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Researchers discover how to shutdown cancer's powerful master proteinPublic release date: 3-Mar-2013 [ | E-mail | Share ]
Contact: Lauren Woods Law2014@med.cornell.edu 646-317-7401 Weill Cornell Medical College
Weill Cornell research offers patients hope for new treatments for an aggressive and common lymphoma
NEW YORK (March 3, 2013) -- The powerful master regulatory transcription factor called Bcl6 is key to the survival of a majority of aggressive lymphomas, which arise from the B-cells of the immune system. The protein has long been considered too complex to target with a drug since it is also crucial to the healthy functioning of many immune cells in the body, not just B cells gone bad.
But now, in the journal Nature Immunology, researchers at Weill Cornell Medical College report that it is possible to shut down Bcl6 in the cancer, known as diffuse large B-cell lymphoma (DLBCL), while not affecting its vital function in T cells and macrophages that are needed to support a healthy immune system.
"The finding comes as a very welcome surprise," says the study's lead investigator, Dr. Ari Melnick, Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
"This means the drugs we have developed against Bcl6 are more likely to be significantly less toxic and safer for patients with this cancer than we realized," says Dr. Melnick, who is also a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
If Bcl6 is completely inhibited, patients might suffer from systemic inflammation and atherosclerosis. Weill Cornell researchers conducted this new study to help clarify possible risks, as well as to understand how Bcl6 controls the various aspects of the immune system.
DLBCL is the most common subtype of non-Hodgkin lymphoma -- the seventh most frequently diagnosed cancer -- and many of these patients are resistant to currently available treatments.
"Scientists have been searching for the right answer to treat this difficult lymphoma, which, after initial treatment, can be at high risk of relapse and resistant to current therapies," Dr. Melnick says. "Believing that Bcl6 could not be targeted, some researchers have been testing alternative therapeutic approaches. This study strongly supports the notion of using Bcl6-targeting drugs."
In fact, the findings in this study were inspired from preclinical testing of two Bcl6-targeting agents that Dr. Melnick and his Weill Cornell colleagues have developed to treat DLBCLs. These experimental drugs are RI-BPI, a peptide mimic, and the small molecule agent 79-6.
Dr. Melnick says the discovery that a master regulatory transcription factor can be targeted offers implications beyond just treating DLBCL. Recent studies from Dr. Melnick and others have revealed that Bcl6 plays a key role in the most aggressive forms of acute leukemia, as well as certain solid tumors.
Transcription factors are responsible for either inhibiting or promoting the expression of genes, and master regulatory transcription factors are the equivalent of the CPU of a computer their actions regulate thousands of genes in different kinds of cells. For example, Bcl6 can control the type of immune cell that develops in the bone marrow -- playing many roles in the development of B cells, T cells, macrophages and other cells -- including a primary and essential role in enabling B-cells to generate specific antibodies against pathogens.
"When cells lose control of Bcl6, lymphomas develop in the immune system. Lymphomas are 'addicted' to Bcl6, and therefore Bcl6 inhibitors powerfully and quickly destroy lymphoma cells," Dr. Melnick says.
The big surprise in the current study is that rather than functioning as a single molecular machine, Bcl6 instead seems to function more like a Swiss Army knife, using different tools to control different cell types. This multi-function paradigm could represent a general model for the functioning of other master regulatory transcription factors.
"In this analogy, the Swiss Army knife, or transcription factor, keeps most of its tools folded, opening only the one it needs in any given cell type," Dr. Melnick says. "For B cells, it might open and use the knife tool; for T cells, the cork screw; for macrophages, the scissors. The amazing thing from a medical standpoint is that this means that you only need to prevent the master regulator from using certain tools to treat cancer. You don't need to eliminate the whole knife," he says. "In fact, we show that taking out the whole knife is harmful since the transcription factor has many other vital functions that other cells in the body need."
Prior to these study results, it was not known that a master regulator could separate its functions so precisely.
"Now we know we can take out a specific tool -- to shut down a specific part of the protein -- that causes the disease we want to treat."
Researchers hope this will be a major benefit to the treatment of DLBCL and perhaps other disorders that are influenced by Bcl6 and other master regulatory transcription factors.
###
Study co-authors include Dr. Chuanxin Huang and Dr. Katerina Chatzi from the Division of Hematology and Oncology at Weil Cornell Medical College.
The research was funded by grants from the National Cancer Institute, The Burroughs Wellcome Foundation and the Chemotherapy Foundation. The research was initially supported by a March of Dimes Scholar Award and facilitated by the Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
The Raymond and Beverly Sackler Center for Biomedical and Physical Sciences
The Raymond and Beverly Sackler Center for Biomedical and Physical Sciences of Weill Cornell Medical College brings together a multidisciplinary team of scientists for the purpose of catalyzing major advances in medicine. By harnessing the combined power of experimental approaches rooted in the physical and biological sciences, Sackler Center investigators can best accelerate the pace of discovery and translate these findings for the benefit of patients with various medical conditions, including but not limited to cancer.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Researchers discover how to shutdown cancer's powerful master proteinPublic release date: 3-Mar-2013 [ | E-mail | Share ]
Contact: Lauren Woods Law2014@med.cornell.edu 646-317-7401 Weill Cornell Medical College
Weill Cornell research offers patients hope for new treatments for an aggressive and common lymphoma
NEW YORK (March 3, 2013) -- The powerful master regulatory transcription factor called Bcl6 is key to the survival of a majority of aggressive lymphomas, which arise from the B-cells of the immune system. The protein has long been considered too complex to target with a drug since it is also crucial to the healthy functioning of many immune cells in the body, not just B cells gone bad.
But now, in the journal Nature Immunology, researchers at Weill Cornell Medical College report that it is possible to shut down Bcl6 in the cancer, known as diffuse large B-cell lymphoma (DLBCL), while not affecting its vital function in T cells and macrophages that are needed to support a healthy immune system.
"The finding comes as a very welcome surprise," says the study's lead investigator, Dr. Ari Melnick, Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
"This means the drugs we have developed against Bcl6 are more likely to be significantly less toxic and safer for patients with this cancer than we realized," says Dr. Melnick, who is also a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
If Bcl6 is completely inhibited, patients might suffer from systemic inflammation and atherosclerosis. Weill Cornell researchers conducted this new study to help clarify possible risks, as well as to understand how Bcl6 controls the various aspects of the immune system.
DLBCL is the most common subtype of non-Hodgkin lymphoma -- the seventh most frequently diagnosed cancer -- and many of these patients are resistant to currently available treatments.
"Scientists have been searching for the right answer to treat this difficult lymphoma, which, after initial treatment, can be at high risk of relapse and resistant to current therapies," Dr. Melnick says. "Believing that Bcl6 could not be targeted, some researchers have been testing alternative therapeutic approaches. This study strongly supports the notion of using Bcl6-targeting drugs."
In fact, the findings in this study were inspired from preclinical testing of two Bcl6-targeting agents that Dr. Melnick and his Weill Cornell colleagues have developed to treat DLBCLs. These experimental drugs are RI-BPI, a peptide mimic, and the small molecule agent 79-6.
Dr. Melnick says the discovery that a master regulatory transcription factor can be targeted offers implications beyond just treating DLBCL. Recent studies from Dr. Melnick and others have revealed that Bcl6 plays a key role in the most aggressive forms of acute leukemia, as well as certain solid tumors.
Transcription factors are responsible for either inhibiting or promoting the expression of genes, and master regulatory transcription factors are the equivalent of the CPU of a computer their actions regulate thousands of genes in different kinds of cells. For example, Bcl6 can control the type of immune cell that develops in the bone marrow -- playing many roles in the development of B cells, T cells, macrophages and other cells -- including a primary and essential role in enabling B-cells to generate specific antibodies against pathogens.
"When cells lose control of Bcl6, lymphomas develop in the immune system. Lymphomas are 'addicted' to Bcl6, and therefore Bcl6 inhibitors powerfully and quickly destroy lymphoma cells," Dr. Melnick says.
The big surprise in the current study is that rather than functioning as a single molecular machine, Bcl6 instead seems to function more like a Swiss Army knife, using different tools to control different cell types. This multi-function paradigm could represent a general model for the functioning of other master regulatory transcription factors.
"In this analogy, the Swiss Army knife, or transcription factor, keeps most of its tools folded, opening only the one it needs in any given cell type," Dr. Melnick says. "For B cells, it might open and use the knife tool; for T cells, the cork screw; for macrophages, the scissors. The amazing thing from a medical standpoint is that this means that you only need to prevent the master regulator from using certain tools to treat cancer. You don't need to eliminate the whole knife," he says. "In fact, we show that taking out the whole knife is harmful since the transcription factor has many other vital functions that other cells in the body need."
Prior to these study results, it was not known that a master regulator could separate its functions so precisely.
"Now we know we can take out a specific tool -- to shut down a specific part of the protein -- that causes the disease we want to treat."
Researchers hope this will be a major benefit to the treatment of DLBCL and perhaps other disorders that are influenced by Bcl6 and other master regulatory transcription factors.
###
Study co-authors include Dr. Chuanxin Huang and Dr. Katerina Chatzi from the Division of Hematology and Oncology at Weil Cornell Medical College.
The research was funded by grants from the National Cancer Institute, The Burroughs Wellcome Foundation and the Chemotherapy Foundation. The research was initially supported by a March of Dimes Scholar Award and facilitated by the Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
The Raymond and Beverly Sackler Center for Biomedical and Physical Sciences
The Raymond and Beverly Sackler Center for Biomedical and Physical Sciences of Weill Cornell Medical College brings together a multidisciplinary team of scientists for the purpose of catalyzing major advances in medicine. By harnessing the combined power of experimental approaches rooted in the physical and biological sciences, Sackler Center investigators can best accelerate the pace of discovery and translate these findings for the benefit of patients with various medical conditions, including but not limited to cancer.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
This frame grab made available by NASA TV shows a view of the SpaceX Dragon capsule on the end of the International Space Station's robotic arm, Sunday, March 3, 2013. SpaceX, the California-based company founded by billionaire Elon Musk, had to struggle with the Dragon following its launch Friday from Cape Canaveral. The spacecraft is delivering more than 1 ton of supplies to the the International Space Station. (AP Photo/NASA TV)
This frame grab made available by NASA TV shows a view of the SpaceX Dragon capsule on the end of the International Space Station's robotic arm, Sunday, March 3, 2013. SpaceX, the California-based company founded by billionaire Elon Musk, had to struggle with the Dragon following its launch Friday from Cape Canaveral. The spacecraft is delivering more than 1 ton of supplies to the the International Space Station. (AP Photo/NASA TV)
This frame grab made available by NASA TV shows a view of the SpaceX Dragon anchoring to the International Space Station Sunday, March 3, 2013. SpaceX, the California-based company founded by billionaire Elon Musk, had to struggle with the Dragon following its launch Friday from Cape Canaveral. The spacecraft is delivering more than 1 ton of supplies to the the International Space Station. (AP Photo/NASA TV)
CAPE CANAVERAL, Fla. (AP) ? A privately owned Dragon capsule arrived at the International Space Station on Sunday, delivering a ton of supplies with high-flying finesse after a shaky start to the mission.
The Dragon's arrival was one day late but especially sweet ? and not because of the fresh fruit on board for the station astronauts who snared the capsule.
SpaceX, the California-based company founded by billionaire Elon Musk, had to struggle with the Dragon following its launch Friday from Cape Canaveral. A clogged pressure line or stuck valve prevented thrusters from working, and it took flight controllers several hours to gain control and salvage the mission.
In the end, the Dragon approached the orbiting lab with its 1-ton load about as smoothly as could be expected, with all of its thrusters, or little maneuvering rockets, operating perfectly. The capture occurred as the two spacecraft zoomed 250 miles above Ukraine.
"As they say, it's not where you start, but where you finish that counts," said space station commander Kevin Ford, "and you guys really finished this one on the mark."
He added: "We've got lots of science on there to bring aboard and get done. So congratulations to all of you."
Among the items on board: 640 seeds of a flowering weed used for research, mouse stem cells, food and clothes for the six men on board the space station, trash bags, computer equipment, air purifiers, spacewalking tools and batteries. The company also tucked away apples and other fresh treats from an employee's family orchard.
The Dragon will remain at the space station for most of March before returning to Earth with science samples, empty food containers and old equipment.
SpaceX ? Space Exploration Technologies Corp. ? has a $1.6 billion contract with NASA to keep the station well stocked. The contract calls for 12 supply runs; this was the second in that series.
This is the third time, however, that a Dragon has visited the space station. The previous two capsules had no trouble reaching their destination. Company officials promise a thorough investigation into what went wrong this time; if the thrusters had not been activated, the capsule would have been lost.
Ford said everything about Sunday's rendezvous ended up being "fantastic."
"There sure were some big smiles all around here," NASA's Mission Control replied from Houston.
The actual anchoring of the Dragon to the space station, 2? hours after its arrival, also unfolded without a hitch. "The Dragon is ours!" Canadian astronaut Chris Hadfield announced via Twitter.
In a tweet following Friday's nerve-racking drama, Musk said, "Just want to say thanks to (at)NASA for being the world's coolest customer. Looking forward to delivering the goods!"
Musk, who helped create PayPal, acknowledged Friday that the problem ? the first ever for an orbiting Dragon ? was "frightening." But he believed it was a one-time glitch and nothing so serious as to imperil future missions. The 41-year-old entrepreneur, who also runs the electric car maker Tesla, oversaw the entire operation from Hawthorne, Calif., home to SpaceX and the company's Mission Control.
The Dragon's splashdown in the Pacific, meanwhile, remains on schedule for March 25.
NASA is counting on the commercial sector to supply the space station for the rest of this decade; it's supposed to keep running until at least 2020. Russia, Europe and Japan are doing their part, periodically launching their own cargo ships. But none of those craft can return items like the Dragon can; they burn up on re-entry
Russia also is providing rides for U.S. astronauts.
SpaceX and other companies are working toward launching astronauts in another few years. Musk leads the charge; he said he can have people flying on a modified Dragon by 2015.
NASA's space shuttles, retired to museums after a 30-year run, used to be the main haulers for the space station. At the White House direction, the space agency opted out of the Earth-to-orbit transportation business in order to focus on deep space exploration. Mars is the ultimate destination.
Thanks to six shutout innings from Chien-Ming Wang, Chinese Taipei took a huge step towards advancing in the World Baseball Classic in Saturday?s opener, beating Australia 4-1.
South Korea is viewed as the lock to advance from Pool B. The winner of today?s opener was in a great position to earn the other spot, with The Netherlands likely to have a tough time winning any of its three games.
Wang managed to get through six innings despite the 65-pitch limit starters work with in round one of the World Baseball Classic. He walked none and got three double play balls before taking a seat. Another familiar name, Hong-Chih Kuo, pitched in relief for Taiwan, throwing a perfect inning.
Both Wang and Kuo are auditioning for spots with big-league clubs during the WBC. Wang made 10 appearances with the Nationals last year, while Kuo was out of the league after developing the yips in his final year with the Dodgers.
Australia got down 3-0 early in the contest and simply didn?t have the offense to make its way back. Cleanup man Stefan Welch homered for the team?s only run. Oft-injured, ex-major leaguer Chris Snelling, batting eighth, singled in his first at-bat and was immediately removed for a pinch-runner because of a leg strain.
Chinese Taipei got a homer from first baseman Cheng-Min Peng. Astros outfielder Che-Hsuan Lin went 2-for-3 with a double.
With the onset of sequestration, Texas stands to lose funding for Head Start services, children?s vaccines and meals for seniors.? Add to this potential losses in law enforcement and education funding, one can see that programs, once aiding children, seniors and the homeless by keeping them out of the emergency room, might cease to address this critical need.? Compound these losses with the pressure being exerted by value based purchasing and the dilemma becomes magnified tenfold.? As if accountable care organizations, medical homes, hospitals and healthcare systems did not have enough on their plate, one wonders where they will find the resources to supplement these activities?
One enterprising non-profit has tackled this challenge head-on.? ?Billed as a nine-year old strategic initiative with a mission to improve the quality, capacity, and accessibility of the healthcare system for vulnerable populations in the City of Camden, the Camden Coalition has analyzed local healthcare system claims data for the purpose of building a repository and sharing data with regards to this typically transient population.? In addition, they operate several health project initiatives that demonstrate a collaborative approach to improving care delivery and patient outcomes in their area.? And by building relationships with executive leadership of the hospitals, social service/public health agencies, state government agencies, leaders at the statewide Medicaid health plans, and policymakers, they have taken a discretely modern approach to healthcare delivery.
Current innovative initiatives garnering attention include the Coalition?s Care Management and Care Transitions programs, aimed at reducing hospital utilization by directing outreach to the ?high flier? population whom frequently lack appropriate access to primary and mental health care.? Designed to target high cost, complex patients for improved care transitions and care coordination, the Coalition is steadfastly working to move these patients into a medical home model.? Upon presenting at the emergency room, patients are divided into one of two groups:? a) those with no primary care access and significant mental/social issues and b) patients with more stable primary care and mental health status.
In the Care Management program, patients meeting specific criteria receive assistance from a social worker, a health outreach worker/medical assistant and a nurse practitioner with primary/specialty care coordination, applying for government assistance, finding temporary shelter and enrolling in medical day programs.? Through stabilization of their social environment and health conditions, the team?s ultimate goal of finding a primary care medical home for the patient can begin.
Patients participating in the Care Transitions program are enrolled in and receive assistance from embedded care management nurses and health coaches from one of two Camden Federally Qualified Health Centers (FQHC) ? CAMcare and Project HOPE.? On the path to becoming patient-centered medical homes, these FQHCs are fostering better care transitions and coordination with their hospital and health system partners.
These bold programs have been facilitated by city-wide use of health information exchange and electronic health record use for this targeted population, thereby allowing providers to share information and analyze data for additional care coordination.? Data analysis also remains integral for the monthly Care Management Committee meeting, held at rotating hospitals, in order to review and refine current processes for these programs. And by bringing together?emergency room physicians, hospitalists, specialists, social workers, and nurse discharge planners across the city, more efficient and effective discharge planning and care coordination can help decrease utilization and improve safety, experience and ultimately, quality of care.
In the first discovery of its kind, a telescope in Chile has detected a baby gas giant forming in the dust cloud around a nearby star.
By Clara Moskowitz,?SPACE.com / February 28, 2013
This artist?s impression shows the formation of a gas giant planet in the ring of dust around the young star HD 100546. This system is also suspected to contain another large planet orbiting closer to the star.
ESO/L. Cal?ada
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Astronomers have captured what may be the first-ever direct photograph of an alien planet in the process of forming around a nearby star.
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The picture, which captured a giant alien planet as it is coming together, was snapped by the European Southern Observatory's Very Large Telescope in Chile. It shows a faint blob embedded in a thick disk of gas and dust around the young star HD 100546. The object appears to be a baby gas giant planet, similar to?Jupiter, forming from the disk's material, scientists say.
"So far, planet formation has mostly been a topic tackled by computer simulations," astronomer Sascha Quanz of ETH Zurich in Switzerland, leader of the research team, said in a statement. "If our discovery is indeed a forming planet, then for the first time scientists will be able to study the?planet formation process?and the interaction of a forming planet and its natal environment empirically at a very early stage."
The star HD 100546, which lies 335 light-years from Earth, was already thought to host another giant planet that orbits it about six times farther out than the Earth is from the sun. The new potential planet lies even farther, about 10 times the distance of its sibling, at roughly 70 times the stretch between the Earth and sun. [Giant Planet In the Making Spotted? (Video)]
The possible planet seems to fit the picture scientists are building of how worlds form. Stars themselves are born in clouds of gas and dust, and after the form, a disk of leftover material often orbits them. From this disk,?baby planets?can take shape. That's what appears to be happening here.
For example, the new photo reveals structures in the disk surrounding the star that could be caused by interactions between its material and the forming planet. Furthermore, the data suggest the material around the planet-blob has been heated up, which is consistent with the planet-forming hypothesis.
The observations were made possible by the NACO adaptive optics instrument?on the Very Large Telescope, which compensates for the blurring caused by Earth's atmosphere. The instrument also uses a special coronagraph that observes in near-infrared wavelengths to block out the bright light from the star, so as to see its surroundings better.
"Exoplanet research is one of the most exciting new frontiers in astronomy, and direct imaging of planets is still a new field, greatly benefiting from recent improvements in instruments and data analysis methods," said Adam Amara, another member of the team. "In this research we used data analysis techniques developed for cosmological research, showing that cross-fertilization of ideas between fields can lead to extraordinary progress."
The findings are detailed in a paper to appear online in today's (Feb. 28) issue of?Astrophysical Journal Letters.
Follow Clara Moskowitz on Twitter?@ClaraMoskowitz?or SPACE.com?@Spacedotcom. We're also onFacebook?&?Google+.?
Copyright 2013?SPACE.com, a TechMediaNetwork company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
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Public release date: 3-Mar-2013
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