State laws and policies governing the storage and use of surplus blood samples taken from newborns as part of the routine health screening process range from explicit to non-existent, leaving many parents ill-informed about how their babies' left over blood might be used, according to a team led by a member of the Johns Hopkins Berman Institute of Bioethics, in collaboration with researchers from the University of Utah. A report on their analysis of the subject is published March 28 in the journal Pediatrics.
The study is believed to be one of the first to provide in-depth analysis of the nation's fragmented newborn screening blood use policies. The authors say that their findings underscore the need for a comprehensive and transparent approach. At a minimum, all states should require that parents be fully informed about how babies' blood samples left over after the screening procedure will be stored and how they might be used, according to Michelle H. Lewis, M.D., J.D., a research scholar at the Berman Institute's Genetics and Public Policy Center.
The residual samples, typically dried blood spots, have been the center of public debate in recent years. In 2009, families in Minnesota and Texas sued their respective state health departments for storing surplus newborn blood samples without their knowledge or consent. News stories about the outrage expressed by parents-who claimed the practice violated their right to genetic privacy and full disclosure-spawned headlines such as CNN's: "The government has your baby's DNA."
"States have developed a wide range of policies regarding the retention and use of residual dried blood samples," says Lewis, "ranging from prohibiting their use for research under any circumstances, to allowing research with anonymous samples without parental consent, to requiring parental consent for any research using the samples."
Newborns in all 50 states, plus the District of Columbia, are routinely screened for a variety of genetic disorders, including phenylketonuria (pku) and sickle cell disease. State newborn screening programs began in the 1960s, and today, nearly all of the 4 million babies born each year in the United States undergo the procedure.
Once the screening has been completed, a small amount of dried blood often remains. This residual blood is often used for quality-assurance purposes to improve the operation of state newborn screening programs. Sometimes, the samples are also used for other types of biomedical research, including research unrelated to newborn screening.
Yet, state law in only 13 states specifies how residual samples of infant blood might be used. But these purposes often are often stated in broad language, according to Lewis and her co-authors. Among the detailed findings the researchers reported:
- Laws in 20 states address the retention and/or use of babies' blood samples.
- In 18 states, newborn screening laws fail to address the retention or use of the samples or their related information.
- Information related to newborn screening is deemed confidential in 26 states although limitations on that protection vary.
- Ten states specify the purposes for which information from the newborn blood samples may be used, such as public-health purposes, scientific research and research concerning medical, psychological or sociological issues.
- In four states, the samples become state property; in two of these states, parents can object in writing.
- Only eight states require that parents be provided information regarding the retention of newborn blood samples.
Overall, most states lack any requirement that parents be informed that their child's blood samples may be retained for future use, the researchers found. This was the problem in Texas, which settled out of court with the suing families last year. As part of the settlement agreement, the state Department of Health agreed to destroy more than 5 million samples that dated back to 2002, and a valuable research resource was lost.
"The destruction of those residual samples demonstrates the damage that can be done to the research enterprise if there is a public perception that states are using the samples for purposes other than that for which they were collected," Lewis says.
"I think some of the parents involved would have consented to the use of their baby's dried blood samples for research if they had been asked. These parents felt that their rights had been violated by not having been asked," Lewis added. "Even if the state did not intend to deceive the parents, there was a perception that the state was being deceptive, and this perception was damaging to the research enterprise."
The researchers agree that public discussion about the storage and use of newborn blood samples is vital, because people are becoming ever more aware that such specimens contain precise, identifying information about their children. People also realize that research is increasingly able to yield valuable information from biological specimens.
"Part of the issue is that some parents are concerned that the state or private companies could profit from the use of their children's blood sample," Lewis says.
Although no state addresses all of these issues in a comprehensive manner, Lewis pointed to South Carolina as one that had more robust policies in place with respect to the information that must be provided to parents. There, state law requires that parents be told that they can ask that their babies' blood samples not be used for research purposes.
"As states move forward in consideration of these issues," Lewis concluded, "it is vital that state policies regarding the retention and use of residual samples not undermine the public's trust in state newborn screening programs-so that these programs can continue to protect the health of our nation's children."
In addition to Lewis, the paper was co-authored by Jeffrey Botkin, a professor of pediatrics at the University of Utah; Aaron Goldenberg, an assistant professor of bioethics at Case Western Reserve University; Rebecca Anderson, a medical ethics researcher at the University of Utah's Department of Pediatrics; and Erin Rothwell, an assistant professor at the University of Utah's School of Nursing and a fellow in the Bioethics Program at the Medical College of Wisconsin.
Their study was funded by a grant from the National Institutes of Health to the University of Utah, titled "Methods for Promoting Public Dialogue on the Use of Residual Newborn Screening Samples for Research."
Source:
Johns Hopkins Medicine
вторник, 31 мая 2011 г.
понедельник, 30 мая 2011 г.
Rare Lung Disease Identified By Diagnostic Blood Test
Researchers at the University of Cincinnati (UC) and Cincinnati Children's Hospital Medical Center have found that a certain blood test can successfully identify lymphangioleiomyomatosis (LAM) in some patients, eliminating the need for surgical lung biopsy to make a diagnosis.
These findings are being published in the July 6, 2010, edition of the journal /i>Chest.
LAM is a rare but serious lung disease that affects women, causing shortness of breath and lung collapse, called a pneumothorax. The disease occurs when an unusual type of cell invades the lungs and causes tissue destruction by creating holes or cysts in the lung. It can be fatal.
Lisa Young, MD, lead author on the study and researcher at UC and Cincinnati Children's, says that these findings will help with diagnosing LAM and may also be helpful in screening for LAM in women with Tuberous Sclerosis Complex (TSC), a genetic disorder that causes tumors to form in many different organs. TSC is a risk factor for the development of LAM.
In this study, the test was used to analyze the amount of a specific protein - vascular endothelial growth factor-D, or VEGF-D - in patients' blood. VEGF-D promotes the growth of lymphatic vessels and blood vessels and can be involved in the spread of cancer.
Researchers performed VEGF-D testing in 195 women and found that serum VEGF-D levels were significantly greater in women with LAM than in women with other lung diseases or healthy individuals. When they prospectively evaluated the VEGF-D test performance in women prior to knowing their diagnosis, the test showed high accuracy for diagnosis of LAM.
"We concluded that a serum VEGF-D level of greater than 800 pg/mL (picograms, or one-trillionth of a gram, per milliliter) in women with typical cystic changes on a high-resolution computed tomography (CT) scan is diagnostically specific for sporadic LAM and identifies LAM in women with TSC," Young says. "However, negative VEGF-D results do not exclude the diagnosis of LAM."
Frank McCormack, MD, senior author and director of pulmonary, critical care and sleep medicine at UC, says that Serum VEGF-D measurement is currently performed as part of a research protocol but will soon be available for clinical application.
"This was a team effort by clinicians around the world to collect blood samples and clinical data from patients with very rare lung diseases," he says. "Through their efforts and the generosity of patients who participated, we are optimistic that serum VEGF-D will join the ranks of diagnostic tests for lung disease, reduce the need for surgical lung biopsy and allow for intervention and trial recruitment earlier in the disease course."
This study was funded by a pilot project grant from The LAM Foundation, The Tante Mela Foundation and a grant from the National Heart, Lung, and Blood Institute.
Source:
Katie Pence
University of Cincinnati Academic Health Center
These findings are being published in the July 6, 2010, edition of the journal /i>Chest.
LAM is a rare but serious lung disease that affects women, causing shortness of breath and lung collapse, called a pneumothorax. The disease occurs when an unusual type of cell invades the lungs and causes tissue destruction by creating holes or cysts in the lung. It can be fatal.
Lisa Young, MD, lead author on the study and researcher at UC and Cincinnati Children's, says that these findings will help with diagnosing LAM and may also be helpful in screening for LAM in women with Tuberous Sclerosis Complex (TSC), a genetic disorder that causes tumors to form in many different organs. TSC is a risk factor for the development of LAM.
In this study, the test was used to analyze the amount of a specific protein - vascular endothelial growth factor-D, or VEGF-D - in patients' blood. VEGF-D promotes the growth of lymphatic vessels and blood vessels and can be involved in the spread of cancer.
Researchers performed VEGF-D testing in 195 women and found that serum VEGF-D levels were significantly greater in women with LAM than in women with other lung diseases or healthy individuals. When they prospectively evaluated the VEGF-D test performance in women prior to knowing their diagnosis, the test showed high accuracy for diagnosis of LAM.
"We concluded that a serum VEGF-D level of greater than 800 pg/mL (picograms, or one-trillionth of a gram, per milliliter) in women with typical cystic changes on a high-resolution computed tomography (CT) scan is diagnostically specific for sporadic LAM and identifies LAM in women with TSC," Young says. "However, negative VEGF-D results do not exclude the diagnosis of LAM."
Frank McCormack, MD, senior author and director of pulmonary, critical care and sleep medicine at UC, says that Serum VEGF-D measurement is currently performed as part of a research protocol but will soon be available for clinical application.
"This was a team effort by clinicians around the world to collect blood samples and clinical data from patients with very rare lung diseases," he says. "Through their efforts and the generosity of patients who participated, we are optimistic that serum VEGF-D will join the ranks of diagnostic tests for lung disease, reduce the need for surgical lung biopsy and allow for intervention and trial recruitment earlier in the disease course."
This study was funded by a pilot project grant from The LAM Foundation, The Tante Mela Foundation and a grant from the National Heart, Lung, and Blood Institute.
Source:
Katie Pence
University of Cincinnati Academic Health Center
воскресенье, 29 мая 2011 г.
Premature Newborns Lack 'Death NET' To Fight Sepsis
When locked in mortal combat with infection, some mature white blood cells have a formidable weapon: they literally cast a DNA net - called a neutrophil extracellular trap (NET) - that captures and kills bacteria that invade the human body. But the ability to form this "death" NET is missing in the white blood cells of newborn infants, born either at term or prematurely, and that, in part, may explain why millions of newborns worldwide are at higher risk for a potentially deadly blood infection, University of Utah medical researchers have discovered.
The finding, published online in the journal Blood, is important because it provides insight into defects in the body's defense against sepsis, a blood infection that poses a major risk for preterm and full-term babies and occurs in up to 25 percent of newborns in some areas of the world. "Neonatal neutrophil dysfunction - a term for these white blood cell abnormalities - affects many infants, because there are so many premature births across the globe," said Christian C. Yost, M.D., assistant professor of pediatrics and the study's lead author. "It's a huge public health issue."
The defect in NET formation also may contribute to other serious infections that plague neonates, such as pneumonia and meningitis, and its identification could generate leads to new drugs for treatment of severe infections in newborn infants.
White blood cells are one of the body's primary weapons to fight infection. When an infection arises, white blood cells called neutrophils are dispatched as part of the first line of defense. Neutrophils live only a few hours, and previously it was thought that when they die in combat with bacterial invaders their defensive mission was over. Recently, however, it was discovered that in the death throes of fighting infection, neutrophils from adults eject a mixture of nuclear material and antibacterial proteins that forms a NET-like structure that captures and kills bacteria even as the blood cell dies.
But that doesn't hold true for the neutrophils in newborn babies. Yost, a neonatal intensive care physician, and his colleagues collected small amounts of umbilical cord blood from 16 premature babies born at Primary Children's Medical Center in Salt Lake City. He found that the infants' neutrophils didn't eject the nuclear mixture and, subsequently, couldn't form the death NET to kill bacteria. "There was no evidence at all that infant neutrolphils make the NETs," Yost said. "Certainly, nuetrophils from premature babies don't make them."
Yost and the study's senior author, Guy A. Zimmerman, M.D., professor of internal medicine and director of the University's program in Human Molecular Biology and Genetics, suspect this may be an important reason why preterm and full-term newborns are at a higher risk for severe infections such as sepsis and have such fragile immune systems.
Zimmerman compares the neutrophils' death NETS to those used as weapons by gladiators in ancient Rome. "We don't know what causes the defect that prevents neutrophils in preterm babies from forming the NET," said Zimmerman. "That regulation process really is unknown."
He and Yost suspect the NET formation defect may stem from deficiency of one or more key factors in the regulatory mechanisms that govern the NET-generating process, and that these factors have not had time to develop in the neutrophils of newborn infants - particularly premature infants. Previously, a group of European investigators, who studied only adult neutrophils, published evidence that molecules called reactive oxygen species (ROS) trigger formation of NETs by these white blood cells. ROS are produced by neutrophils in response to stress and infection. Yost's experiments unequivocally demonstrated that ROS are not sufficient to alone induce NET formation by neonatal neutrophils, however, indicating that other essential regulatory molecules are lacking.
It's possible that defining which molecules are missing could lead to approaches to hasten their development or to replace them, according to Yost. "Since our discovery of deficient NET formation by neutrophils from premature babies, a list of at least three or four candidate molecules to test has emerged from ongoing studies," he said.
Because there is no "knockout" mouse model for neonatal neutrophil dysfunction, Yost had to conduct his research with the blood of human infants. This kind of work is a prime example of translational research, in which relevance to human disease is directly examined.
Preterm births typically defined as birth occurring at 37 weeks or earlier, have increased 20 percent in the United States since 1990, according to a recent Institute of Medicine report. Preterm births in Utah went up 24 percent from 1995 to 2005, the March of Dimes said last November in a report that gave the state and nation "D" grades in how they're addressing the problem of preterm births.
Source: Phil Sahm
University of Utah Health Sciences
The finding, published online in the journal Blood, is important because it provides insight into defects in the body's defense against sepsis, a blood infection that poses a major risk for preterm and full-term babies and occurs in up to 25 percent of newborns in some areas of the world. "Neonatal neutrophil dysfunction - a term for these white blood cell abnormalities - affects many infants, because there are so many premature births across the globe," said Christian C. Yost, M.D., assistant professor of pediatrics and the study's lead author. "It's a huge public health issue."
The defect in NET formation also may contribute to other serious infections that plague neonates, such as pneumonia and meningitis, and its identification could generate leads to new drugs for treatment of severe infections in newborn infants.
White blood cells are one of the body's primary weapons to fight infection. When an infection arises, white blood cells called neutrophils are dispatched as part of the first line of defense. Neutrophils live only a few hours, and previously it was thought that when they die in combat with bacterial invaders their defensive mission was over. Recently, however, it was discovered that in the death throes of fighting infection, neutrophils from adults eject a mixture of nuclear material and antibacterial proteins that forms a NET-like structure that captures and kills bacteria even as the blood cell dies.
But that doesn't hold true for the neutrophils in newborn babies. Yost, a neonatal intensive care physician, and his colleagues collected small amounts of umbilical cord blood from 16 premature babies born at Primary Children's Medical Center in Salt Lake City. He found that the infants' neutrophils didn't eject the nuclear mixture and, subsequently, couldn't form the death NET to kill bacteria. "There was no evidence at all that infant neutrolphils make the NETs," Yost said. "Certainly, nuetrophils from premature babies don't make them."
Yost and the study's senior author, Guy A. Zimmerman, M.D., professor of internal medicine and director of the University's program in Human Molecular Biology and Genetics, suspect this may be an important reason why preterm and full-term newborns are at a higher risk for severe infections such as sepsis and have such fragile immune systems.
Zimmerman compares the neutrophils' death NETS to those used as weapons by gladiators in ancient Rome. "We don't know what causes the defect that prevents neutrophils in preterm babies from forming the NET," said Zimmerman. "That regulation process really is unknown."
He and Yost suspect the NET formation defect may stem from deficiency of one or more key factors in the regulatory mechanisms that govern the NET-generating process, and that these factors have not had time to develop in the neutrophils of newborn infants - particularly premature infants. Previously, a group of European investigators, who studied only adult neutrophils, published evidence that molecules called reactive oxygen species (ROS) trigger formation of NETs by these white blood cells. ROS are produced by neutrophils in response to stress and infection. Yost's experiments unequivocally demonstrated that ROS are not sufficient to alone induce NET formation by neonatal neutrophils, however, indicating that other essential regulatory molecules are lacking.
It's possible that defining which molecules are missing could lead to approaches to hasten their development or to replace them, according to Yost. "Since our discovery of deficient NET formation by neutrophils from premature babies, a list of at least three or four candidate molecules to test has emerged from ongoing studies," he said.
Because there is no "knockout" mouse model for neonatal neutrophil dysfunction, Yost had to conduct his research with the blood of human infants. This kind of work is a prime example of translational research, in which relevance to human disease is directly examined.
Preterm births typically defined as birth occurring at 37 weeks or earlier, have increased 20 percent in the United States since 1990, according to a recent Institute of Medicine report. Preterm births in Utah went up 24 percent from 1995 to 2005, the March of Dimes said last November in a report that gave the state and nation "D" grades in how they're addressing the problem of preterm births.
Source: Phil Sahm
University of Utah Health Sciences
суббота, 28 мая 2011 г.
Novel Orally-Active Kinase Inhibitor Induces Tumor Regression In Multiple Preclinical Models
EntreMed, Inc.
(Nasdaq: ENMD), a clinical-stage pharmaceutical company developing
therapeutics for the treatment of cancer and inflammatory diseases,
announced the presentation of preclinical results for its multi-target
kinase inhibitor, ENMD-981693. The data were presented by EntreMed
scientists at the 48th Annual Meeting of the American Society of Hematology
(ASH) being held December 9-12, 2006 in Orlando, Florida.
ENMD-981693 is a multi-target kinase inhibitor with a unique
selectivity profile and multiple mechanisms of action, including
antiproliferative activity and the inhibition of angiogenesis. In
preclinical studies, ENMD- 981693 has been shown to inhibit a unique
profile of tyrosine kinase targets, in addition to the Aurora kinases.
ENMD-981693 is selective for Aurora A in comparison to Aurora B. Aurora
kinases are key regulators of the process of mitosis or cell division, and
are often over-expressed in human cancers.
ENMD-981693 has shown highly potent activity against oncogenic receptor
tyrosine kinases and cytoplasmic tyrosine kinases in vitro. ENMD-981693
induces cell cycle arrest and apoptosis in a wide variety of cell lines.
ENMD-981693 inhibits the activity of multiple kinases in vitro, including
FLT3, c-Kit and CSF1R, which are involved in hematological cancers.
Additionally, the compound demonstrated potent activity towards a broad
spectrum of targets linked to angiogenesis and lymphangiogenesis (lymphatic
vessels), including KDR (VEGFR2).
In results from in vivo animal models, ENMD-981693 exhibited anti-
angiogenic activity by preventing the formation of new blood vessels and
inducing regression of formed vessels at well-tolerated doses. ENMD-981693
induced strong tumor regression with minimal toxic effects when
administered orally in animal models bearing tumors from a human leukemia
cell line. This activity is consistent with tumor regression induced by
ENMD-981693 in animal models of human tumors derived from leukemia, colon,
and breast cancer cell lines with minimal toxicity.
Carolyn F. Sidor, M.D., M.B.A, EntreMed Vice President and Chief
Medical Officer, commented, "ENMD-981693 is a novel, orally-active,
multi-kinase inhibitor with potent antiproliferative and antiangiogenic
activity. In addition, ENMD-981693 has been shown to induce tumor
regression at well- tolerated doses in multiple animal models. These data
supported the selection of ENMD-981693 as a clinical development candidate
in our kinase inhibitor program."
Dr. Sidor commented further, "Based on the potent preclinical activity
of this compound and its ability to target multiple kinases, we believe
that ENMD-981693 may be suitable for use in a variety of hematological and
solid cancers. We are currently conducting IND-enabling studies for this
compound in anticipation of filing an IND in 2007."
To view the poster presentation, visit Scientific Presentations under
the Therapeutic Pathways section of the Company's web site at entremed/.
About EntreMed
EntreMed, Inc. (Nasdaq: ENMD) is a clinical-stage pharmaceutical
company developing therapeutic candidates primarily for the treatment of
cancer and inflammation. Panzem(R) (2-methoxyestradiol or 2ME2), the
Company's lead drug candidate, is currently in Phase 1 and 2 clinical
trials for cancer, as well as in preclinical development for rheumatoid
arthritis. MKC-1, an oral cell cycle regulator, is in Phase 1 and 2
clinical trials for cancer. ENMD-1198, a novel tubulin binding agent, is
also in Phase 1 studies in advanced cancers. EntreMed's goal is to develop
and commercialize new compounds based on the Company's expertise in
angiogenesis, cell cycle regulation, signaling pathways, and inflammation -
processes vital to the treatment of cancer and other diseases, such as
rheumatoid arthritis. Additional information about EntreMed is available on
the Company's website at entremed/ and in various filings
with the Securities and Exchange Commission.
Forward Looking Statements
This release contains forward-looking statements within the meaning of
the Private Securities Litigation Reform Act with respect to the outlook
for expectations for future financial or business performance (including
the timing of royalty revenues and future R&D expenditures), strategies,
expectations and goals. Forward-looking statements are subject to numerous
assumptions, risks and uncertainties, which change over time.
Forward-looking statements speak only as of the date they are made, and no
duty to update forward-looking statements is assumed. Actual results could
differ materially from those currently anticipated due to a number of
factors, including those set forth in Securities and Exchange Commission
filings under "Risk Factors," including risks relating to the need for
additional capital and the uncertainty of additional funding; variations in
actual sales of Thalomid(R), risks associated with development of product
candidates; the early-stage products under development; results in
preclinical models are not necessarily indicative of clinical results;
uncertainties relating to preclinical and clinical trials; success in the
clinical development of any products; dependence on third parties; future
capital needs; and risks relating to the commercialization, if any, of the
Company's proposed products (such as marketing, safety, regulatory, patent,
product liability, supply, competition and other risks).
EntreMed, Inc.
entremed/
(Nasdaq: ENMD), a clinical-stage pharmaceutical company developing
therapeutics for the treatment of cancer and inflammatory diseases,
announced the presentation of preclinical results for its multi-target
kinase inhibitor, ENMD-981693. The data were presented by EntreMed
scientists at the 48th Annual Meeting of the American Society of Hematology
(ASH) being held December 9-12, 2006 in Orlando, Florida.
ENMD-981693 is a multi-target kinase inhibitor with a unique
selectivity profile and multiple mechanisms of action, including
antiproliferative activity and the inhibition of angiogenesis. In
preclinical studies, ENMD- 981693 has been shown to inhibit a unique
profile of tyrosine kinase targets, in addition to the Aurora kinases.
ENMD-981693 is selective for Aurora A in comparison to Aurora B. Aurora
kinases are key regulators of the process of mitosis or cell division, and
are often over-expressed in human cancers.
ENMD-981693 has shown highly potent activity against oncogenic receptor
tyrosine kinases and cytoplasmic tyrosine kinases in vitro. ENMD-981693
induces cell cycle arrest and apoptosis in a wide variety of cell lines.
ENMD-981693 inhibits the activity of multiple kinases in vitro, including
FLT3, c-Kit and CSF1R, which are involved in hematological cancers.
Additionally, the compound demonstrated potent activity towards a broad
spectrum of targets linked to angiogenesis and lymphangiogenesis (lymphatic
vessels), including KDR (VEGFR2).
In results from in vivo animal models, ENMD-981693 exhibited anti-
angiogenic activity by preventing the formation of new blood vessels and
inducing regression of formed vessels at well-tolerated doses. ENMD-981693
induced strong tumor regression with minimal toxic effects when
administered orally in animal models bearing tumors from a human leukemia
cell line. This activity is consistent with tumor regression induced by
ENMD-981693 in animal models of human tumors derived from leukemia, colon,
and breast cancer cell lines with minimal toxicity.
Carolyn F. Sidor, M.D., M.B.A, EntreMed Vice President and Chief
Medical Officer, commented, "ENMD-981693 is a novel, orally-active,
multi-kinase inhibitor with potent antiproliferative and antiangiogenic
activity. In addition, ENMD-981693 has been shown to induce tumor
regression at well- tolerated doses in multiple animal models. These data
supported the selection of ENMD-981693 as a clinical development candidate
in our kinase inhibitor program."
Dr. Sidor commented further, "Based on the potent preclinical activity
of this compound and its ability to target multiple kinases, we believe
that ENMD-981693 may be suitable for use in a variety of hematological and
solid cancers. We are currently conducting IND-enabling studies for this
compound in anticipation of filing an IND in 2007."
To view the poster presentation, visit Scientific Presentations under
the Therapeutic Pathways section of the Company's web site at entremed/.
About EntreMed
EntreMed, Inc. (Nasdaq: ENMD) is a clinical-stage pharmaceutical
company developing therapeutic candidates primarily for the treatment of
cancer and inflammation. Panzem(R) (2-methoxyestradiol or 2ME2), the
Company's lead drug candidate, is currently in Phase 1 and 2 clinical
trials for cancer, as well as in preclinical development for rheumatoid
arthritis. MKC-1, an oral cell cycle regulator, is in Phase 1 and 2
clinical trials for cancer. ENMD-1198, a novel tubulin binding agent, is
also in Phase 1 studies in advanced cancers. EntreMed's goal is to develop
and commercialize new compounds based on the Company's expertise in
angiogenesis, cell cycle regulation, signaling pathways, and inflammation -
processes vital to the treatment of cancer and other diseases, such as
rheumatoid arthritis. Additional information about EntreMed is available on
the Company's website at entremed/ and in various filings
with the Securities and Exchange Commission.
Forward Looking Statements
This release contains forward-looking statements within the meaning of
the Private Securities Litigation Reform Act with respect to the outlook
for expectations for future financial or business performance (including
the timing of royalty revenues and future R&D expenditures), strategies,
expectations and goals. Forward-looking statements are subject to numerous
assumptions, risks and uncertainties, which change over time.
Forward-looking statements speak only as of the date they are made, and no
duty to update forward-looking statements is assumed. Actual results could
differ materially from those currently anticipated due to a number of
factors, including those set forth in Securities and Exchange Commission
filings under "Risk Factors," including risks relating to the need for
additional capital and the uncertainty of additional funding; variations in
actual sales of Thalomid(R), risks associated with development of product
candidates; the early-stage products under development; results in
preclinical models are not necessarily indicative of clinical results;
uncertainties relating to preclinical and clinical trials; success in the
clinical development of any products; dependence on third parties; future
capital needs; and risks relating to the commercialization, if any, of the
Company's proposed products (such as marketing, safety, regulatory, patent,
product liability, supply, competition and other risks).
EntreMed, Inc.
entremed/
пятница, 27 мая 2011 г.
New Assessment Quantifies Risks And Benefits Of Warfarin Treatment For Atrial Fibrillation
Warfarin therapy for patients with atrial fibrillation - the most common type of significant heart rhythm disorder - appears to be most beneficial for the oldest patients, those who have had a prior stroke and for patients with multiple risk factors for stroke, according to a new study by Kaiser Permanente and Massachusetts General Hospital researchers. This comparative effectiveness research study - among the first and largest to quantify warfarin's net clinical benefit, how much a treatment's potential benefits outweigh its risks, in the usual clinical care of patients with atrial fibrillation - appears in the September 1 Annals of Internal Medicine.
As part of the ongoing ATRIA (AnTicoagulation and Risk Factors In Atrial Fribrillation) study, researchers followed 13,559 adults with atrial fibrillation treated within Kaiser Permanente of Northern California from 1996 to 2003. To evaluate the risks and benefits of warfarin treatment and give patients and physicians quantitative guidance in making therapeutic decisions, the researchers analyzed rates of the two most significant adverse events associated with warfarin therapy - ischemic stroke, the type produced by arterial blockage, and intracranial hemorrhage, bleeding within and around the brain. For patients who did and did not take warfarin, the investigators balanced the reduction in ischemic stroke attributable to treatment against the increase in intracranial bleeding associated with warfarin. Since intracranial hemorrhages usually have worse outcomes than ischemic strokes, bleeding events were given greater weight in the comparison.
While warfarin therapy benefited most atrial fibrillation patients, the balance of benefits over risks was greatest in those at highest risk of stroke - those with multiple risk factors, those with a history of stroke and the oldest patients. The benefits of treatment increased strikingly with age, with no clear benefit in the average patient younger than 65 but a reduction of more than two strokes per 100 patients in those 85 and older.
Occurring when the upper chambers of the heart quiver instead of smoothly contracting, atrial fibrillation affects more than 2.3 million Americans. Because the heart rhythm disturbance promotes the formation of blood clots that can travel to the brain and block an artery, atrial fibrillation increases the risk of stroke fivefold. The condition is highly age-dependent and affects 10 percent of those over age 80. Researchers have long known that warfarin is effective in preventing such strokes, but the treatment can be difficult to control and often leads to hemorrhage. In fact, warfarin is associated with the most emergency admissions for drug-related adverse reactions. Balancing the benefits of warfarin against its most severe risks is critical to making the best therapeutic decisions for individual atrial fibrillation patients, explains the study's senior author Alan S. Go, MD, director of the Comprehensive Clinical Research Unit at the Kaiser Permanente Division of Research.
Daniel Singer, MD, of the Massachusetts General Hospital (MGH) Clinical Epidemiology Unit, the report's lead author, adds, "This comparative effectiveness study gives us more information about which atrial fibrillation patients are most likely to benefit from carefully administered warfarin therapy." He explains that, by assessing warfarin within a "real world" practice setting, the study provides a more contemporary assessment of the therapy's overall effects than do older clinical studies.
Go explains that Kaiser Permanente physicians partner with pharmacist-run anticoagulation clinics to provide thorough and nimble administration and careful monitoring of warfarin therapy for atrial fibrillation patients. This allows for delivery of high-quality anticoagulation therapy through frequent testing and appropriate dose adjustment to account for changes in diet, medications and clinical status that may impact the therapy's narrow therapeutic window.
Singer adds, "One of our distinctive findings is that stroke risk continues to increase in patients age 85 and older and that warfarin provides substantial net protection for these elderly patients. A caution is that all these patients were presumably judged by their physicians to be reasonable candidates for warfarin therapy, so these results do not automatically apply to all elderly atrial fibrillation patients."
Additional researchers on the study are Yuchiao Chang, PhD, and Leila H. Borowsky, MPH, MGH Clinical Epidemiology; Margaret C. Fang, MD, MPH, University of California at San Francisco; and Niela K. Pomernacki, RD, and Natalia Udaltsova, PhD, Kaiser Permanente Division of Research. Funding for the study was provided by the National Institute on Aging, the National Heart, Lung and Blood Institute, and the Eliot B. and Edith C. Shoolman fund of the MGH.
Source:
Sue McGreevey
Massachusetts General Hospital
View drug information on Warfarin Sodium tablets.
As part of the ongoing ATRIA (AnTicoagulation and Risk Factors In Atrial Fribrillation) study, researchers followed 13,559 adults with atrial fibrillation treated within Kaiser Permanente of Northern California from 1996 to 2003. To evaluate the risks and benefits of warfarin treatment and give patients and physicians quantitative guidance in making therapeutic decisions, the researchers analyzed rates of the two most significant adverse events associated with warfarin therapy - ischemic stroke, the type produced by arterial blockage, and intracranial hemorrhage, bleeding within and around the brain. For patients who did and did not take warfarin, the investigators balanced the reduction in ischemic stroke attributable to treatment against the increase in intracranial bleeding associated with warfarin. Since intracranial hemorrhages usually have worse outcomes than ischemic strokes, bleeding events were given greater weight in the comparison.
While warfarin therapy benefited most atrial fibrillation patients, the balance of benefits over risks was greatest in those at highest risk of stroke - those with multiple risk factors, those with a history of stroke and the oldest patients. The benefits of treatment increased strikingly with age, with no clear benefit in the average patient younger than 65 but a reduction of more than two strokes per 100 patients in those 85 and older.
Occurring when the upper chambers of the heart quiver instead of smoothly contracting, atrial fibrillation affects more than 2.3 million Americans. Because the heart rhythm disturbance promotes the formation of blood clots that can travel to the brain and block an artery, atrial fibrillation increases the risk of stroke fivefold. The condition is highly age-dependent and affects 10 percent of those over age 80. Researchers have long known that warfarin is effective in preventing such strokes, but the treatment can be difficult to control and often leads to hemorrhage. In fact, warfarin is associated with the most emergency admissions for drug-related adverse reactions. Balancing the benefits of warfarin against its most severe risks is critical to making the best therapeutic decisions for individual atrial fibrillation patients, explains the study's senior author Alan S. Go, MD, director of the Comprehensive Clinical Research Unit at the Kaiser Permanente Division of Research.
Daniel Singer, MD, of the Massachusetts General Hospital (MGH) Clinical Epidemiology Unit, the report's lead author, adds, "This comparative effectiveness study gives us more information about which atrial fibrillation patients are most likely to benefit from carefully administered warfarin therapy." He explains that, by assessing warfarin within a "real world" practice setting, the study provides a more contemporary assessment of the therapy's overall effects than do older clinical studies.
Go explains that Kaiser Permanente physicians partner with pharmacist-run anticoagulation clinics to provide thorough and nimble administration and careful monitoring of warfarin therapy for atrial fibrillation patients. This allows for delivery of high-quality anticoagulation therapy through frequent testing and appropriate dose adjustment to account for changes in diet, medications and clinical status that may impact the therapy's narrow therapeutic window.
Singer adds, "One of our distinctive findings is that stroke risk continues to increase in patients age 85 and older and that warfarin provides substantial net protection for these elderly patients. A caution is that all these patients were presumably judged by their physicians to be reasonable candidates for warfarin therapy, so these results do not automatically apply to all elderly atrial fibrillation patients."
Additional researchers on the study are Yuchiao Chang, PhD, and Leila H. Borowsky, MPH, MGH Clinical Epidemiology; Margaret C. Fang, MD, MPH, University of California at San Francisco; and Niela K. Pomernacki, RD, and Natalia Udaltsova, PhD, Kaiser Permanente Division of Research. Funding for the study was provided by the National Institute on Aging, the National Heart, Lung and Blood Institute, and the Eliot B. and Edith C. Shoolman fund of the MGH.
Source:
Sue McGreevey
Massachusetts General Hospital
View drug information on Warfarin Sodium tablets.
четверг, 26 мая 2011 г.
Hematologists Can Now Earn CME Credits Through The Journal Blood
The American Society of Hematology (ASH) now offers physicians who diagnose and treat blood disorders a new resource for earning continuing medical education (CME) credits while staying abreast of the latest clinical strategies in the rapidly changing field of hematology. Through a partnership with Medscape, an online network of medical content for physicians and other health professionals, hematologists can earn CME credits by testing their comprehension of articles published in ASH's widely-cited biomedical journal Blood.
The first Blood article to offer CME credit will be included in the January 28 issue, both in print and online. Blood is published weekly, and one CME article will appear in the journal in the fourth week of every month. By completing a set of study questions after reading the selected article, physicians will have a convenient and effective way of earning credits to maintain board certification, enhancing their knowledge on the subject matter, and improving the care they provide to patients.
Medscape is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians, and this activity will be administered by Medscape. A maximum of 0.25 AMA PRA Category 1 Credit™ can be earned through the January 28 article, and future articles may offer even more credit. There is no charge to participants to earn CME credits through this program.
The Blood journal is available on bloodjournal. To earn CME credit for selected Blood articles, physicians should visit cme.medscape/cme/blood. Other CME opportunities offered through ASH can be found at hematology/practice.
Source
American Society of Hematology
The first Blood article to offer CME credit will be included in the January 28 issue, both in print and online. Blood is published weekly, and one CME article will appear in the journal in the fourth week of every month. By completing a set of study questions after reading the selected article, physicians will have a convenient and effective way of earning credits to maintain board certification, enhancing their knowledge on the subject matter, and improving the care they provide to patients.
Medscape is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians, and this activity will be administered by Medscape. A maximum of 0.25 AMA PRA Category 1 Credit™ can be earned through the January 28 article, and future articles may offer even more credit. There is no charge to participants to earn CME credits through this program.
The Blood journal is available on bloodjournal. To earn CME credit for selected Blood articles, physicians should visit cme.medscape/cme/blood. Other CME opportunities offered through ASH can be found at hematology/practice.
Source
American Society of Hematology
среда, 25 мая 2011 г.
Carbon Monoxide Prevents Clotting
Researchers led by Drs. James F. George and Anupam Agarwal at the University of Alabama at Birmingham have found that carbon monoxide (CO) can protect against arterial clotting. They report their data in the July 2009 issue of the American Journal of Pathology.
Carbon monoxide poisoning is extremely toxic; exposure prevents oxygen delivery to body tissues and is often fatal. However, inflamed or injured tissues upregulate heme oxygenase-1 (HO-1), a protein that both protects cells and produces CO, suggesting that low levels of CO may have protective effects.
To determine if HO-1 and CO can protect against arterial clotting, Chen et al examined clotting mechanisms in mice that received arterial transplants. Absence of HO-1 in these mice resulted in significant mortality due to arterial clotting; however, treatment with a CO-releasing molecule both decreased clotting and improved survival.
Drs. George, Agarwal, and colleagues conclude that HO-1/CO plays an "important role …[in] protection against vascular arterial thrombosis in murine aortic allotransplantation."
Chen B, Guo L, Fan C, Bolisetty S, Joseph R, Wright MM, Agarwal A, George JF: Carbon Monoxide Rescues Heme Oxygenase-1-deficient Mice from Arterial Thrombosis in Allogeneic Aortic Transplantation. Am J Pathol 2009, 174: 2832-2839
Source:
Angela Colmone
American Journal of Pathology
Carbon monoxide poisoning is extremely toxic; exposure prevents oxygen delivery to body tissues and is often fatal. However, inflamed or injured tissues upregulate heme oxygenase-1 (HO-1), a protein that both protects cells and produces CO, suggesting that low levels of CO may have protective effects.
To determine if HO-1 and CO can protect against arterial clotting, Chen et al examined clotting mechanisms in mice that received arterial transplants. Absence of HO-1 in these mice resulted in significant mortality due to arterial clotting; however, treatment with a CO-releasing molecule both decreased clotting and improved survival.
Drs. George, Agarwal, and colleagues conclude that HO-1/CO plays an "important role …[in] protection against vascular arterial thrombosis in murine aortic allotransplantation."
Chen B, Guo L, Fan C, Bolisetty S, Joseph R, Wright MM, Agarwal A, George JF: Carbon Monoxide Rescues Heme Oxygenase-1-deficient Mice from Arterial Thrombosis in Allogeneic Aortic Transplantation. Am J Pathol 2009, 174: 2832-2839
Source:
Angela Colmone
American Journal of Pathology
вторник, 24 мая 2011 г.
Verax Biomedical Receives 510 (k) Clearance From FDA For Platelet PGD Test
Verax Biomedical Inc., a
leading developer of rapid tests for detecting bacterial contaminants in
blood cells and tissue, has received 510 (k) clearance for its Platelet PGD
Test System from the U.S. Food and Drug Administration (FDA). This provides
Verax authorization to market the device, which cuts the detection time for
bacterial contamination in leukocyte reduced apheresis platelets to
approximately 30 minutes.
The clearance comes on the heels of the execution of key agreements
with Abbott Diagnostics to serve as distributor and British Biocell
International to serve as manufacturer of the product. The data from US
clinical studies that served as the basis of the Company's 510 (k) filing
will be featured in 7 poster presentations at the upcoming Annual Meeting
of the American Association of Blood Banks (AABB) in Anaheim, California
October 20th - 23rd.
To combat the risk of bacterial contamination, the AABB requires all of
its members to detect and limit contamination in platelets. Recent articles
published in Transfusion, the journal of the AABB, indicate that current
culture testing methods fail to detect half of the contaminated units in
the U.S. inventory and false negative results associated with this testing
have resulted in 26 documented septic transfusion reactions including 5
fatalities since testing began in 2004. The Platelet PGD test is designed
to allow testing after platelets have entered the inventory and offers
clinicians the opportunity to detect contaminated units that slip past
current testing methodologies.
"We are thrilled to achieve this critical milestone," said Jim
Lousararian, chief executive officer of Verax Biomedical. "The increasing
recognition of culture false negative results associated with current
platelet testing clearly illustrates the need for a rapid test like
Platelet PGD. With our ability to enable testing later in platelet unit
life, after bacteria have had a chance to grow, blood bankers will have
access to a critical new tool in the battle against bacterial
contamination."
The Platelet PGD Test is an easy-to-use, disposable device designed to
detect the presence of a broad range of bacterial contaminants in platelets
at a later phase in platelet unit life than current culture methods.
Bacterial contamination in platelets and red blood cells represents the
single greatest risk for lethal infections in transfusion medicine today.
An estimated 10 million platelet units are transfused each year into
patients in North America, Europe and Asia, and experts estimate that as
many as 1 in every 2,000 units are contaminated with bacteria.
The Verax PGD Test is based on Verax Biomedical's proprietary Pan
Genera(R) Detection technology, which targets common antigens found on the
surface of all species of bacteria known to be pathogenic to humans.
About Verax Biomedical, Inc.
Based in Worcester, Mass., Verax Biomedical is a leader in the
development of rapid tests designed to detect a broad range of bacterial
contaminants based upon its proprietary Pan Genera Detection (PGD)
technology. The first target application for its technology is to test for
the presence of bacterial contaminants in the blood supply. Bacterial
contaminants in platelets and red blood cells represent the greatest lethal
infectious risks in transfusion medicine today, and no rapid, simple
methods are presently available to effectively address this threat. Each
year an estimated 17 million patients receive more than 60 million units of
these individual blood components in North America, Europe and Asia.
Verax Biomedical Inc.
rdwgroup
leading developer of rapid tests for detecting bacterial contaminants in
blood cells and tissue, has received 510 (k) clearance for its Platelet PGD
Test System from the U.S. Food and Drug Administration (FDA). This provides
Verax authorization to market the device, which cuts the detection time for
bacterial contamination in leukocyte reduced apheresis platelets to
approximately 30 minutes.
The clearance comes on the heels of the execution of key agreements
with Abbott Diagnostics to serve as distributor and British Biocell
International to serve as manufacturer of the product. The data from US
clinical studies that served as the basis of the Company's 510 (k) filing
will be featured in 7 poster presentations at the upcoming Annual Meeting
of the American Association of Blood Banks (AABB) in Anaheim, California
October 20th - 23rd.
To combat the risk of bacterial contamination, the AABB requires all of
its members to detect and limit contamination in platelets. Recent articles
published in Transfusion, the journal of the AABB, indicate that current
culture testing methods fail to detect half of the contaminated units in
the U.S. inventory and false negative results associated with this testing
have resulted in 26 documented septic transfusion reactions including 5
fatalities since testing began in 2004. The Platelet PGD test is designed
to allow testing after platelets have entered the inventory and offers
clinicians the opportunity to detect contaminated units that slip past
current testing methodologies.
"We are thrilled to achieve this critical milestone," said Jim
Lousararian, chief executive officer of Verax Biomedical. "The increasing
recognition of culture false negative results associated with current
platelet testing clearly illustrates the need for a rapid test like
Platelet PGD. With our ability to enable testing later in platelet unit
life, after bacteria have had a chance to grow, blood bankers will have
access to a critical new tool in the battle against bacterial
contamination."
The Platelet PGD Test is an easy-to-use, disposable device designed to
detect the presence of a broad range of bacterial contaminants in platelets
at a later phase in platelet unit life than current culture methods.
Bacterial contamination in platelets and red blood cells represents the
single greatest risk for lethal infections in transfusion medicine today.
An estimated 10 million platelet units are transfused each year into
patients in North America, Europe and Asia, and experts estimate that as
many as 1 in every 2,000 units are contaminated with bacteria.
The Verax PGD Test is based on Verax Biomedical's proprietary Pan
Genera(R) Detection technology, which targets common antigens found on the
surface of all species of bacteria known to be pathogenic to humans.
About Verax Biomedical, Inc.
Based in Worcester, Mass., Verax Biomedical is a leader in the
development of rapid tests designed to detect a broad range of bacterial
contaminants based upon its proprietary Pan Genera Detection (PGD)
technology. The first target application for its technology is to test for
the presence of bacterial contaminants in the blood supply. Bacterial
contaminants in platelets and red blood cells represent the greatest lethal
infectious risks in transfusion medicine today, and no rapid, simple
methods are presently available to effectively address this threat. Each
year an estimated 17 million patients receive more than 60 million units of
these individual blood components in North America, Europe and Asia.
Verax Biomedical Inc.
rdwgroup
понедельник, 23 мая 2011 г.
Drug Linked To Increase In Brain Hemorrhage Cases
The rate of brain hemorrhages associated with blood thinning drugs quintupled during the 1990s, according to a study published in the January 9, 2007, issue of Neurology, the scientific journal of the American Academy of Neurology. In people over age 80, the rate increased more than tenfold.
Most of the increase is due to greater use of the drug warfarin, which is commonly prescribed to prevent blood clotting. Blood clots can lead to ischemic stroke, the most common type of stroke. An intracerebral brain hemorrhage is a stroke caused by bleeding in the brain.
The use of warfarin increased after studies showed it reduced the risk of stroke caused by blood clots for people with atrial fibrillation, a condition that causes irregular heart rhythm and becomes more common as people age.
"Warfarin is highly effective in preventing ischemic stroke among people with atrial fibrillation," said study author Matthew L. Flaherty, MD, of the University of Cincinnati. "For many people, the benefits of preventing ischemic stroke continue to outweigh the risk of a hemorrhagic stroke.
"Our findings should not discourage the use of warfarin when it's appropriate. Doctors can use these findings to make sure they are weighing the risks and benefits of warfarin use for their patients. For researchers, these results may stimulate efforts to develop safer alternatives to warfarin and better treatments for people with brain hemorrhages."
For the study, researchers identified all patients in the greater Cincinnati area hospitalized with a first-time intracerebral hemorrhage during three years: 1988, 1993-94, and 1999. In 1988, the annual rate of intracerebral hemorrhages associated with use of blood thinning drugs was .8 cases per 100,000 people. In 1999, the rate was 4.4 cases per 100,000 people. For people age 80 and older, the rate increased from 2.5 in 1988 to 45.9 in 1999.
The study was supported in part by the National Institute of Neurological Disorders and Stroke.
The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer's disease, epilepsy, Parkinson disease, and multiple sclerosis. For more information about the American Academy of Neurology, visit aan.
American Academy of Neurology (AAN)
1080 Montreal Ave.
St. Paul, MN 55116
United States
aan/professionals/
View drug information on Warfarin Sodium tablets.
Most of the increase is due to greater use of the drug warfarin, which is commonly prescribed to prevent blood clotting. Blood clots can lead to ischemic stroke, the most common type of stroke. An intracerebral brain hemorrhage is a stroke caused by bleeding in the brain.
The use of warfarin increased after studies showed it reduced the risk of stroke caused by blood clots for people with atrial fibrillation, a condition that causes irregular heart rhythm and becomes more common as people age.
"Warfarin is highly effective in preventing ischemic stroke among people with atrial fibrillation," said study author Matthew L. Flaherty, MD, of the University of Cincinnati. "For many people, the benefits of preventing ischemic stroke continue to outweigh the risk of a hemorrhagic stroke.
"Our findings should not discourage the use of warfarin when it's appropriate. Doctors can use these findings to make sure they are weighing the risks and benefits of warfarin use for their patients. For researchers, these results may stimulate efforts to develop safer alternatives to warfarin and better treatments for people with brain hemorrhages."
For the study, researchers identified all patients in the greater Cincinnati area hospitalized with a first-time intracerebral hemorrhage during three years: 1988, 1993-94, and 1999. In 1988, the annual rate of intracerebral hemorrhages associated with use of blood thinning drugs was .8 cases per 100,000 people. In 1999, the rate was 4.4 cases per 100,000 people. For people age 80 and older, the rate increased from 2.5 in 1988 to 45.9 in 1999.
The study was supported in part by the National Institute of Neurological Disorders and Stroke.
The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer's disease, epilepsy, Parkinson disease, and multiple sclerosis. For more information about the American Academy of Neurology, visit aan.
American Academy of Neurology (AAN)
1080 Montreal Ave.
St. Paul, MN 55116
United States
aan/professionals/
View drug information on Warfarin Sodium tablets.
воскресенье, 22 мая 2011 г.
Some Blood Glucose Meters Can Lead To Excessive Insulin Use, FDA
Blood glucose meters that use GDH-PQQ (glucose dehydrogenase pyrroloquinoline quinone) test strips can produce false results that lead to
excessive use of insulin in patients receiving treatments containing certain non-glucose sugars, said the US Food and Drug Administration (FDA) last
Friday.
If these non-glucose sugars are in a sample of patients' blood that is tested using a GDH-PQQ glucose test strip it could prompt inappropriate clinical
action such as giving patients too much insulin, "potentially resulting in hypoglycemia, coma, or death", said the FDA in a Public Health
Notification.
There is also the added risk that cases of actual hypoglycemia (lower than normal blood glucose) may go unnoticed if patients and their carers rely
soley on results produced with devices that use GDH-PQQ glucose test strips, said the FDA.
The FDA Notification and accompanying Advice for Patients also lists the manufacturers and brands of GDH-PQQ glucose test strips.
The problem arises because it has come to light that GDH-PQQ also reacts with the non-glucose sugars that are present in some therapeutic products
and this leads to a falsely high test results.
The non-glucose sugars that GDH-PQQ also reacts with are maltose, galactose and xylose, and these are present in products such as peritoneal dialysis
solutions and certain immunoglobulins.
Patients who use these products often have very serious conditions like kidney failure and moderate to severe rheumatoid arthritis.
When blood glucose meters containing GDH-PQQ test strips are used to calculate glucose levels in patients receiving these therapies they will get a
reading that is much higher than it should be and this could lead to them using too much insulin.
Most blood glucose meters based on GDH-PQQ test strips are used in health care facilities, said the FDA, whose advice is that they should switch to laboratory assay methods
to measure glucose in patients who are also receiving an interfering product.
The Public Health Notification also lists recommendations on how to minimize the risk of potential shortages until more non-GDH-PQQ strips and
meters are available.
-- FDA Public Health Notification
-- info on
blood sugar management (dLife)
Source: FDA, dLife.
Written by: Catharine Paddock, PhD
excessive use of insulin in patients receiving treatments containing certain non-glucose sugars, said the US Food and Drug Administration (FDA) last
Friday.
If these non-glucose sugars are in a sample of patients' blood that is tested using a GDH-PQQ glucose test strip it could prompt inappropriate clinical
action such as giving patients too much insulin, "potentially resulting in hypoglycemia, coma, or death", said the FDA in a Public Health
Notification.
There is also the added risk that cases of actual hypoglycemia (lower than normal blood glucose) may go unnoticed if patients and their carers rely
soley on results produced with devices that use GDH-PQQ glucose test strips, said the FDA.
The FDA Notification and accompanying Advice for Patients also lists the manufacturers and brands of GDH-PQQ glucose test strips.
The problem arises because it has come to light that GDH-PQQ also reacts with the non-glucose sugars that are present in some therapeutic products
and this leads to a falsely high test results.
The non-glucose sugars that GDH-PQQ also reacts with are maltose, galactose and xylose, and these are present in products such as peritoneal dialysis
solutions and certain immunoglobulins.
Patients who use these products often have very serious conditions like kidney failure and moderate to severe rheumatoid arthritis.
When blood glucose meters containing GDH-PQQ test strips are used to calculate glucose levels in patients receiving these therapies they will get a
reading that is much higher than it should be and this could lead to them using too much insulin.
Most blood glucose meters based on GDH-PQQ test strips are used in health care facilities, said the FDA, whose advice is that they should switch to laboratory assay methods
to measure glucose in patients who are also receiving an interfering product.
The Public Health Notification also lists recommendations on how to minimize the risk of potential shortages until more non-GDH-PQQ strips and
meters are available.
-- FDA Public Health Notification
-- info on
blood sugar management (dLife)
Source: FDA, dLife.
Written by: Catharine Paddock, PhD
суббота, 21 мая 2011 г.
New Blood Thinning Drugs Pose Risk Of Adverse Drug Interactions
Three new oral blood-thinning drugs nearing approval by the Food and Drug Administration are more convenient than the standard drug Coumadin® because they do not require monthly visits to adjust doses.
But the promising drugs also could be subject to dangerous interactions when taken alongside widely used prescription drugs, over-the-counter medicines such as aspirin and even herbal supplements such as St. John's Wort, according to a Loyola University Health System study.
"Many unknowns remain as to how the new anticoagulants will behave in the real world patient population," researchers conclude in a review article in the June issue of the International Journal of Clinical Practice.
While the new drugs offer "significant potential advantages," their lack of extensive clinical experience "should not be underestimated," researchers wrote.
Lead author is blood clot specialist Jeanine Walenga, PhD, a professor in the Cardiovascular Institute and departments of Thoracic and Cardiovascular Surgery and Pathology at Loyola University Chicago Stritch School of Medicine. Co-author is Cafer Adiguzel, MD, who completed a fellowship at Loyola.
Coumadin reduces the risk of life-threatening blood clots in patients who have chronic conditions such as irregular heart rhythms or have undergone recent surgeries such as hip and knee replacements.
Coumadin (generic name, warfarin) must be carefully monitored. If the dose is too high, a patient could experience excessive bruising and be at higher risk for brain hemorrhages. If the dose is too low, the drug would be ineffective in preventing life-threatening blood clots. Patients typically must come in every month for a blood test to determine whether the dose needs to be adjusted.
The three new drugs do not need to be monitored every month, according to their manufacturers. They are rivaroxaban (Xarelto®), dabigatran etexilate (Pradaxa®) and apixaban. Rivaroxaban and dabigatran etexilate have been approved in Europe and apixaban is under development. Manufacturers of all three drugs have asked for or are expected to seek approval from the U.S. Food and Drug Administration.
Interactions with other drugs can make the new blood-thinning drugs either ineffective or too effective. For example, St. John's wort, typically taken for depression, can make the drugs less effective, while aspirin can make them more potent and thereby increase the risk of bleeding.
One study found that one-third of older adults use aspirin. A second study found that 29 percent of adults ages 57 to 85 take at least five prescription drugs.
"A high proportion of adults in the United States consume at least one of the drugs known to have some level of interaction with one of the new oral anticoagulants," the Loyola researchers write.
So far, most of what's known about potential drug interactions comes from animal studies or clinical trials that included relatively healthy patients who were carefully monitored. Less is known about elderly patients who have multiple health problems and might miss doses or take incorrect doses.
"The impact of any drug interaction will only become known with increasing clinical experience of these new oral anticoagulants," researchers wrote.
Source
Loyola University Health System
View drug information on Warfarin Sodium tablets.
But the promising drugs also could be subject to dangerous interactions when taken alongside widely used prescription drugs, over-the-counter medicines such as aspirin and even herbal supplements such as St. John's Wort, according to a Loyola University Health System study.
"Many unknowns remain as to how the new anticoagulants will behave in the real world patient population," researchers conclude in a review article in the June issue of the International Journal of Clinical Practice.
While the new drugs offer "significant potential advantages," their lack of extensive clinical experience "should not be underestimated," researchers wrote.
Lead author is blood clot specialist Jeanine Walenga, PhD, a professor in the Cardiovascular Institute and departments of Thoracic and Cardiovascular Surgery and Pathology at Loyola University Chicago Stritch School of Medicine. Co-author is Cafer Adiguzel, MD, who completed a fellowship at Loyola.
Coumadin reduces the risk of life-threatening blood clots in patients who have chronic conditions such as irregular heart rhythms or have undergone recent surgeries such as hip and knee replacements.
Coumadin (generic name, warfarin) must be carefully monitored. If the dose is too high, a patient could experience excessive bruising and be at higher risk for brain hemorrhages. If the dose is too low, the drug would be ineffective in preventing life-threatening blood clots. Patients typically must come in every month for a blood test to determine whether the dose needs to be adjusted.
The three new drugs do not need to be monitored every month, according to their manufacturers. They are rivaroxaban (Xarelto®), dabigatran etexilate (Pradaxa®) and apixaban. Rivaroxaban and dabigatran etexilate have been approved in Europe and apixaban is under development. Manufacturers of all three drugs have asked for or are expected to seek approval from the U.S. Food and Drug Administration.
Interactions with other drugs can make the new blood-thinning drugs either ineffective or too effective. For example, St. John's wort, typically taken for depression, can make the drugs less effective, while aspirin can make them more potent and thereby increase the risk of bleeding.
One study found that one-third of older adults use aspirin. A second study found that 29 percent of adults ages 57 to 85 take at least five prescription drugs.
"A high proportion of adults in the United States consume at least one of the drugs known to have some level of interaction with one of the new oral anticoagulants," the Loyola researchers write.
So far, most of what's known about potential drug interactions comes from animal studies or clinical trials that included relatively healthy patients who were carefully monitored. Less is known about elderly patients who have multiple health problems and might miss doses or take incorrect doses.
"The impact of any drug interaction will only become known with increasing clinical experience of these new oral anticoagulants," researchers wrote.
Source
Loyola University Health System
View drug information on Warfarin Sodium tablets.
пятница, 20 мая 2011 г.
Cord Blood Transplantation, Even Unrelated And Mismatched, Can Still Help Children With Deadly Conditions
An unrelated cord blood transplant, even from a mismatched donor, can be effective in treating children with a host of life-threatening diseases and disorders including cancer, sickle cell anemia, and other genetic diseases, according to researchers in the Duke Pediatric Blood and Marrow Transplantation Program. Unrelated cord blood may be easier to obtain than adult bone marrow, allowing for the treatment of more patients.
"We have done a terrific job in this country of increasing the number of volunteer donors listed in the National Marrow Donor Program registry over the past several years," said Vinod Prasad, M.D., a pediatric oncologist at Duke. "But the fact remains that for many patients, finding a matched donor can be difficult. Ethnic and racial minorities have the hardest time finding a fully matched donor."
The researchers presented their findings in an oral presentation at the American Society of Bone Marrow Transplantation in Tampa, Florida, on Friday, February 13, 2009. The study was partially funded by the National Institutes of Health.
"Our study found that using cord blood can be effective, without increased complications, and can provide more matches for patients, including ethnic minorities," said Prasad, who was the lead investigator. "Based on the findings of our study, we believe that unrelated cord blood transplant should be considered as an option for many of our young patients in need of a transplant."
Bone marrow transplantation has proven to be an effective treatment for thousands of children in the United States each year diagnosed with diseases such as leukemia and sickle cell disease, and inherited metabolic disorders such as Hurler's syndrome. Patients without a suitable match within their families can turn to the bone marrow registry, which currently lists more than seven million donors. Despite that number, however, many patients, particularly ethnic and racial minorities, are unable to find a completely matched donor.
The vast majority of these patients will find a partially matched donor within the public cord blood banks despite a smaller inventory of donor units, Prasad said.
"In order to match a donor to a recipient, doctors compare HLA typing, a test usually performed on a blood sample. In every individual, HLA typing includes the specific genetic make-up at three locations -- within those locations, you are looking at one set from the mother and one from the father, so it ends up to be six-point comparison," Prasad said. "In this analysis of children whose donor units were matched at four of six points, the transplant was successful in many patients, with low incidence of complications. Results were similar to those seen in patients receiving closer matched transplants. Thus the use of the 4/6 matched donors improved access to transplant for patients, especially those of ethnic and racial minorities."
The researchers studied data taken from 314 patients treated at Duke between 1993 and 2007. The patients ranged in age from six months to 21 years and suffered from both malignant and non-malignant conditions.
"We found that transplantation using 4/6 matched cord blood was effective and also carried a low probability of graft versus host disease, a complication caused by the attacking immune cells from the transplanted blood or marrow that perceive the recipient as 'foreign,' in the same way a healthy body's immune system might fight off a virus," Prasad said. "The incidence of other complications was low as well, and the data suggest that using 4/6 matched cord blood could improve access for all patients."
Duke has the largest cord blood transplantation program in the country, and the first unrelated cord blood transplant was performed by Duke physician Joanne Kurtzberg in 1993, on a patient with leukemia.
Other researchers involved in this study include Premjit Gill, Suhag Parikh, Paul Szabolcs, Timothy Driscoll, Kristin Page, Susan Wood, Deborah Semmel, Paul Martin, and Kurtzberg of Duke; and Adam Mendizabal and Shelly Carter, statisticians at the EMMES Corporation.
Source: Lauren Shaftel Williams
Duke University Medical Center
"We have done a terrific job in this country of increasing the number of volunteer donors listed in the National Marrow Donor Program registry over the past several years," said Vinod Prasad, M.D., a pediatric oncologist at Duke. "But the fact remains that for many patients, finding a matched donor can be difficult. Ethnic and racial minorities have the hardest time finding a fully matched donor."
The researchers presented their findings in an oral presentation at the American Society of Bone Marrow Transplantation in Tampa, Florida, on Friday, February 13, 2009. The study was partially funded by the National Institutes of Health.
"Our study found that using cord blood can be effective, without increased complications, and can provide more matches for patients, including ethnic minorities," said Prasad, who was the lead investigator. "Based on the findings of our study, we believe that unrelated cord blood transplant should be considered as an option for many of our young patients in need of a transplant."
Bone marrow transplantation has proven to be an effective treatment for thousands of children in the United States each year diagnosed with diseases such as leukemia and sickle cell disease, and inherited metabolic disorders such as Hurler's syndrome. Patients without a suitable match within their families can turn to the bone marrow registry, which currently lists more than seven million donors. Despite that number, however, many patients, particularly ethnic and racial minorities, are unable to find a completely matched donor.
The vast majority of these patients will find a partially matched donor within the public cord blood banks despite a smaller inventory of donor units, Prasad said.
"In order to match a donor to a recipient, doctors compare HLA typing, a test usually performed on a blood sample. In every individual, HLA typing includes the specific genetic make-up at three locations -- within those locations, you are looking at one set from the mother and one from the father, so it ends up to be six-point comparison," Prasad said. "In this analysis of children whose donor units were matched at four of six points, the transplant was successful in many patients, with low incidence of complications. Results were similar to those seen in patients receiving closer matched transplants. Thus the use of the 4/6 matched donors improved access to transplant for patients, especially those of ethnic and racial minorities."
The researchers studied data taken from 314 patients treated at Duke between 1993 and 2007. The patients ranged in age from six months to 21 years and suffered from both malignant and non-malignant conditions.
"We found that transplantation using 4/6 matched cord blood was effective and also carried a low probability of graft versus host disease, a complication caused by the attacking immune cells from the transplanted blood or marrow that perceive the recipient as 'foreign,' in the same way a healthy body's immune system might fight off a virus," Prasad said. "The incidence of other complications was low as well, and the data suggest that using 4/6 matched cord blood could improve access for all patients."
Duke has the largest cord blood transplantation program in the country, and the first unrelated cord blood transplant was performed by Duke physician Joanne Kurtzberg in 1993, on a patient with leukemia.
Other researchers involved in this study include Premjit Gill, Suhag Parikh, Paul Szabolcs, Timothy Driscoll, Kristin Page, Susan Wood, Deborah Semmel, Paul Martin, and Kurtzberg of Duke; and Adam Mendizabal and Shelly Carter, statisticians at the EMMES Corporation.
Source: Lauren Shaftel Williams
Duke University Medical Center
четверг, 19 мая 2011 г.
Costs Of Home Hemodialysis Offset By Better Health, Fewer Hospitalizations
Daily hemodialysis administered
in patients' homes is associated with better health outcomes compared
with peritoneal dialysis, according to an article in the October issue
of the American Journal of Kidney Diseases, the official journal of the
National Kidney Foundation.
As a result, the extra cost of providing in-home hemodialysis is
balanced out by lower expenditures for medications and hospital
admissions, physicians at a health maintenance organization in southern
California report.
Dialysis is a way of cleaning blood when a person's kidneys can no
longer do the job. It gets rid of the body's wastes, extra salt and
water, and helps to control blood pressure. There are two kinds of
dialysis: hemodialysis and peritoneal dialysis.
In hemodialysis, blood is pumped out of the patient's body to an
artificial kidney machine where the blood is filtered through a special
membrane, called a dialyzer, and then returned to the body.
In peritoneal dialysis, the inside lining of the patient's own belly
acts as a natural filter. Wastes are taken out by means of a cleansing
fluid called dialysate, which is washed in and out of the abdomen in
cycles through a surgically placed soft plastic tube (catheter).
"You can do hemodialysis at a dialysis center where a nurse or
technician performs the tasks required during treatment," says Dr.
Kerry Willis, Senior Vice President for Scientific Activities at the
National Kidney Foundation. "You can also do hemodialysis at home
where you and a care partner are the ones doing your treatment. At
home, you may be better able to fit your treatments into your daily
schedule."
In addition to the convenience, "many reports indicate that people
using daily home hemodialysis take less medication to control blood
pressure and anemia, feel better during dialysis and less 'washed
out' afterward, and have more energy for daily tasks,," Dr.
Willis pointed out.
However, it has been suggested that better health outcomes may simply
be the result of healthier patients opting for home treatment.
In their article, Dr. Victoria A. Kumar and her associates at the
Southern California Permanente Medical Group in Los Angeles tested this
theory by comparing one group of patients treated with daily home
hemodialysis with a group of patients treated with peritoneal dialysis.
Home dialysis was performed on average 5.4 times per week.
Dr. Kumar's group treated the 22 patients in the daily hemodialysis
group and the 64 in the peritoneal dialysis group for at least 6 months
between 2003 and 2007. The groups were comparable in age, the number of
patients with diabetes, and causes of kidney failure.
Despite these similarities, patients treated by peritoneal dialysis
spent nearly twice as many days each year in the hospital compared with
patients treated with home hemodialysis (average 5.6 days/patient-year
versus 3.3 days/patient-year).
Those treated by daily home hemodialysis were also able to reduce the
number of medications required to keep their blood pressure under
control, and had better nutritional status than they did prior to
starting treatment, as shown by higher serum albumin levels.
Dr. Kumar and her associates point out that their organization could
support the program of home hemodialysis because the cost of equipment,
supplies, and patient training was offset by lower expenditures for
hospital care and medications.
Unfortunately, many patients do not have the option of home dialysis
because Medicare does not fully reimburse health care providers for the
costs associated with such a program and not all dialysis centers offer
education and training for home hemodialysis. Another challenge relating
to home hemodialysis is the need for a care partner.
"If the costs of providing more frequent hemodialysis treatments do
not pose a financial burden on the Medicare system," Dr. Kumar and her
associates state, "the modality should be freely available to
motivated patients with end-stage renal disease."
The National Kidney Foundation, Inc. (NKF) is the major voluntary
health organization dedicated to preventing kidney disease, improving
the health and well-being of individuals and families affected by kidney
disease, and increasing the availability of all organs for
transplantation.
To learn more about chronic kidney disease, risk factors or
hemodialysis, contact the National Kidney Foundation at kidney.
National Kidney Foundation
in patients' homes is associated with better health outcomes compared
with peritoneal dialysis, according to an article in the October issue
of the American Journal of Kidney Diseases, the official journal of the
National Kidney Foundation.
As a result, the extra cost of providing in-home hemodialysis is
balanced out by lower expenditures for medications and hospital
admissions, physicians at a health maintenance organization in southern
California report.
Dialysis is a way of cleaning blood when a person's kidneys can no
longer do the job. It gets rid of the body's wastes, extra salt and
water, and helps to control blood pressure. There are two kinds of
dialysis: hemodialysis and peritoneal dialysis.
In hemodialysis, blood is pumped out of the patient's body to an
artificial kidney machine where the blood is filtered through a special
membrane, called a dialyzer, and then returned to the body.
In peritoneal dialysis, the inside lining of the patient's own belly
acts as a natural filter. Wastes are taken out by means of a cleansing
fluid called dialysate, which is washed in and out of the abdomen in
cycles through a surgically placed soft plastic tube (catheter).
"You can do hemodialysis at a dialysis center where a nurse or
technician performs the tasks required during treatment," says Dr.
Kerry Willis, Senior Vice President for Scientific Activities at the
National Kidney Foundation. "You can also do hemodialysis at home
where you and a care partner are the ones doing your treatment. At
home, you may be better able to fit your treatments into your daily
schedule."
In addition to the convenience, "many reports indicate that people
using daily home hemodialysis take less medication to control blood
pressure and anemia, feel better during dialysis and less 'washed
out' afterward, and have more energy for daily tasks,," Dr.
Willis pointed out.
However, it has been suggested that better health outcomes may simply
be the result of healthier patients opting for home treatment.
In their article, Dr. Victoria A. Kumar and her associates at the
Southern California Permanente Medical Group in Los Angeles tested this
theory by comparing one group of patients treated with daily home
hemodialysis with a group of patients treated with peritoneal dialysis.
Home dialysis was performed on average 5.4 times per week.
Dr. Kumar's group treated the 22 patients in the daily hemodialysis
group and the 64 in the peritoneal dialysis group for at least 6 months
between 2003 and 2007. The groups were comparable in age, the number of
patients with diabetes, and causes of kidney failure.
Despite these similarities, patients treated by peritoneal dialysis
spent nearly twice as many days each year in the hospital compared with
patients treated with home hemodialysis (average 5.6 days/patient-year
versus 3.3 days/patient-year).
Those treated by daily home hemodialysis were also able to reduce the
number of medications required to keep their blood pressure under
control, and had better nutritional status than they did prior to
starting treatment, as shown by higher serum albumin levels.
Dr. Kumar and her associates point out that their organization could
support the program of home hemodialysis because the cost of equipment,
supplies, and patient training was offset by lower expenditures for
hospital care and medications.
Unfortunately, many patients do not have the option of home dialysis
because Medicare does not fully reimburse health care providers for the
costs associated with such a program and not all dialysis centers offer
education and training for home hemodialysis. Another challenge relating
to home hemodialysis is the need for a care partner.
"If the costs of providing more frequent hemodialysis treatments do
not pose a financial burden on the Medicare system," Dr. Kumar and her
associates state, "the modality should be freely available to
motivated patients with end-stage renal disease."
The National Kidney Foundation, Inc. (NKF) is the major voluntary
health organization dedicated to preventing kidney disease, improving
the health and well-being of individuals and families affected by kidney
disease, and increasing the availability of all organs for
transplantation.
To learn more about chronic kidney disease, risk factors or
hemodialysis, contact the National Kidney Foundation at kidney.
National Kidney Foundation
среда, 18 мая 2011 г.
Improving Understanding Of Hematopoiesis Through Systems Biology
Our body reacts to blood loss by stimulating the production of red blood cells (erythrocytes). The cells of the hematopoietic (blood-forming) system in the bone marrow do so upon receipt of a signal by a hormone called erythropoietin, or Epo for short. This hormone is produced mainly by the kidney that increases the Epo level by up to a thousand-fold as a response to falling oxygen saturation of the blood.
The hematopoietic cells receive the Epo signal through Epo receptors on their surface. How do the blood progenitor cells that carry only few receptor molecules manage to react adequately to a high rise in the Epo level and to always provide the required amount of red blood cells? "If too much of the hormone floods too few receptor molecules, we would expect the saturation point to be reached soon. This would mean that the hematopoietic cell can no longer respond to a further increase in the hormone level," says Dr. Ursula KlingmГјller of DKFZ.
Researchers in her department, who participate in the Helmholtz Alliance for Systems Biology and the MedSys Network LungSys funded by the Federal Ministry of Education and Research (BMBF), collaborated with colleagues of a working group headed by Professor Jens Timmer at Freiburg University to find out how hematopoietic cells can react in a linear way if Epo levels increase by several orders of magnitude. To do so, the researchers combined experimental data with mathematical models in a systems biology approach.
The research team was able to show that after binding of Epo to its receptor both molecules are rapidly taken up into the interior of the hematopoietic cells where they are broken down. During the process, the cell surface is continuously equipped with newly synthesized receptor molecules that are supplied from intracellular storage places. "This turnover of receptor molecules is a very rapid process," Jens Timmer explains who is a member of the Freiburg Institute for Advances Studies (FRIAS) as well as the excellence cluster BIOSS. "Thus, the cell keeps being able to recognize further hormone molecules in its environment and to react accordingly."
Genetically engineered Epo is an important medication for treating anemia, for example in dialysis patients who often suffer from low counts of red blood cells because these are destroyed during dialysis and, in addition, the failure of renal function leads to a lack of natural Epo. The results of the Heidelberg and Freiburg scientists may contribute to developing Epo variants with enhanced binding properties and thus increase the effectiveness of anemia treatment.
Verena Becker, Marcel Schilling, Julie Bachmann, Ute Baumann, Andreas Raue, Thomas Maiwald, Jens Timmer, Ursula KlingmГјller: Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor. Science 2010, DOI: 10.1126/science.1184913
Source:
Dr. Sibylle Kohlstaedt
Helmholtz Association of German Research Centres
The hematopoietic cells receive the Epo signal through Epo receptors on their surface. How do the blood progenitor cells that carry only few receptor molecules manage to react adequately to a high rise in the Epo level and to always provide the required amount of red blood cells? "If too much of the hormone floods too few receptor molecules, we would expect the saturation point to be reached soon. This would mean that the hematopoietic cell can no longer respond to a further increase in the hormone level," says Dr. Ursula KlingmГјller of DKFZ.
Researchers in her department, who participate in the Helmholtz Alliance for Systems Biology and the MedSys Network LungSys funded by the Federal Ministry of Education and Research (BMBF), collaborated with colleagues of a working group headed by Professor Jens Timmer at Freiburg University to find out how hematopoietic cells can react in a linear way if Epo levels increase by several orders of magnitude. To do so, the researchers combined experimental data with mathematical models in a systems biology approach.
The research team was able to show that after binding of Epo to its receptor both molecules are rapidly taken up into the interior of the hematopoietic cells where they are broken down. During the process, the cell surface is continuously equipped with newly synthesized receptor molecules that are supplied from intracellular storage places. "This turnover of receptor molecules is a very rapid process," Jens Timmer explains who is a member of the Freiburg Institute for Advances Studies (FRIAS) as well as the excellence cluster BIOSS. "Thus, the cell keeps being able to recognize further hormone molecules in its environment and to react accordingly."
Genetically engineered Epo is an important medication for treating anemia, for example in dialysis patients who often suffer from low counts of red blood cells because these are destroyed during dialysis and, in addition, the failure of renal function leads to a lack of natural Epo. The results of the Heidelberg and Freiburg scientists may contribute to developing Epo variants with enhanced binding properties and thus increase the effectiveness of anemia treatment.
Verena Becker, Marcel Schilling, Julie Bachmann, Ute Baumann, Andreas Raue, Thomas Maiwald, Jens Timmer, Ursula KlingmГјller: Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor. Science 2010, DOI: 10.1126/science.1184913
Source:
Dr. Sibylle Kohlstaedt
Helmholtz Association of German Research Centres
вторник, 17 мая 2011 г.
Surface Logix Starts Phase 2a Clinical Trial Of SLx-4090 In Dyslipidemia
Surface Logix Inc. today announced the
initiation of a Phase 2a clinical trial of SLx-4090 in patients with
dyslipidemia (abnormal levels of lipids in the bloodstream). The trial will
investigate the drug's effect on reducing plasma lipid levels by preventing
the intestinal absorption of cholesterol and triglycerides. SLx-4090 is an
enterocyte-specific microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia.
"This study builds on the positive data from Phase 1 trials completed
last year, in which SLx-4090 was shown to have a clear impact on reducing
the peaks of triglyceride seen after meals and reducing overall levels of
LDL," said Jim Mahoney, President and Chief Executive Officer of Surface
Logix. "The impressive tolerability and safety profile seen to-date
reflects the fact that SLx-4090 works selectively in the gastrointestinal
tract but is not absorbed into the blood stream."
"Based on the preclinical data and the effects seen in the Phase 1
trials, SLx-4090 is predicted in longer-term patient studies to reduce LDL
cholesterol, impact favorably HDL/LDL ratios, and reduce fasting
triglyceride levels," Mahoney continued. "If the data continues as we have
seen to date, we believe SLx-4090 will have utility as an additional
treatment option for patients who do not reach lipid and triglyceride
target levels on current therapies."
The Phase 2a trial is a single center, randomized, double-blind,
placebo- controlled study that will enroll 24 patients with dyslipidemia
(high cholesterol and triglyceride levels). The primary study objective is
to investigate the effect on post prandial plasma triglycerides of repeat
oral doses of SLx-4090 for 14 days. Secondary trial objectives are to
evaluate the effect of SLx-4090 on additional pharmacodynamic parameters
such as HDL, LDL, total cholesterol, and apoB values; and to determine the
candidate's safety, tolerability, and pharmacokinetics.
About SLx-4090 in Dyslipidemia
SLx-4090 is a novel microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia (abnormal
levels of lipids in the bloodstream). Surface Logix designed SLx-4090 using
its proprietary small molecule Pharmacomer(TM) Technology to act
specifically in the gastrointestinal (GI) tract to prevent the transport of
fats through the intestinal wall. This unique feature of intestinal
selectivity allows activity against fat uptake while avoiding toxicity at
other sites of MTP expression including the liver, heart, testis, ovary,
and eye. Surface Logix is also exploring the use of SLx-4090 in other
metabolic disorders, including obesity and diabetes.
Dyslipidemia currently affects approximately 10% of the global
population, with 25% of these patients having elevated triglyceride levels.
In addition, there is an increasing prevalence and medical need for
lipid-modifying drugs in obese patients and patients with type 2 diabetes,
as a high proportion of type 2 diabetic patients have abnormal
concentrations of lipoproteins. In the U.S., Japan and Europe, it is
estimated that there are more than 240 million people with abnormal
lipoprotein levels. Of these, more than 55 million are estimated to have
low high density lipoprotein (HDL) and/or high triglyceride levels.
About Surface Logix Inc.
Surface Logix Inc. uses its expertise in biophysical chemistry to
create and develop novel small molecule drugs (NCE's) with superior
intrinsic drug- like properties that are clearly differentiated from
competitive products. The company is advancing multiple internal programs
focused primarily on cardiovascular, metabolic, inflammatory and fibrotic
diseases. For more information, please visit surfacelogix.
Surface Logix Inc.
surfacelogix
initiation of a Phase 2a clinical trial of SLx-4090 in patients with
dyslipidemia (abnormal levels of lipids in the bloodstream). The trial will
investigate the drug's effect on reducing plasma lipid levels by preventing
the intestinal absorption of cholesterol and triglycerides. SLx-4090 is an
enterocyte-specific microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia.
"This study builds on the positive data from Phase 1 trials completed
last year, in which SLx-4090 was shown to have a clear impact on reducing
the peaks of triglyceride seen after meals and reducing overall levels of
LDL," said Jim Mahoney, President and Chief Executive Officer of Surface
Logix. "The impressive tolerability and safety profile seen to-date
reflects the fact that SLx-4090 works selectively in the gastrointestinal
tract but is not absorbed into the blood stream."
"Based on the preclinical data and the effects seen in the Phase 1
trials, SLx-4090 is predicted in longer-term patient studies to reduce LDL
cholesterol, impact favorably HDL/LDL ratios, and reduce fasting
triglyceride levels," Mahoney continued. "If the data continues as we have
seen to date, we believe SLx-4090 will have utility as an additional
treatment option for patients who do not reach lipid and triglyceride
target levels on current therapies."
The Phase 2a trial is a single center, randomized, double-blind,
placebo- controlled study that will enroll 24 patients with dyslipidemia
(high cholesterol and triglyceride levels). The primary study objective is
to investigate the effect on post prandial plasma triglycerides of repeat
oral doses of SLx-4090 for 14 days. Secondary trial objectives are to
evaluate the effect of SLx-4090 on additional pharmacodynamic parameters
such as HDL, LDL, total cholesterol, and apoB values; and to determine the
candidate's safety, tolerability, and pharmacokinetics.
About SLx-4090 in Dyslipidemia
SLx-4090 is a novel microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia (abnormal
levels of lipids in the bloodstream). Surface Logix designed SLx-4090 using
its proprietary small molecule Pharmacomer(TM) Technology to act
specifically in the gastrointestinal (GI) tract to prevent the transport of
fats through the intestinal wall. This unique feature of intestinal
selectivity allows activity against fat uptake while avoiding toxicity at
other sites of MTP expression including the liver, heart, testis, ovary,
and eye. Surface Logix is also exploring the use of SLx-4090 in other
metabolic disorders, including obesity and diabetes.
Dyslipidemia currently affects approximately 10% of the global
population, with 25% of these patients having elevated triglyceride levels.
In addition, there is an increasing prevalence and medical need for
lipid-modifying drugs in obese patients and patients with type 2 diabetes,
as a high proportion of type 2 diabetic patients have abnormal
concentrations of lipoproteins. In the U.S., Japan and Europe, it is
estimated that there are more than 240 million people with abnormal
lipoprotein levels. Of these, more than 55 million are estimated to have
low high density lipoprotein (HDL) and/or high triglyceride levels.
About Surface Logix Inc.
Surface Logix Inc. uses its expertise in biophysical chemistry to
create and develop novel small molecule drugs (NCE's) with superior
intrinsic drug- like properties that are clearly differentiated from
competitive products. The company is advancing multiple internal programs
focused primarily on cardiovascular, metabolic, inflammatory and fibrotic
diseases. For more information, please visit surfacelogix.
Surface Logix Inc.
surfacelogix
понедельник, 16 мая 2011 г.
The 454 Genome Sequencing System Detects A Novel Virus Responsible For South African Hemorrhagic Fever Outbreak
A study published online in PLoS Pathogens reports that researchers at Columbia University, the South African National Health Laboratory Services, the US Centers for Disease Control, and 454 Life Sciences have discovered a new virus that is responsible for a highly fatal hemorrhagic fever outbreak in Zambia and South Africa late 2008(1). The previously unknown arenavirus, which is distantly related to the Lassa virus and Lymphocytic choriomeningitis virus, was characterized using the rapid and sensitive sequencing technology of 454 Life Sciences. The new species, named "Lujo virus" for the geographic origin of the outbreak (Lusaka, Zambia and Johannesburg, South Africa), is the first hemorrhagic fever-associated arenavirus from Africa identified in the past three decades. Characterization of the novel virus confirms the utility of unbiased high-throughput sequencing for pathogen discovery and provides an opportunity for public health efforts to quickly curb emerging viral pandemics in the future.
In September and October, 2008 five cases of undiagnosed hemorrhagic fever were recognized in South Africa after air transfer of a critically ill individual from Zambia. The disease was fatal in four of the five cases, including the originally infected individual, the paramedic who attended the patient during air transfer, the nurse who attended the patient in the intensive care unit in South Africa, and a member of the hospital staff who cleaned the room after the death of the patient. Unbiased, high-throughput sequencing with the 454 Sequencing system revealed the presence of a previously undiscovered Old World arenavirus. While the distantly related Lymphocytic choriomeningitis virus is generally harmless in healthy humans, the Lujo virus demonstrates an unprecedented high case fatality rate of 80% and unusual degree of pathogenicity.
"Within 72 hours of the sample arriving at JFK Airport, we identified the novel virus using high throughput sequencing," said Thomas Briese, Associate Director of the Center for Infection and Immunity at the Mailman School of Public Health of Columbia University.
"It is reassuring that we now have the tools needed to rapidly detect and respond to the challenges of previously unknown killer viruses. A key challenge that remains is deployment of these technologies to the 'hot spots' where new viruses frequently emerge," explained Ian Lipkin, MD, John Snow Professor of Epidemiology and Professor of Neurology and Pathology at Columbia University and the director of the Center. "We remain committed to this important public health effort as it represents a unique opportunity to prevent the next pandemic, be it a threat like HIV or SARS."
The unbiased, high-throughput 454 Sequencing System has been shown to be a powerful pathogen discovery tool in a series of recent studies. In early 2008, a study published in the New England Journal of Medicine reported the identification of a new virus responsible for the death of three transplant recipients using the technology of 454 Sequencing (2). Another study published last year employed the sequencing system to uncover a novel ebola virus responsible for a 2007 hemorrhagic fever outbreak in Uganda (3).
"454 Sequencing enables researchers to quickly identify the organisms present in a complex sample," explained Michael Egholm, study co-author and Chief Technology Officer and Vice President of Research and Development at 454 Life Sciences. "Our work with Lipkin and colleagues, in developing a comprehensive approach to pathogen detection, has borne fruit in resolving a number of recent disease outbreaks and confirms that it has the potential to be a critical tool for public health. We were honored in this most recent example to work with outstanding investigators at the Centers for Disease Control, World Health Organization, and the National Institute for Communicable Diseases in South Africa. "
454 Life Sciences, a center of excellence of Roche Applied Science, develops and commercializes the innovative 454 Sequencing System for ultra-high-throughput DNA sequencing. Specific applications include de novo sequencing and re-sequencing of genomes, metagenomics, RNA analysis, and targeted sequencing of DNA regions of interest. The hallmarks of the 454 Sequencing System are its simple, unbiased sample preparation and long, highly accurate sequence reads, including paired-end reads. The technology of the 454 Sequencing System has enabled hundreds of peer-reviewed studies in diverse research fields, such as cancer and infectious disease research, drug discovery, marine biology, anthropology, paleontology and many more.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients.
In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: roche.
The 454 GS FLX is sold for life science research use only.
454, 454 SEQUENCING, 454 LIFE SCIENCES and GS FLX TITANIUM are trademarks of Roche.
(1) Briese et al. Genetic detection and characterization of Lujo virus, a new hemorrhagic fever-associated arenavirus from southern Africa. (2009) PloS Pathogens. ePub April xx.
(2) Palacios et al. A new arenavirus in a cluster of fatal transplant-associated diseases. (2008) New England Journal of Medicine 358: 991-998.
(3) Towner et al. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. (2008) PLoS Pathogens 4(11): e1000212.
Source
Roche
In September and October, 2008 five cases of undiagnosed hemorrhagic fever were recognized in South Africa after air transfer of a critically ill individual from Zambia. The disease was fatal in four of the five cases, including the originally infected individual, the paramedic who attended the patient during air transfer, the nurse who attended the patient in the intensive care unit in South Africa, and a member of the hospital staff who cleaned the room after the death of the patient. Unbiased, high-throughput sequencing with the 454 Sequencing system revealed the presence of a previously undiscovered Old World arenavirus. While the distantly related Lymphocytic choriomeningitis virus is generally harmless in healthy humans, the Lujo virus demonstrates an unprecedented high case fatality rate of 80% and unusual degree of pathogenicity.
"Within 72 hours of the sample arriving at JFK Airport, we identified the novel virus using high throughput sequencing," said Thomas Briese, Associate Director of the Center for Infection and Immunity at the Mailman School of Public Health of Columbia University.
"It is reassuring that we now have the tools needed to rapidly detect and respond to the challenges of previously unknown killer viruses. A key challenge that remains is deployment of these technologies to the 'hot spots' where new viruses frequently emerge," explained Ian Lipkin, MD, John Snow Professor of Epidemiology and Professor of Neurology and Pathology at Columbia University and the director of the Center. "We remain committed to this important public health effort as it represents a unique opportunity to prevent the next pandemic, be it a threat like HIV or SARS."
The unbiased, high-throughput 454 Sequencing System has been shown to be a powerful pathogen discovery tool in a series of recent studies. In early 2008, a study published in the New England Journal of Medicine reported the identification of a new virus responsible for the death of three transplant recipients using the technology of 454 Sequencing (2). Another study published last year employed the sequencing system to uncover a novel ebola virus responsible for a 2007 hemorrhagic fever outbreak in Uganda (3).
"454 Sequencing enables researchers to quickly identify the organisms present in a complex sample," explained Michael Egholm, study co-author and Chief Technology Officer and Vice President of Research and Development at 454 Life Sciences. "Our work with Lipkin and colleagues, in developing a comprehensive approach to pathogen detection, has borne fruit in resolving a number of recent disease outbreaks and confirms that it has the potential to be a critical tool for public health. We were honored in this most recent example to work with outstanding investigators at the Centers for Disease Control, World Health Organization, and the National Institute for Communicable Diseases in South Africa. "
454 Life Sciences, a center of excellence of Roche Applied Science, develops and commercializes the innovative 454 Sequencing System for ultra-high-throughput DNA sequencing. Specific applications include de novo sequencing and re-sequencing of genomes, metagenomics, RNA analysis, and targeted sequencing of DNA regions of interest. The hallmarks of the 454 Sequencing System are its simple, unbiased sample preparation and long, highly accurate sequence reads, including paired-end reads. The technology of the 454 Sequencing System has enabled hundreds of peer-reviewed studies in diverse research fields, such as cancer and infectious disease research, drug discovery, marine biology, anthropology, paleontology and many more.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients.
In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: roche.
The 454 GS FLX is sold for life science research use only.
454, 454 SEQUENCING, 454 LIFE SCIENCES and GS FLX TITANIUM are trademarks of Roche.
(1) Briese et al. Genetic detection and characterization of Lujo virus, a new hemorrhagic fever-associated arenavirus from southern Africa. (2009) PloS Pathogens. ePub April xx.
(2) Palacios et al. A new arenavirus in a cluster of fatal transplant-associated diseases. (2008) New England Journal of Medicine 358: 991-998.
(3) Towner et al. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. (2008) PLoS Pathogens 4(11): e1000212.
Source
Roche
воскресенье, 15 мая 2011 г.
First Structure Of A Class Of Proteins That Help Guide Blood Cell Movement Revealed: Findings May Lead To New Drugs For Cancer, Immune Disorders Aids
Researchers have determined the structure of a protein that helps guide blood-forming stem cells, or hematopoetic stem cells. The protein is also one of the main receptors used by the human immunodeficiency virus (HIV) to get inside blood cells.
The findings are described in the journal Science.
The structure offers a detailed view of how the cell surface receptor, called CXCR4, interacts with molecules outside the cell. The results have implications for developing new drugs for hematopoetic stem cell transplantation, a therapeutic path to treat cancer and immune disorders, as well as for treating HIV infection.
"The structures open up entire new areas for understanding fundamental principles in chemokine GPCR signaling," said Scripps Research Professor Raymond C. Stevens, who is senior author of the collaborative study.
Sniffing Out Signals
CXCR4 belongs to a large family of more than 700 proteins known as G protein-coupled receptors (GPCRs). These proteins sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger the appropriate response inside the cell.
"My lab is really interested in how this one protein family recognizes millions of different types of ligands with incredible specificity," said Stevens, "and how when one ligand binds a receptor it may have one intracellular effect such as activation and a closely related ligand can have an opposite effect such as antagonism."
To understand how these receptors function, the Stevens group has already determined the structures of two other GPCRs: the adrenergic receptor, involved in the fight-or-flight response, and the A2A adenosine receptor, sometimes also referred to as the "caffeine" receptor. The newly solved protein CXCR4 belongs to a different group of GPCRs, one that binds to protein molecules called chemokines, which primarily function to steer the movement of blood and immune cells to their appropriate locations in the body.
Comparing Wine Glasses
To get the first-ever glimpse of a chemokine receptor bound to a ligand, Stevens and colleagues turned to GPCR biochemistry, receptor stabilization and X-ray crystallography.
"One challenging aspect of this research is the biochemistry - learning what the receptor likes and dislikes," said Stevens. "Each receptor and receptor-ligand complex has a distinctly different biophysical personality."
The crystal structure of CXCR4, just like that of other known GPCRs, resembles a wine glass stuck inside the cell membrane, with the glass opening (where the ligands bind) facing the outside of the cell and the stem portion the inside. But there are important differences.
"The adrenergic receptor looks like a pinot noir glass that curves inward towards the top to hold in the wine vapors; the A2A receptor looks like a champagne flute," explained Stevens. "The CXCR4 structure looks like chardonnay glass with a wider opening and shorter depth."
The wider mouth allows CXCR4 to bind to its chemokine ligand, CXCL-12, which is a protein and thus a larger molecule than the ligands that bind the adrenergic and A2Areceptors. CXCL-12 is the signal in the blood that guides hematopoetic stem cells to the bone marrow, a process known as homing.
Finding Therapies
One of the biggest surprises of the CXCR4 structure was that this receptor, unlike the adrenergic and A2A receptors, likes to form pairs or dimers.
"The dimerization observation was very intriguing," said Stevens. "We solved five different crystal structures in multiple crystal forms, and each one had the same dimer interface. It has long been debated how GPCRs might dimerize, if they did at all. This is the first solid observation about a consistent structural GPCR dimer."
Preventing dimerization might provide a new way to block CXCR4 function. Drugs that block CXCR4 appear to be capable of releasing hematopoietic stem cells from the bone marrow into the bloodstream - a step that is critical for stem cell transplantation. Only one such drug, called Mozobil, is currently on the market. In addition, drugs that block CXCR4 are useful in treating HIV infection.
Having determined the structure of CXCR4, Stevens and colleagues were able to determine which portions of the protein are critical to chemokine recognition. This knowledge can now be used to understand basic principles of chemokine recognition and signaling, as well as to design new therapeutic candidates or improve the affinity and efficacy of existing drugs.
Like all membrane proteins, GPCRs are notoriously difficult to crystallize, but CXCR4 was a particularly difficult structure to crack, according to Stevens.
"Each GPCR structure is a tour de force and this one took a team of several people three years to complete," he said. " I wish I could identify one step that was the most challenging, but I would say every step was hard."
Stevens credits the perseverance and creativity of Research Associate Beili Wu, (who was first author of the paper), Scientific Associate Ellen Chien, and Assistant Professor Vadim Cherezov for noteworthy breakthroughs. Stevens also notes that working in close collaboration with colleagues Alexei Brooun, Chris Bi, and Peter Wells at Pfizer La Jolla and Professors Tracy Handel and Ruben Abagyan at the University of California, San Diego (UCSD) led to much of the success where chemistry, biological insight, and structural biology were brought together in a synergistic and productive manner.
In addition to Stevens, Wu, Chien, Cherezov, Brooun, Bi, Wells, Handel, and Abagayan, the paper, "Structure of the CXCR4 chemokine receptor with small molecule and cyclic peptide antagonists," was authored by Clifford D. Mol, Gustavo Fenalti, Wei Liu, and Peter Kuhn of Scripps Research, and Vsevolod Katrich and Damon J. Hamel of UCSD.
This work was supported by the National Institutes of Health Protein Structure Initiative, NIH Common Fund, and Pfizer.
Source:
Mika Ono
Scripps Research Institute
View drug information on Mozobil.
The findings are described in the journal Science.
The structure offers a detailed view of how the cell surface receptor, called CXCR4, interacts with molecules outside the cell. The results have implications for developing new drugs for hematopoetic stem cell transplantation, a therapeutic path to treat cancer and immune disorders, as well as for treating HIV infection.
"The structures open up entire new areas for understanding fundamental principles in chemokine GPCR signaling," said Scripps Research Professor Raymond C. Stevens, who is senior author of the collaborative study.
Sniffing Out Signals
CXCR4 belongs to a large family of more than 700 proteins known as G protein-coupled receptors (GPCRs). These proteins sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger the appropriate response inside the cell.
"My lab is really interested in how this one protein family recognizes millions of different types of ligands with incredible specificity," said Stevens, "and how when one ligand binds a receptor it may have one intracellular effect such as activation and a closely related ligand can have an opposite effect such as antagonism."
To understand how these receptors function, the Stevens group has already determined the structures of two other GPCRs: the adrenergic receptor, involved in the fight-or-flight response, and the A2A adenosine receptor, sometimes also referred to as the "caffeine" receptor. The newly solved protein CXCR4 belongs to a different group of GPCRs, one that binds to protein molecules called chemokines, which primarily function to steer the movement of blood and immune cells to their appropriate locations in the body.
Comparing Wine Glasses
To get the first-ever glimpse of a chemokine receptor bound to a ligand, Stevens and colleagues turned to GPCR biochemistry, receptor stabilization and X-ray crystallography.
"One challenging aspect of this research is the biochemistry - learning what the receptor likes and dislikes," said Stevens. "Each receptor and receptor-ligand complex has a distinctly different biophysical personality."
The crystal structure of CXCR4, just like that of other known GPCRs, resembles a wine glass stuck inside the cell membrane, with the glass opening (where the ligands bind) facing the outside of the cell and the stem portion the inside. But there are important differences.
"The adrenergic receptor looks like a pinot noir glass that curves inward towards the top to hold in the wine vapors; the A2A receptor looks like a champagne flute," explained Stevens. "The CXCR4 structure looks like chardonnay glass with a wider opening and shorter depth."
The wider mouth allows CXCR4 to bind to its chemokine ligand, CXCL-12, which is a protein and thus a larger molecule than the ligands that bind the adrenergic and A2Areceptors. CXCL-12 is the signal in the blood that guides hematopoetic stem cells to the bone marrow, a process known as homing.
Finding Therapies
One of the biggest surprises of the CXCR4 structure was that this receptor, unlike the adrenergic and A2A receptors, likes to form pairs or dimers.
"The dimerization observation was very intriguing," said Stevens. "We solved five different crystal structures in multiple crystal forms, and each one had the same dimer interface. It has long been debated how GPCRs might dimerize, if they did at all. This is the first solid observation about a consistent structural GPCR dimer."
Preventing dimerization might provide a new way to block CXCR4 function. Drugs that block CXCR4 appear to be capable of releasing hematopoietic stem cells from the bone marrow into the bloodstream - a step that is critical for stem cell transplantation. Only one such drug, called Mozobil, is currently on the market. In addition, drugs that block CXCR4 are useful in treating HIV infection.
Having determined the structure of CXCR4, Stevens and colleagues were able to determine which portions of the protein are critical to chemokine recognition. This knowledge can now be used to understand basic principles of chemokine recognition and signaling, as well as to design new therapeutic candidates or improve the affinity and efficacy of existing drugs.
Like all membrane proteins, GPCRs are notoriously difficult to crystallize, but CXCR4 was a particularly difficult structure to crack, according to Stevens.
"Each GPCR structure is a tour de force and this one took a team of several people three years to complete," he said. " I wish I could identify one step that was the most challenging, but I would say every step was hard."
Stevens credits the perseverance and creativity of Research Associate Beili Wu, (who was first author of the paper), Scientific Associate Ellen Chien, and Assistant Professor Vadim Cherezov for noteworthy breakthroughs. Stevens also notes that working in close collaboration with colleagues Alexei Brooun, Chris Bi, and Peter Wells at Pfizer La Jolla and Professors Tracy Handel and Ruben Abagyan at the University of California, San Diego (UCSD) led to much of the success where chemistry, biological insight, and structural biology were brought together in a synergistic and productive manner.
In addition to Stevens, Wu, Chien, Cherezov, Brooun, Bi, Wells, Handel, and Abagayan, the paper, "Structure of the CXCR4 chemokine receptor with small molecule and cyclic peptide antagonists," was authored by Clifford D. Mol, Gustavo Fenalti, Wei Liu, and Peter Kuhn of Scripps Research, and Vsevolod Katrich and Damon J. Hamel of UCSD.
This work was supported by the National Institutes of Health Protein Structure Initiative, NIH Common Fund, and Pfizer.
Source:
Mika Ono
Scripps Research Institute
View drug information on Mozobil.
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