhibition is found to be beneficial, it is still unclear whether this effect will be homogeneous or vary based on individual metabolism.
  • anacetrapib-induced HDL (especially the apoE-rich HDL2 particles) may have an enhanced ability for reverse cholesterol transport without any known adverse effects. Importantly, if a threshold effect for HDL-C augmentation exists, the vast majority of patients taking anacetrapib would be expected to cross it.
  • Despite a difficult beginning for the class of CETP inhibitors, anacetrapib and evacetrapib hold promise as future therapies for patients with atherosclerosis
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Paralysis by Sequestration and the Medical Revolution

Reporter: Larry H Bernstein, MD, FACP

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http://pharmaceuticalintelligence.com/2013/04/03/paralysis-by-s…cal-revolution/

Dysfunction and the Medical Revolution

http://www.genomeweb.com/blog/dysfunction-and-medical-revolution
April 02, 2013
The federal sequestration is cutting back or halting grants that fund “potentially groundbreaking” personalized medicine research funded by the National Institutes of Health, Institute for Systems Biology President Lee Hood opines. Taking his pen to the pages of The Hill, Hood writes that political three-way fisticuffs between lawmakers in both houses and the White House that led to the sequester — an across-the-board five percent whack to all agency budgets — could imperil advances in personalized medicine research that ISB is pursuing.
Hood praises the promise of what he calls P4 medicine, the convergence of new big data and genomic technologies to develop “medicine that is predictive, personalized, preventive, and participatory.”
The forward march of P4 will bring about a new type of medicine, Hood writes, that will improve care through diagnoses and targeted therapies. It also will save money in the long run because new and better treatments and predictive medicine will “reduce the skyrocketing costs of healthcare” and help create new “wellness sector” markets and companies that don’t yet exist, he says.
“In 1986, the automated DNA sequencer I invented was first brought to market, paving the way for the Human Genome Project completed in 2003. In 2010 alone, human genome sequencing activities generated $67 billion in US economic output and created 310,000 US jobs,” he says.
Hood doesn’t want to see a dysfunctional political culture on Capitol Hill hinder the advance of these technologies, markets, and medical innovations.
“On the 10th anniversary of the completion of the Human Genome Project, we can’t let the ongoing tug-of-war in Congress over spending priorities threaten the revolutionary work that is taking place in medical science,” he writes.
Submitted by Scott_K on Tue, 04/02/2013
Couldn’t agree more. I was just up on the Hill meeting with Representatives, and they are sadly bogged down in the sequester. Meanwhile, Medicare has suspended reimbursements for molecular diagnostic testing. Congress is missing an entire paradigm change where the art of patient care has led to the rapid emergence of Personalized Medicine. Without appropriate funding, we will not be able to educate patients, clinicians, reimbursement directors, and Congress themselves on the astounding advancements that have been made in personalized medicine. We can perform whole genome sequencing to identify clinically relevant mutations in individual patient’s tumors- morally, this technology could and should be available to all late stage cancer patients immediately. Frustratingly, we lack the political leadership and vision. In an environment where jobs for many experienced, bright scientists are so desperately needed, the failure of governmental leadership has led to the siphoning off of technological development and jobs to other more perceptive countries. This is a mess that can be corrected in no time with appropriate leadership from the three branches that Dr. Hood mentions. Here’s hoping that Dr. Hood’s communication will open some eyes.

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Curator: Aviva Lev-Ari, PhD, RN

On 3/13/2013 Forbes Science Writer, Metthew Herper, presented a curated article about the protein Cas9. With a compelling title like 

This Protein Could Change Biotech Forever, we drew over 40 comments. 

A tiny molecular machine used by bacteria to kill attacking viruses could change the way that scientists edit the DNA of plants, animals and fungi, revolutionizing genetic engineering. The protein, called Cas9, is quite simply a way to more accurately cut a piece of DNA.

“This could significantly accelerate the rate of discovery in all areas of biology, including gene therapy in medicine, the generation of improved agricultural goods, and the engineering of energy-producing microbes,” says Luciano Marraffini of Rockefeller University.

The ability to make modular changes in the DNA of bacteria and primitive algae has resulted in drug and biofuel companies such as Amyris and LS9. But figuring out how to make changes in the genomes of more complicated organisms has been tough.

http://www.forbes.com/sites/matthewherper/2013/03/19/the-protein-that-could-change-biotech-forever/?goback=.gde_48920_member_227143277

In this article we bring all the pieces to one place, telling the evolution of a series of discoveries, which together may have the Protein, Cas9,  changing the Biotech Industry forever with its contributions to Diagnosing Diseases and Gene Therapy by Precision Genome Editing and Cost-effective microRNA Profiling. 

MicroRNA detection on the cheap

MIT alumni’s startup provides rapid, cost-effective microRNA profiling, which is beneficial for diagnosing diseases.
Rob Matheson, MIT News Office
March 28, 2013
Current methods of detecting microRNA (miRNA) — gene-regulating molecules implicated in the onset of various diseases — can be time-consuming and costly: The custom equipment used in such tests costs more than $100,000, and the limited throughput of these systems further hinders progress.
Two MIT alumni are helping to rectify these issues through their fast-growing, Cambridge-headquartered startup, Firefly BioWorks Inc., which provides technology that allows for rapid miRNA detection in a large number of samples using standard lab equipment. This technology has helped the company thrive — and also has the potential to increase the body of research on miRNA, which could help lead to better disease diagnosis and screening.The company’s core technology, called Optical Liquid Stamping (OLS) — which was invented at MIT by Firefly co-founder and Chief Technical Officer Daniel C. Pregibon PhD ’08 — works by imprinting (or stamping) microparticle structures onto photosensitive fluids. The resulting three-dimensional hydrogel particles, encoded with unique “barcodes,” can be used for the detection of miRNAs across large numbers of samples. These particles are custom-designed for readout in virtually any flow cytometer, a cost-effective device that’s accessible to most scientists.“Our manufacturing process allows us to make very sophisticated particles that can be read on the most basic instruments,” says co-founder and CEO Davide Marini PhD ’03.The company’s first commercial product, FirePlex miRSelect, an miRNA-detection kit that uses an assay based on OLS-manufactured particles and custom software, began selling about a year ago. Since then, the company has drawn a steady influx of customers (primarily academic and clinical scientists) while seeing rapid revenue growth.

To date, most of the company’s revenue has come from backers who see value in Firefly’s novel technology. In addition to a cumulative $2.5 million awarded through Small Business Innovation Research grants — primarily from the National Cancer Institute — the company has attracted $3 million from roughly 20 independent investors. Its most recent funding came from a $500,000 grant from the Massachusetts Life Sciences Center.

Pregibon developed the technology in the lab of MIT chemical engineering professorPatrick Doyle, a Firefly co-founder who serves on the company’s scientific advisory board. Firefly’s intellectual property is partially licensed through the Technology Licensing Office at MIT, along with several other Firefly patents. Firefly’s technology, from OLS to miRNA detection, has been described in papers published in several leading journals, including ScienceNature MaterialsNature Protocols and Analytical Chemistry.

Shifting complexity from equipment to particle

The success of the technology, Marini says, derives from an early business decision to focus attention on the development of the hydrogel particle instead of the equipment needed. Essentially, this allowed the co-founders to focus on developing a high-quality miRNA assay and hit the market quickly with particles that are universally readable on basic lab instrumentation.

“Imagine sticking a microscopic barcode on a microscopic product,” Marini says. “How do you scan it? At the beginning we thought we would have to build our own scanner. This would have been an expensive proposition. Instead, by using a few clever tricks, we redesigned the barcode to make it readable by existing instruments. You can write these ‘barcodes,’ and all you need is one scanner to read different codes. To quote an investor: ‘It shifts the complexity from the equipment to the particle.’”

Firefly’s particles appear to a standard flow cytometer as a series of closely spaced cells; these data are recorded and the company’s FireCode software then regroups them into particle information, including miRNA target identification and quantity.

But why, specifically, did the company choose a flow cytometer as its primary “scanner”? Pregibon answers: “To start, there are nearly 100,000 cytometers worldwide. In addition, we are now seeing a trend where flow cytometers are getting smaller and closer to the bench — closer to the actual researcher. We’re finding that people are tight for money because of the economy and are trying to conserve capital as much as possible. In order to use our products, they can either buy a very inexpensive bench-top flow cytometer or use one that already exists in their core facility.”

In turn, opting out of equipment development and manufacturing costs has helped the company stay financially sound, says Marini, who worked in London’s financial sector before coming to MIT. As an additional perk, the manufacturers of flow cytometers have begun “courting” Firefly, Marini says, because “our products help expand the capability of their systems, which are now exclusively used to analyze cells.”

The company’s FirePlex kit allows researchers to assay (or analyze) roughly 70 miRNA targets simultaneously across 96 samples of a wide variety — including serum, plasma and crude cell digests — in approximately three hours.

This is actually a “middle-ground” assaying technique, Pregibon says, and saves researchers time and money: Until now, scientists were forced to use separate techniques to look at a few miRNA targets over thousands of samples, or vice versa.

Marini adds that if a scientist suspects a number of miRNAs, perhaps 50 or so, could be involved in a pancreatic-cancer pathway, the only way to know for sure is to test those 50 targets over hundreds of samples. “There’s nowhere to do this today in a cost-effective, timely manner. Our tech now allows that,” he says.

‘Over the bridge of validation’

Because miRNAs are so important in the regulation of genes, and ultimately proteins, they have implications in a broad range of diseases, from cancer to Alzheimer’s disease. Several studies have suggested these relationships, but the field currently lacks the validation required to definitively demonstrate clinical utility.

With that in mind, Pregibon hopes that Firefly’s technology will help push miRNA-based diagnoses “over the bridge of validation,” giving scientists the means to validate miRNA signatures they discover in diagnosing diseases such as cancer. “That’s where we want to fit in,” he says. “With the help of a technology like ours, you’ll start to see more tests hitting the market and ultimately, more people benefitting from early cancer detection.”

Firefly’s aim is to strengthen preventive medicine in the United States. “In the long term, we see these products helping in the shift from reactive to preventative medicine,” Marini says. “We believe we will see a proliferation of tools for detection of diseases. We want to move away from the system we have now, which is curing before it’s too late.”

Pregibon says Firefly’s technology can be used across several molecule classes that are important in development and disease research: proteins, messenger RNA and DNA, among many others. “Essentially, the possibilities are endless,” Pregibon says.

Editing the genome with high precision

New method allows scientists to insert multiple genes in specific locations, delete defective genes.
Anne Trafton, MIT News Office
 
Researchers at MIT, the Broad Institute and Rockefeller University have developed a new technique for precisely altering the genomes of living cells by adding or deleting genes. The researchers say the technology could offer an easy-to-use, less-expensive way to engineer organisms that produce biofuels; to design animal models to study human disease; and  to develop new therapies, among other potential applications.To create their new genome-editing technique, the researchers modified a set of bacterial proteins that normally defend against viral invaders. Using this system, scientists can alter several genome sites simultaneously and can achieve much greater control over where new genes are inserted, says Feng Zhang, an assistant professor of brain and cognitive sciences at MIT and leader of the research team.“Anything that requires engineering of an organism to put in new genes or to modify what’s in the genome will be able to benefit from this,” says Zhang, who is a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.Zhang and his colleagues describe the new technique in the Jan. 3 online edition ofScience. Lead authors of the paper are graduate students Le Cong and Ann Ran.Early effortsThe first genetically altered mice were created in the 1980s by adding small pieces of DNA to mouse embryonic cells. This method is now widely used to create transgenic mice for the study of human disease, but, because it inserts DNA randomly in the genome, researchers can’t target the newly delivered genes to replace existing ones.

In recent years, scientists have sought more precise ways to edit the genome. One such method, known as homologous recombination, involves delivering a piece of DNA that includes the gene of interest flanked by sequences that match the genome region where the gene is to be inserted. However, this technique’s success rate is very low because the natural recombination process is rare in normal cells.

More recently, biologists discovered that they could improve the efficiency of this process by adding enzymes called nucleases, which can cut DNA. Zinc fingers are commonly used to deliver the nuclease to a specific location, but zinc finger arrays can’t target every possible sequence of DNA, limiting their usefulness. Furthermore, assembling the proteins is a labor-intensive and expensive process.

Complexes known as transcription activator-like effector nucleases (TALENs) can also cut the genome in specific locations, but these complexes can also be expensive and difficult to assemble.

Precise targeting

The new system is much more user-friendly, Zhang says. Making use of naturally occurring bacterial protein-RNA systems that recognize and snip viral DNA, the researchers can create DNA-editing complexes that include a nuclease called Cas9 bound to short RNA sequences. These sequences are designed to target specific locations in the genome; when they encounter a match, Cas9 cuts the DNA.

This approach can be used either to disrupt the function of a gene or to replace it with a new one. To replace the gene, the researchers must also add a DNA template for the new gene, which would be copied into the genome after the DNA is cut.

Each of the RNA segments can target a different sequence. “That’s the beauty of this — you can easily program a nuclease to target one or more positions in the genome,” Zhang says.

The method is also very precise — if there is a single base-pair difference between the RNA targeting sequence and the genome sequence, Cas9 is not activated. This is not the case for zinc fingers or TALEN. The new system also appears to be more efficient than TALEN, and much less expensive.

The new system “is a significant advancement in the field of genome editing and, in its first iteration, already appears comparable in efficiency to what zinc finger nucleases and TALENs have to offer,” says Aron Geurts, an associate professor of physiology at the Medical College of Wisconsin. “Deciphering the ever-increasing data emerging on genetic variation as it relates to human health and disease will require this type of scalable and precise genome editing in model systems.”

The research team has deposited the necessary genetic components with a nonprofit called Addgene, making the components widely available to other researchers who want to use the system. The researchers have also created a website with tips and tools for using this new technique.

Engineering new therapies

Among other possible applications, this system could be used to design new therapies for diseases such as Huntington’s disease, which appears to be caused by a single abnormal gene. Clinical trials that use zinc finger nucleases to disable genes are now under way, and the new technology could offer a more efficient alternative.

The system might also be useful for treating HIV by removing patients’ lymphocytes and mutating the CCR5 receptor, through which the virus enters cells. After being put back in the patient, such cells would resist infection.

This approach could also make it easier to study human disease by inducing specific mutations in human stem cells. “Using this genome editing system, you can very systematically put in individual mutations and differentiate the stem cells into neurons or cardiomyocytes and see how the mutations alter the biology of the cells,” Zhang says.

In the Science study, the researchers tested the system in cells grown in the lab, but they plan to apply the new technology to study brain function and diseases.

The research was funded by the National Institute of Mental Health; the W.M. Keck Foundation; the McKnight Foundation; the Bill & Melinda Gates Foundation; the Damon Runyon Cancer Research Foundation; the Searle Scholars Program; and philanthropic support from MIT alumni Mike Boylan and Bob Metcalfe, as well as the newscaster Jane Pauley.

SOURCE:
Published online 2012 September 4. doi:  10.1073/pnas.1208507109
PMCID: PMC3465414
PNAS Plus

Cas9–crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria

ABSTRACT

Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide adaptive immunity against viruses and plasmids in bacteria and archaea. The silencing of invading nucleic acids is executed by ribonucleoprotein complexes preloaded with small, interfering CRISPR RNAs (crRNAs) that act as guides for targeting and degradation of foreign nucleic acid. Here, we demonstrate that the Cas9–crRNA complex of the Streptococcus thermophilus CRISPR3/Cas system introduces in vitro a double-strand break at a specific site in DNA containing a sequence complementary to crRNA. DNA cleavage is executed by Cas9, which uses two distinct active sites, RuvC and HNH, to generate site-specific nicks on opposite DNA strands. Results demonstrate that the Cas9–crRNA complex functions as an RNA-guided endonuclease with RNA-directed target sequence recognition and protein-mediated DNA cleavage. These findings pave the way for engineering of universal programmable RNA-guided DNA endonucleases.

Keywords: nuclease, site-directed mutagenesis, RNA interference, DNA interference

Comparison with Other RNAi Complexes

The mechanism proposed here for the cleavage of dsDNA by the Cas9–crRNA complex differs significantly from that for the type I-E (former “Ecoli”) system (7). In the E. coli type I-E system crRNA and Cas proteins assemble into a large ribonucleoprotein complex, Cascade, that facilitates target recognition by enhancing sequence-specific hybridization between the crRNA and complementary target sequences (7). Target recognition is dependent on the PAM and governed by the seed crRNA sequence located at the 5′ end of the spacer region (24). However, although the Cascade–crRNA complex alone is able to bind dsDNA containing a PAM and a protospacer, it requires an accessory Cas3 protein for DNA cleavage. Cas3 is an ssDNA nuclease and helicase that is able to cleave ssDNA, producing multiple cuts (10). It has been demonstrated recently that Cas3 degrades E. coli plasmid DNA in vitro in the presence of the Cascade–crRNA complex (25). Thus, current data clearly show that the mechanistic details of the interference step for the type I-E system differ from those of type II systems, both in the catalytic machinery involved and the nature of the molecular mechanisms.

In type IIIB CRISPR/Cas systems, present in many archaea and some bacteria, Cmr proteins and cRNA assemble into an effector complex that targets RNA (612). In Pyrococcus furiosus the RNA-silencing complex, comprising six proteins (Cmr1–Cmr6) and crRNA, binds to the target RNA and cleaves it at fixed distance from the 3′ end. The cleavage activity depends on Mg2+ ions; however, individual Cmr proteins responsible for target RNA cleavage have yet to be identified. The effector complex of Sulfolobus solfataricus, comprising seven proteins (Cmr1–Cmr7) and crRNA, cuts invading RNA in an endonucleolytic reaction at UA dinucleotides (13). Importantly, these two archaeal Cmr–crRNA complexes perform RNA cleavage in a PAM-independent manner.

Overall, we have shown that the Cas9–crRNA complex in type II CRISPR/Cas systems is a functional homolog of Cascade in type I systems and represents a minimal DNAi complex. The simple modular organization of the Cas9–crRNA complex, in which specificity for DNA targets is encoded by crRNAs and the cleavage enzymatic machinery is brought by a single, multidomain Cas protein, provides a versatile platform for engineering universal RNA-guided DNA endonucleases. Indeed, by altering the RNA sequence within the Cas9–crRNA complex, programmable endonucleases can be designed both for in vitro and in vivo applications. To provide proof of principle of such a strategy, we engineered de novo into a CRISPR locus a spacer targeted to a specific sequence on a plasmid and demonstrated that such a plasmid is cleaved by the Cas9–crRNA complex at a sequence specified by the designed crRNA. Experimental demonstration that RuvC and HNH active-site mutants of Cas9 are functional as strand-specific nicking enzymes opens the possibility of generating programmed DNA single-strand breaks de novo. Taken together, these findings pave the way for the development of unique molecular tools for RNA-directed DNA surgery.

SOURCE:

Cheap and easy technique to snip DNA could revolutionize gene therapy

By Robert Sanders, Media Relations | January 7, 2013

BERKELEY —A simple, precise and inexpensive method for cutting DNA to insert genes into human cells could transform genetic medicine, making routine what now are expensive, complicated and rare procedures for replacing defective genes in order to fix genetic disease or even cure AIDS.

Cas9 protein on DNA
The bacterial enzyme Cas9 is the engine of RNA-programmed genome engineering in human cells. Graphic by Jennifer Doudna/UC Berkeley.
IMAGE SOURCE:

Discovered last year by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical Institute and University of California, Berkeley, and Emmanuelle Charpentier of the Laboratory for Molecular Infection Medicine-Sweden, the technique was labeled a “tour de force” in a 2012 review in the journal Nature Biotechnology.

That review was based solely on the team’s June 28, 2012, Science paper, in which the researchers described a new method of precisely targeting and cutting DNA in bacteria.

Two new papers published last week in the journal Science Express demonstrate that the technique also works in human cells. A paper by Doudna and her team reporting similarly successful results in human cells has been accepted for publication by the new open-access journal eLife.

“The ability to modify specific elements of an organism’s genes has been essential to advance our understanding of biology, including human health,” said Doudna, a professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute Investigator at UC Berkeley. “However, the techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics.

“This is going to remove a major bottleneck in the field, because it means that essentially anybody can use this kind of genome editing or reprogramming to introduce genetic changes into mammalian or, quite likely, other eukaryotic systems.”

“I think this is going to be a real hit,” said George Church, professor of genetics at Harvard Medical School and principal author of one of the Science Express papers. “There are going to be a lot of people practicing this method because it is easier and about 100 times more compact than other techniques.”

“Based on the feedback we’ve received, it’s possible that this technique will completely revolutionize genome engineering in animals and plants,” said Doudna, who also holds an appointment at Lawrence Berkeley National Laboratory. “It’s easy to program and could potentially be as powerful as the Polymerase Chain Reaction (PCR).”

The latter technique made it easy to generate millions of copies of small pieces of DNA and permanently altered biological research and medical genetics.

Cruise missiles

Two developments – zinc-finger nucleases and TALEN (Transcription Activator-Like Effector Nucleases) proteins – have gotten a lot of attention recently, including being together named one of the top 10 scientific breakthroughs of 2012 by Science magazine. The magazine labeled them “cruise missiles” because both techniques allow researchers to home in on a particular part of a genome and snip the double-stranded DNA there and there only.

Researchers can use these methods to make two precise cuts to remove a piece of DNA and, if an alternative piece of DNA is supplied, the cell will plug it into the cut instead. In this way, doctors can excise a defective or mutated gene and replace it with a normal copy. Sangamo Biosciences, a clinical stage biospharmaceutical company, has already shown that replacing one specific gene in a person infected with HIV can make him or her resistant to AIDS.

Both the zinc finger and TALEN techniques require synthesizing a large new gene encoding a specific protein for each new site in the DNA that is to be changed. By contrast, the new technique uses a single protein that requires only a short RNA molecule to program it for site-specific DNA recognition, Doudna said.

In the new Science Express paper, Church compared the new technique, which involves an enzyme called Cas9, with the TALEN method for inserting a gene into a mammalian cell and found it five times more efficient.

“It (the Cas9-RNA complex) is easier to make than TALEN proteins, and it’s smaller,” making it easier to slip into cells and even to program hundreds of snips simultaneously, he said. The complex also has lower toxicity in mammalian cells than other techniques, he added.

“It’s too early to declare total victory” over TALENs and zinc-fingers, Church said, “but it looks promising.”

Based on the immune systems of bacteria

Doudna discovered the Cas9 enzyme while working on the immune system of bacteria that have evolved enzymes that cut DNA to defend themselves against viruses. These bacteria cut up viral DNA and stick pieces of it into their own DNA, from which they make RNA that binds and inactivates the viruses.

UC Berkeley professor of earth and planetary science Jill Banfield brought this unusual viral immune system to Doudna’s attention a few years ago, and Doudna became intrigued. Her research focuses on how cells use RNA (ribonucleic acids), which are essentially the working copies that cells make of the DNA in their genes.

Doudna and her team worked out the details of how the enzyme-RNA complex cuts DNA: the Cas9 protein assembles with two short lengths of RNA, and together the complex binds a very specific area of DNA determined by the RNA sequence. The scientists then simplified the system to work with only one piece of RNA and showed in the earlier Science paper that they could target and snip specific areas of bacterial DNA.

“The beauty of this compared to any of the other systems that have come along over the past few decades for doing genome engineering is that it uses a single enzyme,” Doudna said. “The enzyme doesn’t have to change for every site that you want to target – you simply have to reprogram it with a different RNA transcript, which is easy to design and implement.”

The three new papers show this bacterial system works beautifully in human cells as well as in bacteria.

“Out of this somewhat obscure bacterial immune system comes a technology that has the potential to really transform the way that we work on and manipulate mammalian cells and other types of animal and plant cells,” Doudna said. “This is a poster child for the role of basic science in making fundamental discoveries that affect human health.”

Doudna’s coauthors include Jinek and Alexandra East, Aaron Cheng and Enbo Ma of UC Berkeley’s Department of Molecular and Cell Biology.

Doudna’s work was sponsored by the Howard Hughes Medical Institute.

RELATED INFORMATION

SOURCE:
http://newscenter.berkeley.edu/2013/01/07/cheap-and-easy-technique-to-snip-dna-could-revolutionize-gene-therapy/

Matthew Herper, Forbes Staff on 3/24/2013

 A Cancer Patient’s Quest Hits DNA Pay Dirt

 

Kathy Giusti

Kathy Giusti has faced her cancer with the verve of an entrepreneur. Now her fight with multiple myeloma has moved to a new front: DNA.

Giusti was a 37-year-old marketing executive at Searle (now part of Pfizer) when she was diagnosed in 1996 with myeloma, a deadly blood and bone marrow cancer. She had a 1-year-old daughter. Sixty percent of myeloma patients die within five years, but Giusti beat the odds, living for a decade and a half through multiple rounds of drug therapy and a bone marrow transplant from her twin sister.

She has also changed the way her disease is treated. Giusti founded an advocacy group, the Multiple Myeloma Research Foundation, that works with companies like NovartisCelgene, and Merck to develop new treatments. It played a key role in the development of Velcade and Revlimid, two of the biggest advances in treating the disease, which is diagnosed in 20,000 patients a year.

Now a new research effort, funded with $14 million of MMRF money, has revealed new hints at what causes the disease and potential avenues for treating it. “This is going to be the next wave of how health care gets changed over time,” Giusti says. The results are published in the current issue of Nature.

Working with patient samples collected by the MMRF and using DNA sequencers made by Illumina of San Diego, researchers at the Broad Institute of MIT and Harvard sequenced the genes of 38 myeloma tumors and the DNA of the patients in whom they were growing. Tumors are twisted versions of the people in which they are growing; their DNA is mutated and disfigured, turning them deadly. By comparing DNA from healthy cells with malignant ones, researchers can find genetic differences that might be what led the tumors to go bad in the first place.

This experiment would have been unthinkable just a few years ago, when sequencing a human being was so expensive that all the people whose DNA had been read out could fit in a small room. In 2005, the idea of producing 38 DNA sequences was laughable. Now it’s par for the course, and researchers expect thousands of genomes will be sequenced by the end of the year – and experiments like this are expected to become commonplace.

What’s so exciting is that sometimes the DNA changes scientists find are completely unexpected. “There were genes we found to be recurrently mutated and yet no one had any clue that they had anything to do with multiple myeloma or any other cancer,” says Todd Golub, the Broad researcher who led the study. He splits his time with the Dana-Farber Cancer Institute.

One gene, called FAM46C, was mutated in 13% of the cancers, but has never been studied in humans. “It appears no one had been working on it,” says Golub, but from studies in yeast and bacteria it appears that it has to do with how the recipes in genes are used to make proteins, the building blocks of just about everything in the body.

Another surprise gene, called BRAF, is generating excitement because it is the target of a skin cancer drug developed by Plexxikon, a small biotech firm that is partnered with Roch and is being purchased by Daiichi Sankyo. For the 4% of myeloma patients who have this mutation, this drug might be an option. The challenge will be testing it: it will be difficult to find enough of these patients to conduct a clinical trial. The MMRF says early discussions on such a study are moving forward. Giusti imagines that in the future, the MMRF may fund studies not of myeloma, but of a mix of different cancers caused by similar genetic mutations.

Several of the genes seem involved in the proteins that help guide epigenetics, a kind of molecular code written on DNA that may represent another kind of genetic code. The MMRF is already supporting some small drug companies that hope to create cancer drugs that target this second code.

Golub, the Broad scientist, says that right now it doesn’t make sense for most multiple myeloma patients to get their full DNA sequences outside of clinical trials, although he can imagine that for patients who have failed every available treatment it might make sense as a way to come up with another drug to try.

Giusti says, however, that the kinds of genetic tests that are done are changing the way that patients understand their disease. “Patients like me are starting to know, ‘I have this DNA translocation, maybe a proteasome inhibitor [a type of drug] is better for me.’ We become forerunners in the role patient can plan and the importance it has in drug development.”

Moving past old ways of thinking about inventing new medicines to a new path that is based on genetics and a flood of biological data is going to be difficult. But Giusti has never been afraid of hard — and she is sure there will be ways to drive the science forward.

SOURCE:

http://www.forbes.com/sites/matthewherper/2011/03/24/a-cancer-patients-quest-hits-dna-pay-dirt/

REFERENCES

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465414/

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20. Garneau JE, et al. The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature. 2010;468:67–71. [PubMed]
21. Deltcheva E, et al. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III.Nature. 2011;471:602–607. [PMC free article] [PubMed]
22. Armalyte E, et al. Mva1269I: A monomeric type IIS restriction endonuclease from Micrococcus varians with two EcoRI- and FokI-like catalytic domains. J Biol Chem. 2005;280:41584–41594.[PubMed]
23. Chan SH, Stoddard BL, Xu SY. Natural and engineered nicking endonucleases—from cleavage mechanism to engineering of strand-specificity. Nucleic Acids Res. 2011;39:1–18. [PMC free article][PubMed]
24. Semenova E, et al. Interference by clustered regularly interspaced short palindromic repeat (CRISPR) RNA is governed by a seed sequence. Proc Natl Acad Sci USA. 2011;108:10098–10103. [PMC free article][PubMed]
25. Westra ER, et al. CRISPR immunity relies on the consecutive binding and degradation of negatively supercoiled invader DNA by Cascade and Cas3. Mol Cell. 2012;46:595–605. [PMC free article] [PubMed]
26. Tamulaitis G, Zaremba M, Szczepanowski RH, Bochtler M, Siksnys V. Nucleotide flipping by restriction enzymes analyzed by 2-aminopurine steady-state fluorescence. Nucleic Acids Res.2007;35:4792–4799. [PMC free article] [PubMed]

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Curator: Aviva Lev-Ari, PhD, RN

In their discussion, the researchers argue that the U.S. Supreme Court now has a chance to shape the balance between the medical good versus inventor protection, adding that, in their opinion, the court should limit the patenting of existing nucleotide sequences, due to their broad scope and non-specificity in the human genome.

“I am extremely pro-patent, but I simply believe that people should not be able to patent a product of nature,” Dr. Mason says. “Moreover, I believe that individuals have an innate right to their own genome, or to allow their doctor to look at that genome, just like the lungs or kidneys. Failure to resolve these ambiguities perpetuates a direct threat to genomic liberty, or the right to one’s own DNA.”

http://www.sciencedaily.com/releases/2013/03/130326101614.htm

Supreme Court May Decide Whether We Own Our Genes

March 26, 2013
 
Image Credit: Photos.com

Brett Smith for redOrbit.com – Your Universe Online

They may be responsible for everything in your life, from conception to death, they may be inside every living cell in your body – but you do not own your own genes, legally speaking.

According to a report in Genome Medicine, patents essentially cover the entire human genome, hampering research and raising the question of “genomic liberty.”

The legal standing of genomic patents could change next month when the Supreme Court reviews patent rights for two key breast and ovarian cancer genes, BRCA1 and BRCA2, which include segments of genetic code as small as 15 nucleotides, known as 15mers.

“This is, so to speak, patently ridiculous,” said report co-author Dr. Christopher E. Mason of Weill Cornell Medical College. “If patent claims that use these small DNA sequences are upheld, it could potentially create a situation where a piece of every gene in the human genome is patented by a phalanx of competing patents.”

In their report, Mason and Dr. Jeffrey Rosenfeld, an assistant professor of medicine at the University of Medicine & Dentistry of New Jersey, looked at patents for two different categories of DNA fragments:

  • long and
  • short.

They revealed 41 percent of the human genome is covered by “long” DNA patents that can include whole genes. Because many genes share similar sequences within their code that are patented, the combination of all these “short” DNA patents covers 100 percent of the genome.

“This demonstrates that short patent sequences are extremely non-specific and that a 15mer claim from one gene will always cross-match and patent a portion of another gene as well,” Mason said. “This means it is actually impossible to have a 15mer patent for just one gene.”

To reach their conclusions, the researchers first looked at small sequences within BRCA1 and noticed one of the company’s BRCA1 patents also covered almost 690 other human genes. Some of these genes are unrelated to breast cancer – instead being associated with brain development and heart functioning.

Next, researchers determined how many known genes are covered by 15mers in current patent claims. They found 58 patents covered at least ten percent of all bases of all human genes. The broadest patent claim matched 91.5 percent of human genes. When the team took patented 15mers and matched them to known genes, they found 100 percent of known genes are patented.

Finally, the team also looked at “long” DNA sequences from existing gene patents, ranging from a few dozen to thousands of base pairs. They found these long sequences added up to 41 percent of known human genes.

“There is a real controversy regarding gene ownership due to the overlap of many competing patent claims. It is unclear who really owns the rights to any gene,” Rosenfeld said. “While the Supreme Court is hearing one case concerning just the BRCA1 patent, there are also many other patents whose claims would cover those same genes.

“Do we need to go through every gene to look at who made the first claim to that gene, even if only one small part? If we resort to this rule, then the first patents to be granted for any DNA will have a vast claim over portions of the human genome,” he added.

Another legal question surrounds patented DNA sequences that cross species boundaries. The researchers found one company has the rights to 84 percent of all human genes for a patent they received for cow breeding.

Source: Brett Smith for redOrbit.com – Your Universe Online

Topics: Health Medical PharmaGeneticsGene patentBiologyGeneLiving modified organismAssociation for Molecular Pathology v. U.S. Patent and Trademark OfficeBRCA1DNASupreme CourtHuman genome

SOURCE:

Human Genome: Name Your Price

Posted March 27, 2013 – 12:51 by a staff writer

Weill Cornell Medical College researchers have issued a warning that, according to the patent system, the vast majority of humans on the planet don’t ‘own’ their own genes, and in fact their biological make-up is being exploited for profit. Even seemingly innocent research into cow breeding can cover human genetic make-up.

As spotted by a Slashdot user, two researchers combing through patents on human DNA discovered that over 40,000 patents on DNA molecules have effectively declared the human genome for profit. A report in medical journal Genome Medicine said that humans may be losing their grip on “individual genomic liberty”.

Looking at two kinds of patented DNA sequences, or long and short fragments, 41 percent of the human genome is covered by DNA patents that can cover entire genes. According to the research, if all of the short sequence patents were allowed in aggregate they could cover 100 percent of the human genome.

Lead author Dr Christopher E Mason and co-author Dr Jeffrey Rosenfeld warned that short sequences from patents cover “virtually the entire genome, even outside of genes”. A Weill Cornell assistant professor asked: “How is it possible that my doctor cannot look at my DNA without being concerned about patent infringement?”

There will be a Supreme Court hearing about genomic patent rights next month that will debate the morality of a molecular diagnostic company claiming patents on key cancer genes, as well as on any small sequence of code within the BRCA1 gene. Cornell explained that at present, genes are able to be patented by researchers working in companies and institutions who discover genes that have potentially useful applications, like in testing for cancer risks. Because the patents can be held by companies or organisations, it is possible for the patent owner to charge doctors thousands of dollars for each diagnostic test.

The authors pointed out that in their studies, while engaged in research, it is common to come across a gene that’s patented “almost every day”. Their paper promises to examine how genes may have been impacted by held patents, and the extent of intellectual property on the genome. Gene patents can also relate between different species – for example, a company may have a patent for breeding cows that also covers a large percentage of human genes. They cited one company that owns 84 percent of all human genes because of a patent for cow breeding.

“There is a real controversy regarding gene ownership due to the overlap of many competing patent claims. It is unclear who really owns the rights to any gene,” Dr Rosenfeld said. “Do we need to go through every gene to look at who made the first claim to that gene, even if only one small part? If we resort to this rule, then the first patents to be granted for any DNA will have a vast claim over portions of the human genome.”

Lead author Dr Mason insisted he is pro-patent, but believes people “should not be able to patent a product of nature”.

“I believe that individals have an innate right to their own genome,” he said.

http://www.tgdaily.com/hardware-brief/70513-human-genome-name-your-price#BUKfEtjWKb3gq7X3.99 

Other related articles on Genomics and Ethics on this Open Access Online Scientific Journal include the following:

Aviva Lev-Ari, PhD, RN

20.2 Understanding the Role of Personalized Medicine

Larry H Bernstein, MD, FACP

20.3 Attitudes of Patients about Personalized Medicine

Larry H Bernstein, MD, FACP

20.4  Genome Sequencing of the Healthy

Larry H. Bernstein, MD, FACP and Aviva Lev-Ari, PhD, RN

20.5   Genomics in Medicine – Tomorrow’s Promise

Larry H. Bernstein, MD, FACP

20.6  The Promise of Personalized Medicine

Larry H. Bernstein, MD, FACP

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Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Reporter/Curator: Stephen J. Williams, Ph.D.

ethicspersonalizedmedicine-page1

Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing[1]

Direct-to-consumer (DTC) genetic testing and genetic health information in 2007 with the advent of personalized testing services by companies who offered microarray-based genotyping of single-nucleotide-polymorphisms (SNP) which had strong correlations to disease risk.  Three companies started to offer such services directly to the consumer:

A common test which is offered analyzes the consumers BRCA1/2 mutation status.  Three mutations in the BRCA gene are known to predispose women to hereditary breast and ovarian cancer: BRCA1 185delAG, BRCA1 538insC, and BRCA2 617delT.  These BRCA1 mutation confer a 60% breast cancer risk and a 40% risk of ovarian cancer while the BRCA2 mutation confers a breast cancer risk of 50% and 20% risk of ovarian cancer.

However, the commercial availability of this genetic disease-risk associated testing has led to certain ethical issues concerning communication and responses of risk information by:

  1. Consumers who request BRCA1/2 testing (focus of the Francke article
  2. BRCA1/1 testing and communication of results to minors and relatives (Bradbury: see below)

There has been much opinion, either as commentary in literature, meeting proceedings, or communiques from professional societies warning that this type of “high-impact” genetic information should not be given directly to the consumer as consumers will not fully understand the information presented to them, be unable to make proper risk-based decisions, results could cause panic and inappropriate action such as prophylactic oophorectomy or unwarranted risk-reduction mastectomy, or false reassurance in case of negative result and reduced future cancer screening measures taken by the consumer.  However, there have been few studies to investigate these concerns.

A report by Dr. Uta Francke in the open access journal PeerJ, assesses and quantifies the emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service® report of the three BRCA mutations known to be associated with high risk for breast/ovarian cancer.  One hundred thirty six (136) individuals, who tested positive for BRCA1 and/or BRCA2 mutations as well as 160 users of the service, who tested mutation-free were invited to participate in phone interviews addressing personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of results, emotional responses, perception of personal cancer risk, information sharing, and actions taken.  Thirty two (32) mutation carriers (16 female and 16 male) and 31 non-carriers responded to the phone questionnaire.

Questions were based on the following themes:

  1. When you purchased the 23andME Personal Genome Service® were you aware that it included testing for mutations that predispose to breast and ovarian cancer?
  2. Were you aware that having Ashkenazi Jewish ancestry influences your risk of carrying one of the three mutations?
  3. Have you or a first or second degree relative been diagnosed with breast, ovarian or any other cancer?
  4. What did you learn from your results?
  5. Were you surprised by the result?
  6. How did you feel about this information (extremely, moderately, somewhat upset or extremely relieved)?

Results:  Eleven women and 14 men had received an unexpected result that they are carriers of one of the three mutations however none of them reported extreme anxiety and only four reported moderate anxiety which did not last long.  Participants were at least 8 years of age. Five women and six men described their reaction as neutral.  Most carrier women sought medical advice and four underwent risk-reducing procedures. Some to the male carriers felt burdened to share their test results with their female relatives, which led to additional screenings of relatives.  Almost all of the mutation-positive customers appreciated learning their BRCA mutational status.

Other highlights of the results include:

  • More women got tested if they had a first or second degree relative previously diagnosed with breast/ovarian cancer
  • Ten mutation-positive individuals who were surprised at the test results cited the lack of family history of breast/ovarian cancer as the reason for their surprise.  The rest who were surprised at their positive test results believed that the frequency of these mutations were low in the general population so they shouldn’t have been affected.
  • For the mutation-positive group, none of the 32 reported as being “extremely upset”.
  • Interestingly, on male who learned, for the first time, he was a positive carrier for BRCA mutation, reported feeling “relieved” because his daughter who was also tested by 23andMe had not acquired his mutation.

A brief interview with Dr. Francke follows:

Q:     In your results you had noted that none of the mutation carriers showed extreme anxiety about their reports however there were many of Ashkenazi descent who was well aware of the increased risk to breast cancer.  In another study by Dr. Angela Bradbury, anxieties and communication to their children depended on mutation status and education status.  Do you feel that most women in your study were initially aware they could be in a high risk category for cancer, whether breast, ovarian, or other?

Dr. Francke:   As we show in Table 1, 6 of 16 women and 6 of 16 men who found out that they were BRCA mutation carriers had not been aware that being of Ashkenazi descent confers an increased risk of breast/ovarian cancer.  In Table S1, we show that 6 of these 32 people did not self-identify as Ashkenazi.
Q:     The reporting and communication of test results to offspring and genetic testing of offspring as a result of positive tests has been under much debate.  I had noticed that there was a high proportion of relatives who went for screening after learning of a family members BRCA testing, whether it showed a mutation or not.  Some studies have shown that offspring of carriers may misinterpret genetic testing results and take inappropriate action, such as considering having early testing  before age 25.  It appears some anxiety may be due to misinformation and lack of genetic counseling.  Should these test results be considered in guidelines for oncologist such as NCCN guidelines with respect to informing family members using genetic counselors as an intermediary?

Dr. Francke:    The “high proportion of relatives who went for screening after learning of a family member’s BRCA testing”, were only those related to a BRCA-positive person. Most of the BRCA testing of relatives was done through health care providers at Myriad as these people were eligible for insurance coverage of the test. In our interviews we found no evidence for inappropriate action of carriers or non-carriers. With one exception, we found no evidence for misinterpretation or “anxiety due to lack of genetic counseling”.  In our online reports we recommend genetic counseling for all customers who have questions about their results.

Q:     I was also particularly interested the male carrier felt a heightened burden to tell their offspring.  This has been suggested in other studies.  I would assume the mothers and not the fathers would feet more pressure to tell their children.  Is there a reason for this?
Dr. Francke:     The heightened burden reported by the male carriers was mostly about the realization of the risk for their daughters, not so much about to telling their offspring.  Female carriers were primarily concerned about their own health risk and management, and decision-making about preventive measures – therefore, the risk for offspring appeared to be of secondary concern for them.

However, the availability of this type of predictive genetic testing for hereditary cancer has raised some ethical issues regarding the communication of risk and genetic results to family members and especially offspring, specifically whether informing minors would incur unnecessary testing, anxiety among minors of parents who tested positive for genetic risk-factors, or even premature risk-reduction surgeries or medical interventions.

The aforementioned ethical issues concerning communicating results of BRCA mutational testing to offspring was addressed by two large studies conducted by Dr. Angela Bradbury M.D. and colleagues at Fox Chase Cancer Center Family Risk Assessment Program (now she is at University of Pennsylvania) and University of Chicago Cancer Risk Clinic.  These studies evaluated the parental opinions regarding BRCA1/2 testing of minors, and how parents communicate BRCA1/2 genetic testing with their children.

In the JCO article (Parent Opinions Regarding the Genetic Testing of Minors for BRCA1/2)[2], Bradbury and colleagues used semistructured interviews (yes/no questions and open-ended questions) of 246 parents at Fox Chase and University of Chicago, who underwent BRCA1/2 whether they supported testing of minors in general and testing of their own offspring.  Parents were asked, “If you were deciding, do you think children under 18 years old should be given the opportunity to be tested” and followed by the open-ended question: “Why do (don’t) you support the genetic testing of minors for BRCA1/2?”.

Results:  In response to the first question (Would you support testing in minors) 37% of parents supported testing of minors in the general population.  The follow-up open-ended question revealed that 4% support testing minors in some or all circumstances.  This decision was independent of parent sex or race.  44% of parents would test their own offspring.  Parents who opposed testing in minors thought testing would cause fear and anxiety for their children but those who supported unconditional testing (regardless of whether they were positive for the BRCA mutation or not) mentioned that the medical information would foster better health behaviors in their offspring.  21% of parents who opposed testing minors, in general, actually supported testing of their own children.  Interestingly parents who tested positive for the BRCA1 overwhelmingly (64%) opposed testing of minors, in general.  In addition, statistical analysis of the open-ended questions revealed that parents who did not have a college degree, had a negative test result, and were non white favored testing of their own children.  The authors had suggested larger studies before any guidelines were given as to whether testing in minors of BRCA mutation carriers should be standard.

In a recent publication by Dr. Bradbury and colleagues (Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls)[3],  studied how adolescent girls understood and responded to breast cancer risk by interviewing 11-19 year-old girls at high-risk and population-risk for breast cancer. Although most girls said they were aware of increased risk because either a family member had or was predisposed to breast cancer (66 %) only 17 % of girls were aware of BRCA1/2 genes. Mother was the most frequently reported source of information for breast cancer among both high-risk (97 %) and population-risk (89 %) girls.  The study also showed that most girls who believe they are at high-risk could alter their lifestyles or change dietary habits to lower their risk.

In an adjacent study in the journal Cancer[4], Bradbury and colleagues at Fox Chase Cancer Center had gauged the frequency with which parents had told their children of their BRCA1/2 teat results and how their children felt about the results.

When parents disclose BRCA1/2 test results: Their communication and perceptions of offspring response[4]

Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least 1 child <25 YO.  A total of 253 parents completed interviews (61% response rate), reporting on 505 offspring. Twenty-nine percent of parents were BRCA1/2 mutation carriers. Three hundred thirty-four (66%) offspring learned of their parent’s test result. Older offspring age (P ≤ .01), offspring gender (female, P = .05), parents’ negative test result (P = .03), and parents’ education (high school only, P = .02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). Thirteen percent of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent’s BRCA1/2 positive or variant of uncertain significance result.

CONCLUSIONS:

Many parents communicate their BRCA1/2 test results to young offspring. Parents’ perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk life span.

Below is an excellent article by Steven Reinberg from HealthDay interviewing Dr. Angela Bradbury concerning their JCO study: (reported for ABC News at http://abcnews.go.com/Health/Healthday/story?id=4508346&page=1#.UVNJUVef2RM)

Many Parents Share Genetic Test Findings With Kids

By Steven Reinberg
HealthDay Reporter

Mar. 23

FRIDAY, Aug. 17 (HealthDay News) — As genetic testing for diseases becomes more commonplace, the impact of those findings on family members may be underestimated, researchers say.

For instance, some women who discover they have the BRCA gene mutation, which puts them at higher risk for breast cancer, choose to tell their children about it before the children are old enough to understand the significance or deal with it, a new study found.

“Parents with the BRCA mutation are discussing their genetic test results with their offspring often many years before the offspring would need to do anything,” said study author Dr. Angela Bradbury, director of the Fox Chase Cancer Center’s Family Risk Assessment Program, in Philadelphia.

According to Bradbury, more than half of parents she surveyed told their children about genetic test results. Some parents reported that their children didn’t seem to understand the significance of the information, and some had initial negative reactions to the news.

“A lot of genetic information is being shared within families and there hasn’t been a lot of guidance from health-care professionals,” Bradbury said. “While this genetic risk may be shared accurately, there is risk of inaccurate sharing.”

In the study, Bradbury’s team interviewed 42 women who had the BRCA mutation. The researchers found that 55 percent of parents discussed the finding and the risk of breast cancer with at least one of their children who was under 25.

Also, most of the women didn’t avail themselves of the services of a doctor or genetic counselor in helping to tell their children, Bradbury’s group found.

Bradbury is concerned that sharing genetic information with young children can create anxiety. “The children could be overly concerned about their own risk at a time when there is nothing that they need to do,” she said.

But, she added, “it may be possible that sharing may be good for children in adapting to this information.”

The findings are published in the Aug. 20 issue of the Journal of Clinical Oncology.

The lack of definitive data on when — or if — to discuss genetic test results with children is a real problem, Bradbury said.

“As we move genetic testing forward for cancer or other illnesses, we have to consider the context of the whole family and focus our counseling to the whole family, and not just the person who comes in for testing,” Bradbury said. “We should learn more about how and when we should talk to children about this, so that we can promote healthy behaviors without causing too much anxiety for the offspring.”

Barbara Brenner, executive director of Breast Cancer Action, agreed that the psychological component of genetic testing needs more attention.

“This is the tip of a very scary iceberg,” Brenner said. “We don’t know the psychological consequences [of BRCA testing], not only to the person who has the test, but to her family members.”

Brenner thinks guidelines to help parents deal with this information are needed. So is help from doctors and genetic counselors in counseling family members, especially children, she added.

LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth), supported by the National Institutes of Health. This study will follow the girls prospectively in order to evaluate epidemiologic and epigenetic pathways of childhood exposures in relation to pubertal development, age at menarche, breast tissue characteristics, biomarkers of exposure, genomic DNA methylation, and the psychosocial impact of increased breast cancer susceptibility in 6-13 YO girls. http://legacygirlsstudy.org/

 

1.         Francke U, Difamco C, Kiefer AK, Eriksson N, Moiseff B, Tung JY, Mountain JL: Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing. PeerJ 2013:1-21.

2.         Bradbury AR, Patrick-Miller L, Egleston B, Sands CB, Li T, Schmidheiser H, Feigon M, Ibe CN, Hlubocky FJ, Hope K et al: Parent opinions regarding the genetic testing of minors for BRCA1/2. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010, 28(21):3498-3505.

3.         Bradbury AR, Patrick-Miller L, Egleston BL, Schwartz LA, Sands CB, Shorter R, Moore CW, Tuchman L, Rauch P, Malhotra S et al: Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls. Breast cancer research and treatment 2012, 136(3):749-757.

4.         Bradbury AR, Patrick-Miller L, Egleston BL, Olopade OI, Daly MB, Moore CW, Sands CB, Schmidheiser H, Kondamudi PK, Feigon M et al: When parents disclose BRCA1/2 test results: their communication and perceptions of offspring response. Cancer 2012, 118(13):3417-3425.

Sources:

http://abcnews.go.com/Health/Healthday/story?id=4508346&page=1#.UVNJUVef2RM

Other article on Ethics and Personalized Medicine on the site include:

Genomics in Medicine- Tomorrow’s Promise

Attitudes of Patients about Personalized Medicine

Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?

Volume One: Genomics Orientations for Individualized Medicine

Directions for Genomics in Personalized Medicine

The Way With Personalized Medicine: Reporters’ Voice at the 8th Annual Personalized Medicine Conference,11/28-29, 2012, Harvard Medical School, Boston, MA

Highlights from 8th Annual Personalized Medicine Conference, November 28-29, 2012, Harvard Medical School, Boston, MA

Clinical Genetics, Personalized Medicine, Molecular Diagnostics, Consumer-targeted DNA – Consumer Genetics Conference (CGC) – October 3-5, 2012, Seaport Hotel, Boston, MA

Genetic basis of Complex Human Diseases: Dan Koboldt’s Advice to Next-Generation Sequencing Neophytes

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Improving Mammography-based imaging for better treatment planning

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Acute Lymphoblastic Leukemia and Bone Marrow Transplantation

Author, Editor: Tilda Barliya PhD

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Word Cloud By Danielle Smolyar

Acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells  was  previously discussed for the genetic origin and the prognostic factors used in clinical trials (1). We will now  focus on the treatment options with emphasis on the bone marrow transplantation (2).

According to the National Cancer Institute (NCI), the treatment of childhood ALL usually has 3 phases (3a):

  1. Induction Therapy: The goal is to kill leukemia cells in both the blood and the bone marrow and induce a remission.
  2. Consolidation/Intensification Therapy: It begins once the leukemia is in remission. The goal is to kill any remaining leukemia cells that may not be active but may regrow and cause relapse.
  3. Maintenance Therapy: The goal is to kill any remaining leukemia cells that may regrow and cause relapse. In this phase the different cancer treatments are usually been given at lower doses than those in the previous phases.

Four types of cancer treatment are used:

  • Chemotherapy – The way the chemotherapy is given depends on the child’s risk group. Children with high-risk ALL receive more anticancer drugs, higher doses of anticancer drugs, and receive treatment for a longer time than children with standard-risk ALL.. The full list of approved drug (3b)
  • Radiation Therapy– is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters  that are placed directly into or near the cancer. External radiation therapy may be used to treat childhood ALL that has spread, or may spread, to the brain and spinal cord.
  • Chemotherapy with stem cell transplantation – A method inwhich stem cells (immature blood cells) are removed from the blood or bone marrow of a donor. After the patient receives treatment, the donor’s stem cells are given to the patient through an infusion. These reinfused stem cells grow into (and restore) the patient’s blood cells. Stem cell transplant is rarely used as initial treatment for children and teenagers with ALL. It is used more often as part of treatment for ALL that relapses
  • Targeted TherapyTyrosine Kinase Inhibitors (TKIs) are targeted therapy drugs that block the enzyme, tyrosine kinase, which causes stem cells to become more white blood cells or blasts than the body needs. For example, imatinib mesylate (Gleevec) is a TKI used in the treatment of children with Philadelphia chromosome-positive ALL. However, because patients can develop resistance to these drugs, new tyrosine kinase inhibitors are being investigated. For example, nilotinib (AMN-107) is being studied for patients with Philadelphia chromosome positive ALL who are resistant to imatinib

Bone Marrow or Peripheral Blood Stem cell Transplant for ALL

Stem cell transplants (SCT) offer a way for doctors to use high doses of chemo. Although the drugs destroy the patient’s bone marrow, transplanted stem cells can restore the bone marrow’s ability to make blood. Stem cells for a transplant come from either the blood or from the bone marrow. Bone marrow transplants were more common in the past, but they have largely been replaced by peripheral blood stem cell transplant (PBSCT).

Types of Transplants (4).

The stem cells can come from either the patient (an autologous transplant) or from a matched donor (an allogeneic transplant).

  • Allogeneic stem cell transplant: In an allogeneic transplant, the stem cells come from someone else – usually a donor whose tissue type is a very close match to the patient’s. The donor may be a brother or sister if they are a good match. Less often, an unrelated donor may be found. An allogeneic transplant is the preferred type of transplant for ALL when it is available.
  • “Mini-transplant”: “mini-transplant” (also called a non-myeloablative transplant or reduced-intensity transplant), where they get lower doses of chemo and radiation that do not destroy all the cells in their bone marrow. They then are given the donor stem cells. These cells enter the body and form a new immune system, which sees the leukemia cells as foreign and attacks them (a graft-versus-leukemia effect). This is not a standard treatment for ALL, and is being studied to find out how useful it may be.
  • Autologous stem cell transplant: In an autologous transplant, a patient’s own stem cells are removed from his or her bone marrow or blood. They are frozen and stored while the person gets treatment (high-dose chemo and/or radiation). The stem cells are then given back to the patient after treatment.

One problem with autologous transplants is that it is hard to separate normal stem cells from leukemia cells in the bone marrow or blood samples. Even after treating the stem cells in the lab to try to kill or remove any leukemia cells, there is the risk of returning some leukemia cells with the stem cell transplant

Stem cell transplants and side effects (4):

Early side effects: Early side effects are much the same as those caused by any other type of high-dose chemo, such as nausea, vomiting, loss of appetite, mouth sores, and hair loss. Because of the high doses of chemo used, these can sometimes be severe.

Infection resulting from a weakened immune system is the most common side effect. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 – 12 months post-transplant for a patient’s immune system to fully recover. Immune systems of patients with graft-versus-host disease can take even longer to function normally. Low red cell count and platelet counts are also early-side effects that when happens are treated with blood transfusion.

A rare but serious side effect of stem cell transplant is called veno-occlusive disease of the liver (VOD). In this disease, the high doses of chemo given for the transplant damage the liver. Symptoms include weight gain (from fluid collecting), liver swelling, and yellowing of the skin and eyes (jaundice). When severe, it can lead to liver failure, kidney failure, and even death.

Long-term side effects: Some side effects can last for a long time, or may not happen until years after the transplant. These long-term side effects can include the following:

  • Acute/Chronic Graft-versus-host disease (GVHD), which occurs only in a donor transplant
  • Organ damage:  lungs ( shortness of breath), ovaries (infertility and loss of menstrual period), thyroid, eyes (cataract), bone etc.
  • Developing another type of leukemia or other cancer several years later.

ALL (and AML), Bone Marrow transplant and Clinical Trials

Back in the early 80’s, chemotherapy was shown to cure a substantial portions of patients with ALL. Yet some patients had high risk of relapse when treated using conventional regimens, due to patient- and disease-related variables.  Bone marrow transplantation (BMT) was found to have encouraging results depending on the circumstances, yet the relative role between chemo and BMT to high-risk patients was controversial.

It was believed that the factors which predict poor outcome with chemo do not adversely affect the transplant outcome, yet this assumption was not based on comparing similar predicting factors . More so, the prognostic factors for outcome after BMT were not well-defined and the optimal regimen for transplant was not agreed upon. Thus, researches aimed to identify the characteristics and factors affecting good outcome after transplantation for ALL in first and second remission.

For this, 690 patients with HLA-identical sibling receiving allogeneic BMT either after first or second complete remission (CR). Numerous factors were accounted for including; age, sex, donor-recipient sex match, chemo regimen and presence of GVHD.

Of the many factors evaluated, several were highly significant in BMT outcome:

  • GVHD – It may have both favorable and unfavorable effect on the outcome. On one hand it may reduce leukemia relapse but on the other hand it may increase transplant-related mortality.
  • Conditioning chemo regimens –  most chemo regimens had negative effects of the BTM outcome. By, since the study group included only a small number of patients and these studies were conducted before the new chemo types/regimes using high-does etoposide, this factor may need to be reevaluated.
  • Donor-recipient sex match –  This factor was found to be highly significant in female receiving donors from male-matched donors. These patients had higher risk of relapse and treatment failure. This was probably due to host sensitization to the H-Y antigens. This data is also needed to be handled with cautious due to the small number of patients.
  • Immune phenotype –  Blood cell type and leukocyte levels at the beginning of the treatment is a another crucial factor. Higher leukocyte levels and non-T cell phenotype resulted in adverse outcome which led to remission.
  • Patient age – Age did not play a role when comparing the outcome after first relapse, but was found to be more favorable for younger ages (<16) when comparing the outcome after second relapse.
  • First relapse – a failure of first therapy override any other variable. The medical situation ( on/off chemo) at the time of a first relapse is highly important.  If relapse occurred while OFF chemo, patients had better prognosis.

A recent study conducted by Wing Leung, M.D., Ph.D from St. Jude Children Hospital shows that that transplantation offers real hope of survival to patients with high-risk leukemia that is not curable with intensive chemotherapy. Bone marrow transplant survival more than doubled in recent years for young, high-risk leukemia patients who lacked genetically matched donors (5).

Five years after transplantation, survival was 65 percent for the 37 St. Jude patients with high-risk ALL treated at the hospital between 2000 and 2007, compared to 28 percent for the 57 St. Jude ALL patients who underwent treatment between 1991 and 1999. For AML patients, success rates grew from 34 % to 74%.

Dr. Leung explains that historically, transplant patients fared best and suffered fewer complications when the donors were relatives who carried the same six proteins on their white blood cells. Known as HLA proteins, they serve as markers to help the immune system distinguish between an individual’s healthy tissue and diseased cells that should be eliminated.

However, St. Jude investigators pioneered the use of haploidentical transplants (=partially genetically matched donors such as parents), demonstrating that careful matching of patients and donors and proper processing of the hematopoietic donor cells enhances the anti-cancer effect of transplantation without significantly increasing side effects.

The process involves careful testing and HLA screening of potential donors to identify the one whose immune system is likely to mount the most aggressive attack against remaining leukemia cells using specialized immune cells known as natural killer cells (5).

Dr. Leung further explains that the odds of finding a good haploidentical donor are 70 to 80 percent, compared to about a 25 percent chance of having a matched sibling donor, Leung said. The likelihood of finding a genetically identical, unrelated donor ranges from about 60 to 90 percent depending on the patient’s race or ethnicity.

Summary

Previous study have identified several factors that may affect the outcome of BMT in high-risk patients and included GVHD, blood count, chemo regimen prior to the transplantation, donor-sex matched and others. In a more recent study, however,  the results indicated that all patients with very high-risk leukemia should be considered as candidates for HCT  (Allogeneic hematopoietic cell transplantation) early in the course of diagnosis or relapse treatment, regardless of the availability of a matched donor or the intensity of prior chemotherapy. HLA typing, donor search, and transplant center referral should be performed as soon as possible. Patients with persistent minimal residual disease (MRD) or hematologic relapse while on therapy are also considered candidates for HCT in current protocols. There are several major differences between previous years study-analyses and this current one that needs to be taken into consideration before including or excluding each of them. [A]; 24% of the allogeneic HCTs in patients younger than 20 years worldwide were performed using cord blood grafts vs the previous bone marrow transplant procedure, [B] differences chemo-regimens between the previous and current years,  [C] different transplant approaches evolved simultaneously, and therefore it is difficult to conduct retrospective analyses and [D] matching in HLA-C was not required for unrelated donor HCTs before 2008 in several institutes and therefore outcomes after contemporary 8 of 8 loci-matched transplantations may even be better than those favorable rates reported.

The data reported within is highly important and may increase patients survival rates and increased quality of lives. It is therefore necessary that different clinical-trial centers will re-evaluate current protocols and consider this new approach.

REFERENCES:

1. Acute Lymphoblastic Leukemia (ALL) and Nanotechnology. Author Tilda Barliya PhD

http://pharmaceuticalintelligence.com/2013/03/21/acute-lymphoblastic-leukemia-all-and-nanotechnology/

2.  In Focus: Identity of Cancer Stem Cells. Author Ritu Saxena

http://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

3a. NCI: Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®).

http://www.cancer.gov/cancertopics/pdq/treatment/childALL/Patient/page4

3b. Drugs Approved for Acute Lymphoblastic Leukemia (ALL)

http://www.cancer.gov/cancertopics/druginfo/leukemia#dal1

4. American Cancer Society: Leukemia–Acute Lymphocytic Overview

http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/overviewguide/leukemia-all-overview-treating-bone-marrow-stem-cell.

5. W. Leung, D. Campana, J. Yang, D. Pei, E. Coustan-Smith, K. Gan, J. E. Rubnitz, J. T. Sandlund, R. C. Ribeiro, A. Srinivasan, C. Hartford, B. M. Triplett, M. Dallas, A. Pillai, R. Handgretinger, J. H. Laver, C.-H. Pui. High success of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemiaBlood, 2011; DOI: 10.1182/blood-2011-01-333070

http://bloodjournal.hematologylibrary.org/content/118/2/223.full

6. AJ Barrett, MM Horowitz, RP Gale, JC Biggs, BM Camitta, KA Dicke, E Gluckman, RA Good, RH Herzig, and MB Lee. Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood August 1, 1989vol. 74 no. 2 862-871

http://bloodjournal.hematologylibrary.org/content/74/2/862.full.pdf+html

7. Fujii H, Tradeau JD., Teachey DT., Fish JD., Grupp SA., Schlts KR and Reid GS. In vivo control of acute lymphoblastic leukemia by immunostimulatory CpG oligonucleotides. Blood 2007, 109: 2008-2013. 

http://bloodjournal.hematologylibrary.org/content/109/5/2008.full.pdf+html

8.   Schrauder A, Reiter A,  Gadner H, Niethammer D, Klingebiel T, Kremens B,  Wolfram Ebell P,  Zimmermann M, Niggli F, Wolf-Dieter Ludwig, Riehm H, Welte K, and Schrappe M. Superiority of Allogeneic Hematopoietic Stem-Cell Transplantation Compared With Chemotherapy Alone in High-Risk Childhood T-Cell Acute Lymphoblastic Leukemia: Results From ALL-BFM 90 and 95. J Clin Oncol 2006 24:5742-5749.

http://jco.ascopubs.org/content/24/36/5742.full.pdf+html

9.  O. Ringde´n, M. Labopin, A. Bacigalupo, W. Arcese, U.W. Schaefer, R. Willem. Transplantation of Peripheral Blood Stem Cells as Compared With Bone Marrow From HLA-Identical Siblings in Adult Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia. Journal of Clinical Oncology 2002, Vol 20, No 24 (December 15),: pp 4655-4664.

http://jco.ascopubs.org/content/20/24/4655.full.pdf+html

10. Bunin N, Carston M, Wall D, Adams R, Casper J, Kamani N, King R, and the National Marrow Donor Program Working Group. Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission.  Blood 2002, May 1, vol 99: 3151-3157.  http://bloodjournal.hematologylibrary.org/content/99/9/3151.full.pdf+html

11. Mehmet Uzunel, Jonas Mattsson, Marie Jaksch, Mats Remberger, and Olle Ringde´n. The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. Blood 2001 98: 1982-1985. http://bloodjournal.hematologylibrary.org/content/98/6/1982.full.pdf+html

12. Marina Cetkovic-Cvrlje, Bertram A. Roers, Barbara Waurzyniak, Xing-Ping Liu, and Fatih M. Uckun. Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice. Blood 2001 98: 1607-1613. http://bloodjournal.hematologylibrary.org/content/98/5/1607.full.pdf+html

13. Kate A. Wheeler, Susan M. Richards, Clifford C. Bailey, Brenda Gibson, Ian M. Hann, Frank G. H. Hill, and Judith M. Chessells for the Medical Research Council Working Party on Childhood Leukaemia. Bone marrow transplantation versus chemotherapy in the treatment of very high–risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI. Blood 2000 96: 2412-2418. http://bloodjournal.hematologylibrary.org/content/96/7/2412.full.pdf+html

14. O. Ringde´n, M. Remberger, T. Ruutu, J. Nikoskelainen, L. Volin, L. Vindeløv, T. Parkkali, S. Lenhoff, B. Sallerfors, L. Mellander, P. Ljungman, and N. Jacobsen, for the Nordic Bone Marrow Transplantation Group.  Increased Risk of Chronic Graft-Versus-Host Disease, Obstructive Bronchiolitis, and Alopecia With Busulfan Versus Total Body Irradiation: Long-Term Results of a Randomized Trial in Allogeneic Marrow Recipients With Leukemia. 1999 93: 2196-2201. http://bloodjournal.hematologylibrary.org/content/93/7/2196.full.pdf+html

15.  Christopher J.C. Knechtli, Nicholas J. Goulden, Jeremy P. Hancock, Victoria L.G. Grandage, Emma L. Harris, Russell J. Garland, Claire G. Jones, Anthony W. Rowbottom, Linda P. Hunt, Ann F. Green, Emer Clarke, Alan W. Lankester, Jacqueline M. Cornish, Derwood H. Pamphilon, Colin G. Steward, and Anthony Oakhill.  Minimal Residual Disease Status Before Allogeneic Bone Marrow Transplantation Is an Important Determinant of Successful Outcome for Children and Adolescents With Acute Lymphoblastic Leukemia. Blood 1998 92: 4072-4079. http://bloodjournal.hematologylibrary.org/content/92/11/4072.full.pdf+html

16.  Daniel J. Weisdorf, Amy L. Billett, Peter Hannan, Jerome Ritz, Stephen E. Sallan, Michael Steinbuch, and Norma K.C. Ramsay.  Autologous Versus Unrelated Donor Allogeneic Marrow Transplantation for Acute Lymphoblastic Leukemia. Blood 1997 90: 2962-2968. http://bloodjournal.hematologylibrary.org/content/90/8/2962.full.pdf+html

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Microchemistry Implant Device

Reporter: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/03/26/microchemistry-implant-device/

The world’s smallest implantable blood monitoring implant for early detection of acute coronary syndrome and other monitoring has been reported by the IFCC.

World’s smallest blood monitoring implant tells your smartphone when you’re about to have a heart attack

By John Hewitt on March 21, 2013
International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)

In announcing  the world’s smallest medical implant to monitor critical chemicals in the blood, a 14mm device measures up to five indicators, including proteins like troponin, glucose, and lactate, scientists at Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland have developed a device that can measure and transmit the data to a smartphone for tracking.  It is powered by a 100 milliwatts patch that the device requires by wireless inductive charging through the skin. Each sensor is coated with an enzyme that reacts with blood-borne chemicals to generate a detectable signal. For patient monitoring, a device like this would quickly become indispensable once introduced, especially for continuous dosage monitoring. This would be partcularly useful when patient’s ability to break down and excrete the drug is compromized by either impaired functioning of  liver or kidney in drug elimination.
http://www.youtube.com/watch?feature=player_embedded&v=DBa41wej-NE
To be fail-safe, this depends on the patient having access to their data. Dependence on the integrity of multiple weak links to the cloud, to the doctor, and back again — as is often the prescribed future care scenario — are unacceptable, particularly when heart attacks might be counted on to occur precisely at those times when those links may not be there. Assuming the battles for patient rights will be won sooner rather than later, the next important choice would be getting the proper ringtone when that fateful troponin call comes.
Ions and respiratory gases in the blood at different body locations can also be mapped. When coupled with powerful analysis packages, a device like this could help make the patient the customer once again. For now, the device is limited to the lifetime of the enzymes — typically after a month or two they can be considered expired.

http://www.extremetech.com/wp-content/uploads/2013/03/EPFL-implant-300×264.jpg
As a final note, it should be observed that the EPFL device is not the only one on the horizon. Tricorder-style blood scanners are just beginning to gain a foothold in the medical community. A new $100 million research fund has just been announced by Blackberry mastermind Mike Lazaridis. The new fund is called Quantum Valley Investments, and is emphasizing all things quantum.

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Cancer Screening Programs at Sourasky Medical Center’s Cancer Prevention Center in Tel-Aviv

Author: Ziv Raviv, PhD

Cancer is one of the leading causes of death in the World. Major efforts are devoted for its eradication. There are several strategies to fighting cancer. Considerable research efforts were allocated over the last 50 years to elucidate the genetic factors causing cancer and the molecular mechanisms governing its biology for the purpose of developing anti-cancer treatments. It is important to note that cancer is a disease that environmental and life style factors play crucial role in its development.

It is accepted in the Medical community that the earlier the cancer has being detected, the greater are the odds for better prognosis and often the attainment of complete remission. Thus, it is important that more efforts should be addressed into prevention and early detection programs. Several medical centers and research institutes have set up prevention programs, among them is the integrated cancer prevention center (ICPC) of Tel-Aviv Sourasky medical center (TASMC) directed by Prof. Nadir Arber. A comprehensive cancer screening is applied by specialist physicians aimed at identification of potential cancer patients. The Screening program is supported by an integrated research laboratory, that develops and implements innovative technologies and approaches for early detection and therapy of cancer.

ICPC program is considered to be unique in the World. The Screening involves a comprehensive examination, on the spot, for the early detection of at least 11 different most common cancers taking advantage of up-to-date contemporary as well as innovative tests, which are carried out under the same roof and require a single visit taking only few hours, where results are given within few weeks. That is instead of doing separate examinations for the detection of each cancer type, a process when performed through the ordinary health care pathway could consume much of the patient time and involves several bureaucratic levels.

The cancers being tested for by the center include among others:

  • Skin
  • Colon
  • Breast
  • Lung
  • Ovarian
  • Prostate

Respectively, the screenings performed include careful body and skin examination, imaging, blood tests for cancer markers accompanied with standard clinical tests, as well as personal interview evaluating the family history and risk factors of the client. However, it is important to note that the ICPC is not restricted only to patients with known family history of cancer incidents and/or with high risk factors, rather, ICPC is providing its services to any person whom would like to be examined if having cancer. The goal of ICPC is indeed to create the atmosphere among the general public to give attitude to this screening as it is a standard process of body checkup that should be performed periodically on a regular basis. The visit at ICPC clinic consumes relatively small effort from the patient in terms of time and costs. In addition, the persons arriving to ICPC are receiving dietary as well as life style counseling. If cancer or a pre-cancerous condition is been discovered, the client is being referred for further evaluation of treatment options. Personalized approach is applied that includes performing a personal questionnaire and interview before screening as mentioned above, as well as ongoing documentation and follow-ups that are initiated after the results are obtained and shared with the patient.

The cost of this sequence of checkups and tests is seemingly expensive, and there is an impression that this is a “rich people only clinic”, too expensive for the average pocket. Yet, when thinking carefully the costs are rather low, only few hundreds of American dollars, a price which is definitely low comparing to the costs of some of these tests, and as Prof. Arber stated: “the cost is not higher than that one pays for his annual car service, so why not giving the same attention to your own body as given to your car.” The fees being paid by the patients for the screening and genetic testing are not covering the costs. However, in the long run, it is believed that this approach is worthwhile if taking in consideration the costs benefits of cancer early detection, of reducing hospitalization days and medicines prescription. Therefore, a governmental intervention should take place in the form of subsidizing the costs of the cancer screening. In addition, the various health care insurance plans should cover at least in part the fees required to be paid by the patient for this screening, thus, making the visit to the cancer prevention center affordable to every citizen.

ICPC reported that, around 10 percent of people following the screening protocol, were found to be carrying premature tumors, emphasizing the importance of the existence of such a preventive center. Now it is remained to evaluate if the program is being accepted broadly by the general public. PR is needed in order to support public awareness to this program. It is important to note that aside from rising public responsiveness for the existence of ICPC, overcoming psychological barriers is another issue that requires attention on as many people do not like to “know what the future holds” especially when it comes to diseases.

ICPC, a cancer prevention center located within a major hospital, integrates specialized medical doctors with state of the art facilities, performing comprehensive tests for cancer detection in an intensive one-day visit, is unique and very important for performing a good cancer prevention program. The ICPC and other similar prevention centers (see references) should give example for other medical centers around the globe willing to adopt the approach of cancer prevention in the ongoing battle against cancer. The more centers as such will exist, the greater are the chances for early Cancer detection and increase the potential of significantly reducing the rate of cancer incidences worldwide.

REFERENCES:

http://www.tasmc.org.il/sites/en/internalmed/ICPC/Pages/ICPC.aspx

MD Anderson Cancer Prevention Center

St. Joseph Hospital cancer programs Related article on this Open Access Online Scientific Journal, include the following:

http://pharmaceuticalintelligence.com/2013/03/07/the-importance-of-cancer-prevention-programs-new-perceptions-for-fighting-cancer/

 

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Author: Tilda Barliya PhD

Acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells, affects both children and adults,
with peak prevalence between the ages of 2 and 5 years (2). Acute lymphocytic leukemia (ALL) is a heterogeneous disease, both in terms of its pathology and the populations that it affects. Disease pathogenesis involves a number of deregulated pathways controlling cell proliferation, differentiation, and survival that are important determinants of treatment response (3). Approximately 5200 new cases of ALL are estimated to have occurred in the United States in 2007 and survival varies with age and disease biology (3). Although five-year survival rates for ALL approach 90 percent with available chemotherapy treatments, the harmful side effects of the drugs, including secondary cancers and fertility, cognitive, hearing, and developmental problems, present significant concern for survivors and their families.

Biological and Clinical Prognostic Factors in ALL: Setting the Stage for Risk-Adapted Therapy

Of the many variables that influence prognosis the genetic subsets, initial white blood cell count (WBC), age at diagnosis, and early treatment response are the most important.

Childhood Acute Lymphoblastic Leukemia

Pathobiology

Acute lymphoblastic leukaemia is thought to originate  from various important genetic lesions in blood-progenitor  cells that are committed to differentiate in the T-cell or B-cell pathway, including mutations that impart the  capacity for unlimited self-renewal and those that lead to  precise stage-specific developmental arrest. In some  cases, the first mutation along the multistep pathway to  overt acute lymphoblastic leukaemia might arise in a  haemopoietic stem cell possessing multilineage developmental capacity.

The dominant theme of contemporary research in pathobiology of acute lymphoblastic leukaemia is to understand the outcomes of frequently arising genetic lesions, in terms of their effects on cell proliferation, differentiation, and survival, and then to devise selectively targeted treatments against the altered gene products to which the leukaemic clones have become addicted (2).

Table 1.

Prognostic factors used in pediatric and adult clinical trials

The Table  illustrates the different prognostic factors in children and adults that may be used for risk stratification in current clinical trials (3).

Genetics

  • Chromosomal translocations that activate specifi c genes
    are a defi ning characteristic of human leukaemias and
    of acute lymphoblastic leukaemia in particular.
  • About 25% of cases of B-cell precursor acute lymphoblastic leukaemia, the most frequent form of acute leukaemia in children, harbour the TEL-AML1 fusion gene—generated by the t(12;21)(p13;q22) chromosomal translocation.

The presence of the TEL-AML1 fusion
protein in B-cell progenitors seems to lead to disordered
early B-lineage lymphocyte development, a hallmark of
leukaemic lymphoblasts.

Analysis of TEL-AML1-induced cord blood cells suggests that the fusion gene serves as a first-hit mutation by endowing the preleukemic cell with altered self-renewal and survival properties.

  • In adults, the most frequent chromosomal translocation  is t(9;22), or the Philadelphia chromosome, which causes  fusion of the BCR signalling protein to the ABL  non-receptor tyrosine kinase, resulting in constitutive  tyrosine kinase activity and complex interactions of this  fusion protein with many other transforming elements.  BCR-ABL off ers an attractive therapeutic  target, and imatinib mesilate, a small-molecule inhibitor  of the ABL kinase, has proven effective against leukaemias that express BCR-ABL
  • More than 50% of cases of T-cell acute lymphoblastic  leukaemia have activating mutations that involve  NOTCH1. NOTCH1, which translocates to the nucleus and regulates by transcription a diverse set of responder genes, including the MYC oncogene.  The precise  mechanisms by which aberrant NOTCH signalling (due  to mutational activation) causes T-cell acute lymphoblastic  leukaemia are still unclear but probably entail constitutive  expression of oncogenic responder genes, such as MYC,  and cooperation with other signalling pathways (pre-TCR  [T-cell receptor for antigen] and RAS, for example).  Interference with NOTCH signalling by small-molecule  inhibition of γ-secretase activity has the potential to induce remission of T-cell acute lymphoblastic  leukemia.

Additionally A recent discussion has aimed to reveal the genetic origin of the disease (1). Several of these genes, including ARID5B, IKZF1, and CEBPE, have been implicated in processes such as hematopoietic differentiation and development of ALL. These gene obviously adds up to a number of other gene mutations and translocation already discovered and are associated with disease progression (2)  “The fact that alterations in these genes lead to ALL raises the question of what would happen if we restore these pathways in ALL and also make them possible exciting therapeutic targets as well.”

Nanotechnology and therapeutic

Dr. Rajasekaran, director and head of the Membrane Biology Laboratory University of Delaware,  says that there are currently seven or eight drugs that are used for chemotherapy to treat leukemia in children. They are all toxic and do their job by killing rapidly dividing cells. these drugs don’t differentiate cancer cells from other healthy cells. “The good news is that these drugs are 80 to 90 percent effective in curing leukemia. The bad news is that many chemotherapeutic treatments cause severe side effects, especially in children.  In preclinical models of leukemia, Dr. Rajasekaran research team have created NP  with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals (ECT2). The researches have been encapsulated with dexamethasone as one third of the typical dose, with good treatment results and no discernible side effects.In addition, the mice that received the drugs delivered via nanoparticles survived longer than those that received the drug administered in the traditional way (4).

In another preclinical study Uckun F et al  developed nanoparticle (NP) constructs of WHI-P131. WHI-P131 (CAS 202475-60-3) is a dual-function inhibitor of JAK3 tyrosine kinase that demonstrated potent in vivo anti-inflammatory and anti-leukemic activity in several preclinical animal models (5). Notably, WHI-P131-NP was capable of causing apoptotic death in primary leukemia cells from chemotherapy-resistant acute lymphoblastic leukemia (ALL) as well as chronic lymphocytic leukemia (CLL) patients. WHI-P131-NP was also active in the RS4;11 SCID mouse xenograft model of chemotherapy-resistant B-lineage ALL. The life table analysis showed that WHI-P131-NP was more effective than WHI-P131 (P = 0.01), vincristine (P<0.0001), or vehicle (P<0.0001). These experimental results demonstrate that the nanotechnology-enabled delivery of WHI-P131 shows therapeutic potential against leukemias with constitutive activation of the JAK3-STAT3/STAT5 molecular target (5).

Summary:

Acute Lymphoblastic Leukemia (ALL) is a pediatric type of cancer that affects adults to lesser degree. The current rate of cure if 80% in  children whereas in adults only 30-40% will survive. Much of the success is due to understanding the mechanisms that lead to the development and progression of cancer. Several gene mutations and gene-translocation have already been identified,  and targeting them enabled some of the major success in curing these kids.

Thus far, nanotechnology has been  mainly focusing on solid tumors affecting adults. Not much attention is been made on childhood cancer in general and hematopoietic types per se. Two examples of preclinical studies have been discussed above and although they show promise in treatment and reduction of side effects, yet  additional research is needed to evaluated their effect in human clinical trials.

Ref:

1. The Genetic Origin of Childhood Acute Lymphoblastic Leukemia (ALL).  Reported by Aviva Lev-Ari, PhD, RN. March 20, 2013 http://pharmaceuticalintelligence.com/2013/03/20/the-genetic-origin-of-childhood-acute-lymphoblastic-leukemia-all/

2. Ching-Hon Pui, Leslie L Robison, A Thomas Look. Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030–43.

http://www.med.upenn.edu/timm/documents/PuiLookLancetLeukemiareview.pdf

3. Wendy Stock. Adolescents and Young Adults with Acute Lymphoblastic Leukemia. Hematology December 4, 2010 vol. 2010 no. 1 21-29. http://asheducationbook.hematologylibrary.org/content/2010/1/21.full

4. Vinu Krishnan,  Xian Xu,, Sonali P. BarweXiaowei YangKirk CzymmekScott A. WaldmanRobert W. MasonXinqiao Jia, and Ayyappan K. Rajasekaran. Dexamethasone-Loaded Block Copolymer Nanoparticles Induce Leukemia Cell Death and Enhance Therapeutic Efficacy: A Novel Application in Pediatric Nanomedicine. Mol. Pharmaceutics 2012 ahead of print.

http://pubs.acs.org/doi/abs/10.1021/mp300350e?prevSearch=Rajasekaran&searchHistoryKey=

5. Uckun FMDibirdik IQazi SYiv S. Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells. Arzneimittelforschung 2010; 60(4): 210-217.

http://www.ncbi.nlm.nih.gov/pubmed/20486472

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