Research leading to the discovery of streptomycin - the first effective pharmaceutical treatment for tuberculosis - will
be designated a National Historic Chemical Landmark at Rutgers University in a special ceremony in New Brunswick, New Jersey,
on May 24. The American Chemical Society, the world's largest scientific society, sponsors the landmarks program.
Beginning in the 1930s, Selman Waksman, Ph.D., and his students began the search for antibiotics produced from actinomycetes,
microbes in the soil that are related to bacteria and fungi. The culmination was the isolation of streptomycin in 1943 by
Albert Schatz, a graduate student of Waksman's, using soil screening methods developed by Waksman. This deliberate search for
chemotherapeutic agents contrasts with the discovery of penicillin, which came through a chance observation by Alexander
Fleming, who noted that a mold contaminant on a Petri dish culture had inhibited the growth of bacteria.
Streptomycin was the third antimicrobial agent isolated under Waksman's direction at Martin Hall at Cook College, Rutgers
University. Streptomycin, however, was the first agent not toxic to humans, and it attacked a type of bacteria resistant to
penicillin. In addition to treating tuberculosis, streptomycin was effective against typhoid fever, cholera, bubonic plague
and other diseases. Among the other antibiotics isolated in Waksman's laboratory was neomycin, still used as a topical
antibacterial agent.
William F. Carroll, Ph.D., president of the Society, will present a commemorative bronze plaque to Tim Casey, Ph.D., Dean of
Academic and Student Programs at Cook College, Rutgers University. H. Boyd Woodruff, Ph.D., who isolated the first two
actinomycete antibiotics, will be the featured speaker. The award presentation takes place in conjunction with the ACS Middle
Atlantic Regional Meeting. The MARM meeting is being held on the nearby Busch Campus of Rutgers in Piscataway, New Jersey,
May 22-25.
Selman Waksman was born in Russia in 1888. He immigrated to the United States in 1910 and entered Rutgers University a few
years later. After completing graduate work at the University of California, Waksman joined the Rutgers faculty in 1918. Even
as an undergraduate student, Waksman studied actinomycetes in the soil, but it was not until late 1930s that he turned his
attention to the searching for microbes that attacked other microbes.
Waksman received the Nobel Prize for physiology or medicine in 1952 for "ingenious, systematic and successful studies of the
soil microbes" that led to the discovery of streptomycin. He died in 1973.
The American Chemical Society is a nonprofit organization, chartered by the U.S. Congress, with a multidisciplinary
membership of more than 158,000 chemists and chemical engineers. It publishes numerous scientific journals and databases,
convenes major research conferences and provides educational, science policy and career programs in chemistry. Its main
offices are in Washington, D.C., and Columbus, Ohio.
Contact: Judah Ginsberg
j_ginsbergacs
202-872-4400
American Chemical Society
chemistry
Michele Hujber
hujberaesop.rutgers
732-932-9559
Rutgers University
rutgers
понедельник, 13 июня 2011 г.
пятница, 10 июня 2011 г.
Method For Computing Evolutionary Trees Could Revolutionize Evolutionary Biology
Detailed, accurate evolutionary trees that reveal the relatedness of living things can now be determined much faster and for thousands of species with a computing method developed by computer scientists and a biologist at The University of Texas at Austin.
They report their new method in the journal Science.
Since Charles Darwin, biologists have constructed evolutionary trees to explain the relatedness of plants, animals and other organisms. The science of figuring out these trees, known as systematics, has progressed significantly in the last two decades largely due to advances in computation, genetics and molecular biology.
However, many of the relationships among the world's 1.5 million described species (the true number could be 10 million or more) remain to be figured out, and surprises still remain. Figuring out these relationships requires analyzing large amounts of molecular data, such as DNA and protein sequences.
Computer scientist Tandy Warnow, biologist Randy Linder and their graduate students have created an automated computing method, called SATГ©, that can analyze these molecular data from thousands of organisms, simultaneously figuring out how the sequences should be organized and computing their evolutionary relatedness in as little as 24 hours.
Previous simultaneous methods like Warnow and Linder's have been limited to analyzing 20 species or fewer and have taken months to complete.
"SATГ© could completely change the practice of making evolutionary trees and revolutionize our understanding of evolution," says Warnow, professor of computer science and lead author of the study.
In addition, SATГ© can accurately analyze DNA sequences that are rapidly evolving. These sequences have been previously avoided due to concern that the resulting trees would be poor.
Before a tree, or phylogeny, can be determined, DNA and protein sequence data must be organized. This process is called alignment. Key to Warnow and Linder's program is its ability to quickly and accurately align these data.
"Our process is novel because it rapidly and simultaneously aligns sequences and looks for the best phylogenies," says Linder, associate professor of integrative biology. "The old way of doing this for a large number of sequences was basically to align the data once, but we can look at many arrangements to find better ones."
This is important because different alignments can lead to significantly different phylogenies, and scientists must find the phylogeny that best represents the evolutionary relationships among the species in question.
For their paper, Warnow, Linder and their students tested SATГ© using computer-generated data and real biological data. The biological data had been previously aligned manually by other experts.
The new phylogenies closely match those existing, both validating the method's potential, and, in some cases, validating the evolutionary trees themselves.
"Instead of doing things by hand, evolutionary biologists can now trust our automated program," says Warnow. "It will enable the creation of much more accurate trees, especially for the Tree of Life, which deals with hundreds of thousands of gene sequences from the millions of species on Earth."
"Warnow and Linder have created a method that speeds up the process and removes any subjectivity," says Michael Braun, an evolutionary biologist at the Smithsonian Institution not associated with this project. "This is a major step forward for evolutionary biology."
Computer science graduate student Kevin Liu is first author on the paper. Students Sindhu Raghavan and Serita Nelesen also contributed to the project and co-authored the paper.
Source:
Tandy Warnow
University of Texas at Austin
They report their new method in the journal Science.
Since Charles Darwin, biologists have constructed evolutionary trees to explain the relatedness of plants, animals and other organisms. The science of figuring out these trees, known as systematics, has progressed significantly in the last two decades largely due to advances in computation, genetics and molecular biology.
However, many of the relationships among the world's 1.5 million described species (the true number could be 10 million or more) remain to be figured out, and surprises still remain. Figuring out these relationships requires analyzing large amounts of molecular data, such as DNA and protein sequences.
Computer scientist Tandy Warnow, biologist Randy Linder and their graduate students have created an automated computing method, called SATГ©, that can analyze these molecular data from thousands of organisms, simultaneously figuring out how the sequences should be organized and computing their evolutionary relatedness in as little as 24 hours.
Previous simultaneous methods like Warnow and Linder's have been limited to analyzing 20 species or fewer and have taken months to complete.
"SATГ© could completely change the practice of making evolutionary trees and revolutionize our understanding of evolution," says Warnow, professor of computer science and lead author of the study.
In addition, SATГ© can accurately analyze DNA sequences that are rapidly evolving. These sequences have been previously avoided due to concern that the resulting trees would be poor.
Before a tree, or phylogeny, can be determined, DNA and protein sequence data must be organized. This process is called alignment. Key to Warnow and Linder's program is its ability to quickly and accurately align these data.
"Our process is novel because it rapidly and simultaneously aligns sequences and looks for the best phylogenies," says Linder, associate professor of integrative biology. "The old way of doing this for a large number of sequences was basically to align the data once, but we can look at many arrangements to find better ones."
This is important because different alignments can lead to significantly different phylogenies, and scientists must find the phylogeny that best represents the evolutionary relationships among the species in question.
For their paper, Warnow, Linder and their students tested SATГ© using computer-generated data and real biological data. The biological data had been previously aligned manually by other experts.
The new phylogenies closely match those existing, both validating the method's potential, and, in some cases, validating the evolutionary trees themselves.
"Instead of doing things by hand, evolutionary biologists can now trust our automated program," says Warnow. "It will enable the creation of much more accurate trees, especially for the Tree of Life, which deals with hundreds of thousands of gene sequences from the millions of species on Earth."
"Warnow and Linder have created a method that speeds up the process and removes any subjectivity," says Michael Braun, an evolutionary biologist at the Smithsonian Institution not associated with this project. "This is a major step forward for evolutionary biology."
Computer science graduate student Kevin Liu is first author on the paper. Students Sindhu Raghavan and Serita Nelesen also contributed to the project and co-authored the paper.
Source:
Tandy Warnow
University of Texas at Austin
вторник, 7 июня 2011 г.
Distinct Mammalian Precursors Are Committed To Generate Neurons With Defined Dendritic Projection Patterns
The mammalian brain contains a large number of different classes of
neurons that are connected in a specific manner. A long-standing question
is how
such stereotyped connections emerge during the assembly of the brain. In a
new study published online this week in the open-access journal PLoS
Biology, Wolfgang Kelsch, Carlos Lois, and colleagues investigated whether
neonatal and adult brain stem cells give rise to neurons whose connections
can be influenced by the partners that they encounter while maturing, or
alternatively, whether these connections are predetermined from the moment
that a neuron is born.
They observed the existence of distinct populations
of precursor cells committed to generating neurons with a specific pattern
of connections. Furthermore, the pattern of connections formed by these
neurons was largely independent of the environment in which the neurons
matured. These results have important implications for the formation of
neuronal circuits, as they indicate that the connections of a new neuron
can
be determined in their precursors.
In particular, these observations
suggest that for neuronal replacement therapies to be successful, it will
be
necessary to understand the genetic programs that control how stem cells
are prespecified to produce neurons with a stereotypic pattern of
connections.
Citation: Kelsch W, Mosley CP, Lin CW, Lois C (2007) Distinct mammalian
precursors are committed to generate neurons with defined dendritic
projection
patterns. PLoS Biol
5(11): e300. doi:10.1371/journal.pbio.0050300
Please click here
plosbiology
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of
scientists and physicians committed to making the world's scientific and
medical
literature a freely available public resource.
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
neurons that are connected in a specific manner. A long-standing question
is how
such stereotyped connections emerge during the assembly of the brain. In a
new study published online this week in the open-access journal PLoS
Biology, Wolfgang Kelsch, Carlos Lois, and colleagues investigated whether
neonatal and adult brain stem cells give rise to neurons whose connections
can be influenced by the partners that they encounter while maturing, or
alternatively, whether these connections are predetermined from the moment
that a neuron is born.
They observed the existence of distinct populations
of precursor cells committed to generating neurons with a specific pattern
of connections. Furthermore, the pattern of connections formed by these
neurons was largely independent of the environment in which the neurons
matured. These results have important implications for the formation of
neuronal circuits, as they indicate that the connections of a new neuron
can
be determined in their precursors.
In particular, these observations
suggest that for neuronal replacement therapies to be successful, it will
be
necessary to understand the genetic programs that control how stem cells
are prespecified to produce neurons with a stereotypic pattern of
connections.
Citation: Kelsch W, Mosley CP, Lin CW, Lois C (2007) Distinct mammalian
precursors are committed to generate neurons with defined dendritic
projection
patterns. PLoS Biol
5(11): e300. doi:10.1371/journal.pbio.0050300
Please click here
plosbiology
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of
scientists and physicians committed to making the world's scientific and
medical
literature a freely available public resource.
Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
понедельник, 6 июня 2011 г.
Latent Inhibition Of Predator Recognition By Embryonic Amphibians
It is crucial for prey to be able to learn to discriminate between predators and non-predators. While this task can be challenging and dangerous for prey animals, it appears that amphibian embryos have found a way to get a head start on their homework.
The present study indicates that woodfrogs can learn to distinguish their future predators from their future non-predators while still in the egg. Woodfrog embryos repeatedly exposed to a novel odour (salamander odour) without any reinforcement are subsequently unable to label this odour as threatening.
This mechanism, known as latent inhibition, is likely useful at limiting the number of stimuli mistakenly recognized as potentially dangerous by prey.
Royal Society Journal Biology Letters
Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.
Biology Letters
The present study indicates that woodfrogs can learn to distinguish their future predators from their future non-predators while still in the egg. Woodfrog embryos repeatedly exposed to a novel odour (salamander odour) without any reinforcement are subsequently unable to label this odour as threatening.
This mechanism, known as latent inhibition, is likely useful at limiting the number of stimuli mistakenly recognized as potentially dangerous by prey.
Royal Society Journal Biology Letters
Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.
Biology Letters
Discovery Of The Cell's Water Gate May Lead To New Cancer Drugs
The flow of water into and out from the cell may play a crucial role in several types of cancer. Scientists at the University of Gothenburg have now found the gate that regulates the flow of water into yeast cells. The discovery, which has been published in the journal PLoS Biology, raises hopes of developing a drug that inhibits the spread and growth of tumours.
All living organisms must be able to regulate the flow of water into and out from cells, in order to maintain cell form and size. This regulation is carried out by special proteins known as "aquaporins". These act as water channels and control the flow of water into and out from the cell.
Involved in cancer diseases
Aquaporins are found in most organisms, and are believed to be involved in several diseases, including cancer. Research on mice has shown that inhibiting the function of aquaporins can dramatically reduce the spread and growth of tumours.
Important for research
It is therefore extremely important for cancer research to increase our knowledge of aquaporins. Scientists at the University of Gothenburg have recently achieved a minor breakthrough in the field. Karin Lindkvist at the Department of Cell and Molecular Biology and Richard Neutze at the Department of Chemistry, University of Gothenburg have determined the three-dimensional structure of the yeast aquaporin.
Highest resolution
The structure has been determined using X-ray crystallography and is the highest resolution structure that has been determined for a membrane protein. The unique high resolution has enabled the scientists to answer one of the unsolved mysteries of biology. The aquaporins in yeast have long "tails", known as amino-terminal extensions. The function of these tails has, until now, been unknown.
"Our study shows that the amino-terminal extensions in yeast act as a gate that can be opened and closed depending on how much water the cell must release or absorb. Computer simulations and biological experiments suggest that the channel is regulated with a combination of mechanical regulation and phosphorylation", says Karin Lindkvist.
Similar to human
Yeast cells are similar to human cells in many respects, and Karin Lindkvist's research can have applications in cancer research and other fields.
"The structure of the yeast aquaporin that we have determined can be used to create inhibitors for human aquaporins, and this may in the long term lead to drugs that slow the growth of a cancer tumour", says Karin Lindkvist.
The article has been published in PloS Biology on 16 June.
Source: University of Gothenburg
All living organisms must be able to regulate the flow of water into and out from cells, in order to maintain cell form and size. This regulation is carried out by special proteins known as "aquaporins". These act as water channels and control the flow of water into and out from the cell.
Involved in cancer diseases
Aquaporins are found in most organisms, and are believed to be involved in several diseases, including cancer. Research on mice has shown that inhibiting the function of aquaporins can dramatically reduce the spread and growth of tumours.
Important for research
It is therefore extremely important for cancer research to increase our knowledge of aquaporins. Scientists at the University of Gothenburg have recently achieved a minor breakthrough in the field. Karin Lindkvist at the Department of Cell and Molecular Biology and Richard Neutze at the Department of Chemistry, University of Gothenburg have determined the three-dimensional structure of the yeast aquaporin.
Highest resolution
The structure has been determined using X-ray crystallography and is the highest resolution structure that has been determined for a membrane protein. The unique high resolution has enabled the scientists to answer one of the unsolved mysteries of biology. The aquaporins in yeast have long "tails", known as amino-terminal extensions. The function of these tails has, until now, been unknown.
"Our study shows that the amino-terminal extensions in yeast act as a gate that can be opened and closed depending on how much water the cell must release or absorb. Computer simulations and biological experiments suggest that the channel is regulated with a combination of mechanical regulation and phosphorylation", says Karin Lindkvist.
Similar to human
Yeast cells are similar to human cells in many respects, and Karin Lindkvist's research can have applications in cancer research and other fields.
"The structure of the yeast aquaporin that we have determined can be used to create inhibitors for human aquaporins, and this may in the long term lead to drugs that slow the growth of a cancer tumour", says Karin Lindkvist.
The article has been published in PloS Biology on 16 June.
Source: University of Gothenburg
Great Ape Diseases Are Threat To Humans
Humans may be more vulnerable to catching diseases from great apes chimpanzees and gorillas as these species are the closest relatives to us, says research published in Proceedings of the Royal Society B: Biological Sciences, today (Wednesday 30 April 2008).
Researchers from the Universities of California and Sheffield show that humans are almost four times more likely to share infectious diseases and viruses with chimpanzees which last shared a common ancestor with humans around 8 million years ago, than with a colobus monkey, which diverged from humans over 34 million years ago.
Emerging infectious diseases are increasingly impacting human health and species conservation. Many of the most deadly diseases known to mankind have originated among wild animals, for example AIDS and Ebola and these new findings could prove critical in predicting future trends of emerging diseases.
Dr Jonathan Davies, from the University of California and co-author of the study, said: "Infectious diseases crossing species barriers pose a huge and increasing threat to human health and the conservation of wild species. Our study helps us to understand where and how diseases jump between species, and provides a critical first step in predicting future outbreaks."
The Royal Society
Researchers from the Universities of California and Sheffield show that humans are almost four times more likely to share infectious diseases and viruses with chimpanzees which last shared a common ancestor with humans around 8 million years ago, than with a colobus monkey, which diverged from humans over 34 million years ago.
Emerging infectious diseases are increasingly impacting human health and species conservation. Many of the most deadly diseases known to mankind have originated among wild animals, for example AIDS and Ebola and these new findings could prove critical in predicting future trends of emerging diseases.
Dr Jonathan Davies, from the University of California and co-author of the study, said: "Infectious diseases crossing species barriers pose a huge and increasing threat to human health and the conservation of wild species. Our study helps us to understand where and how diseases jump between species, and provides a critical first step in predicting future outbreaks."
The Royal Society
Protein Has Pivotal Role In Obesity, Metabolic Syndrome
A protein known to play a role in development and the formation of organs is also an important factor in the control of obesity and diabetes, said researchers from Baylor College of Medicine in a report that appears in the current issue of the journal Cell Metabolism.
Drs. Ming-Jer and Sophia Tsai, professors of molecular and cellular biology at BCM, have studied COUP-TFII (Chicken Ovalbumin Upstream Promoter Transcription Factor II) for decades, but only when they bred mice that had only one gene copy for the factor did they find that the animals had smaller fat cells and increased energy metabolism as well as enhanced response to insulin.
"If a mouse loses one copy of the gene, the animal becomes lean," said Ming-Jer Tsai. "It is more sensitive to the effects of insulin and resistant to obesity from a high fat diet."
Their studies raise the likely possibility that one can use COUP-TFII as a potential drug target for diabetes and obesity treatment.
Identifying a drug that could reduce the effect of COUP-TFII activity has become a future focus for their research, said Sophia Tsai.
"We don't need to inhibit it totally," she said. "Partial inhibition will do the trick as when you lose one copy of the gene, your fat cells are already much smaller and the animal is lean."
The animals not only have less fat, they also have more muscle and burn more energy, said Ming-Jer Tsai.
Drs. Luoping Li and Xin Xie, postdoctoral associates in Dr. Tsai's laboratory were major contributors to the work. Others who took part include Jun Qin, George S. Jeha, Pradip K. Saha, Jun Yan, Claire Menoza Haueter and Lawrence Chan, all of BCM.
Funding for this research came from the National Institutes of Health and the Baylor Diabetes and Endocrinology Research Center funded by the National Institute of Diabetes and Digestive and Kidney Diseases at BCM.
This report will be available at cell/cell-metabolism/home.
For more basic science from Baylor College of Medicine, please go to bcm/fromthelab.
Source: Graciela Gutierrez
Baylor College of Medicine
Drs. Ming-Jer and Sophia Tsai, professors of molecular and cellular biology at BCM, have studied COUP-TFII (Chicken Ovalbumin Upstream Promoter Transcription Factor II) for decades, but only when they bred mice that had only one gene copy for the factor did they find that the animals had smaller fat cells and increased energy metabolism as well as enhanced response to insulin.
"If a mouse loses one copy of the gene, the animal becomes lean," said Ming-Jer Tsai. "It is more sensitive to the effects of insulin and resistant to obesity from a high fat diet."
Their studies raise the likely possibility that one can use COUP-TFII as a potential drug target for diabetes and obesity treatment.
Identifying a drug that could reduce the effect of COUP-TFII activity has become a future focus for their research, said Sophia Tsai.
"We don't need to inhibit it totally," she said. "Partial inhibition will do the trick as when you lose one copy of the gene, your fat cells are already much smaller and the animal is lean."
The animals not only have less fat, they also have more muscle and burn more energy, said Ming-Jer Tsai.
Drs. Luoping Li and Xin Xie, postdoctoral associates in Dr. Tsai's laboratory were major contributors to the work. Others who took part include Jun Qin, George S. Jeha, Pradip K. Saha, Jun Yan, Claire Menoza Haueter and Lawrence Chan, all of BCM.
Funding for this research came from the National Institutes of Health and the Baylor Diabetes and Endocrinology Research Center funded by the National Institute of Diabetes and Digestive and Kidney Diseases at BCM.
This report will be available at cell/cell-metabolism/home.
For more basic science from Baylor College of Medicine, please go to bcm/fromthelab.
Source: Graciela Gutierrez
Baylor College of Medicine
First Functional Stem-Cell Niche Model Created By Stanford Scientists
Like it or not, your living room probably says a lot about you. Given a few uninterrupted moments to poke around, a stranger could probably get a pretty good idea of your likes and dislikes, and maybe even your future plans. Scientists at the Stanford University School of Medicine employing a similar "peeping Tom" tactic to learn more about how stem cells develop have taken a significant step forward by devising a way to recreate the cells' lair - a microenvironment called a niche - in an adult animal.
"We have isolated the cells in mouse bone that make bone and cartilage from scratch and attract wandering blood stem cells," said Irving Weissman, MD, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and the director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "The stem cells can and do settle in these 'niches' and make blood that is exported to the body."
The research marks the first time that scientists have successfully recreated a functional stem-cell niche for further study. Weissman and his colleagues plan to use the model system to determine how the niche environment interacts with the blood stem cells to affect their development and fate, and how leukemias respond to these niches. They will also investigate the bone and cartilage healing capacity of these cells.
Weissman is the senior author of the study, which will be published Dec.10 in the advance online issue of Nature. Graduate student Charles Chan shares first authorship with postdoctoral scholars Ching-Cheng Chen, PhD, and Cynthia Luppen, PhD.
Blood-forming stem cells typically reside in the bone marrow. The researchers found that a specific subset of fetal mouse bone cells could not only take up residence and produce bone when injected near the kidney of an adult animal, but they also generated a bone marrow cavity that sheltered host-derived blood stem cells. In contrast, other subsets of fetal bone cells generated only bone.
"An amazing part of this study was the formation of organized bone, cartilage and blood stem cell niches from an initially dispersed set of cells," said Weissman, who is also a member of the Stanford Cancer Center. "If we can find the daughter cell in this population that is responsible for niche formation, we may learn enough to eventually be able to expand blood stem cell numbers so that a small number, say from umbilical cord blood, can be made into enough to treat several patients with failure of blood formation."
Suppressing the expression of factors involved in a specialized bone-building process called endochondrial ossification in the host mouse stopped the formation of the marrow cavity and the recruitment of host stem cells. Using similar fetal bone cells from parts of the skeleton that do not undergo the process - such as the skull and the jaw - also blocks cavity formation. The findings suggest that endochondrial ossification is a necessary step in setting up house for stem cells.
Other Stanford scientists involved in the research include postdoctoral scholar Jae-Beom Kim, PhD; associate professor of surgery Jill Helms, DDS, PhD; associate professor of medicine Calvin Kuo, MD, PhD; and senior postdoctoral fellow, Daniel Kraft, MD.
The research was funded by the National Institutes of Health and by Hope Street Kids.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford.
Source: Krista Conger
Stanford University Medical Center
"We have isolated the cells in mouse bone that make bone and cartilage from scratch and attract wandering blood stem cells," said Irving Weissman, MD, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and the director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "The stem cells can and do settle in these 'niches' and make blood that is exported to the body."
The research marks the first time that scientists have successfully recreated a functional stem-cell niche for further study. Weissman and his colleagues plan to use the model system to determine how the niche environment interacts with the blood stem cells to affect their development and fate, and how leukemias respond to these niches. They will also investigate the bone and cartilage healing capacity of these cells.
Weissman is the senior author of the study, which will be published Dec.10 in the advance online issue of Nature. Graduate student Charles Chan shares first authorship with postdoctoral scholars Ching-Cheng Chen, PhD, and Cynthia Luppen, PhD.
Blood-forming stem cells typically reside in the bone marrow. The researchers found that a specific subset of fetal mouse bone cells could not only take up residence and produce bone when injected near the kidney of an adult animal, but they also generated a bone marrow cavity that sheltered host-derived blood stem cells. In contrast, other subsets of fetal bone cells generated only bone.
"An amazing part of this study was the formation of organized bone, cartilage and blood stem cell niches from an initially dispersed set of cells," said Weissman, who is also a member of the Stanford Cancer Center. "If we can find the daughter cell in this population that is responsible for niche formation, we may learn enough to eventually be able to expand blood stem cell numbers so that a small number, say from umbilical cord blood, can be made into enough to treat several patients with failure of blood formation."
Suppressing the expression of factors involved in a specialized bone-building process called endochondrial ossification in the host mouse stopped the formation of the marrow cavity and the recruitment of host stem cells. Using similar fetal bone cells from parts of the skeleton that do not undergo the process - such as the skull and the jaw - also blocks cavity formation. The findings suggest that endochondrial ossification is a necessary step in setting up house for stem cells.
Other Stanford scientists involved in the research include postdoctoral scholar Jae-Beom Kim, PhD; associate professor of surgery Jill Helms, DDS, PhD; associate professor of medicine Calvin Kuo, MD, PhD; and senior postdoctoral fellow, Daniel Kraft, MD.
The research was funded by the National Institutes of Health and by Hope Street Kids.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford.
Source: Krista Conger
Stanford University Medical Center
Newsweek, Boston Globe Examine Ways To Combat Mosquito-Borne Illness
Newsweek Examines Efforts To Stop Disease Spread By Genetically Modifing Mosquitoes
Newsweek examines the genetic modification of mosquitoes in an effort to stem the spread of dengue fever and malaria. Dengue fever, which is transmitted by the Aedes Aegypti mosquito, "is spreading fast," according to the magazine, with more than 100 million people afflicted yearly. "There is no vaccine, no cure and no solution," it reports.
According to Newsweek, researchers "have devised a genetic modification that sterilizes the male Aedes, transforming the critter into his own worst enemy. He can still mate - but he can't breed." Scientists are also looking into ways of "tweaking the genome of the Anopheles gambiae mosquito, the species that carries the malaria parasite, which kills at least a million people each year."
The idea of genetically modified mosquitoes isn't new, "[b]ut it's only recently gained the support of mainstream health officials," and the Bill & Melinda Gates Foundation has invested $38 million into the research, Newsweek writes. Nonetheless, some environmental groups are raising issues, believing that "any tinkering with the world's delicately balanced ecosystems is unacceptable," according to the magazine (Underhill, Newsweek, 6/27).
Boston Globe Columnist Looks At DDT Home Spraying Debate In Uganda
Boston Globe columnist Derrick Jackson looks at household DDT spraying in Uganda to battle malaria, where the country's vice president, Gilbert Bukenya, recently said of the pesticide's critics, "You can start with [spraying] my house. Those shouting against it are shouting ignorance. They are simply not informed.'' Jackson writes that "the issue arouses great passion in sub-Saharan Africa, where access to the best drugs is woeful, and where simple home protections, such as window screens, are lacking." Jackson interviews regional malaria control director, Abwang Bernard, who said, "I understand the environmental arguments, but sometimes they cry so much fear, their arguments become inhuman to the people. It's almost like they want the people to perish for the animals. No chemical has no side effects. But let us first reduce infant mortality. That is the environment I care about right now.'' Bernard also discusses the challenges of using insecticide treated nets in Uganda (Jackson, Boston Globe, 6/27).
This information was reprinted from globalhealth.kff with kind permission from the Henry J. Kaiser Family Foundation. You can view the entire Kaiser Daily Global Health Policy Report, search the archives and sign up for email delivery at globalhealth.kff.
© Henry J. Kaiser Family Foundation. All rights reserved.
Newly Defined Signaling Pathway Could Mean Better Biofuel Sources
A newly defined biochemical pathway in plants may provide the scientific tools to design plants that will yield larger quantities of alternative transportation fuels than currently can be produced, according to Purdue University researchers.
The pathway moves materials that determine cell shape and size through a system of signaling proteins, said Dan Szymanski, a plant geneticist and cellular biologist. By learning more about the growth and development process, it may be possible to engineer plants with improved properties such as cell walls that are more massive or are more easily fermented in the biofuel process.
"We expect that cell wall material will to be a major source of biomass from plants designated for biofuel production," Szymanski said. "We need to learn more about how plant cells control the quality and amount of cell wall material."
He and his research team investigated plant growth and cell wall development from several scientific approaches in determining the cascade of events that leads to changes in the cell wall. They discovered that a protein called "SPIKE1" directs the protein signaling pathway. They report their findings in "Early Edition," the online publication of the journal Proceedings of the National Academy of Sciences. The study also will be published in the journal's March 11 print issue.
"Plant cells grow by expansion, which is cell wall synthesis coupled with an increase in cell size," Szymanski said. "The key questions we need to answer in trying to create plants more valuable for biofuel production center on understanding how plants integrate metabolism, cell growth and biomass production."
To answer those questions and be able to engineer plants for improved growth of biomass for alternative fuels, Szymanski and other scientists must investigate molecular function.
"Our research is focused on understanding signaling mechanisms," he said. "How does a cell interpret multiple types of information and then translate that information to a signal that says, 'Grow here, or modify or reinforce the cell wall here.' Or how does a cell know to make new cytoskeleton filaments at a certain time and place to define regions of growth that determine the cell's shape and size?"
Actin filaments comprise the cytoskeleton, which is the roadway for delivery and recycling of materials that drive plant growth and determine the cell shape and size. Actin is an abundant protein in organisms that have multiple cells with nuclei.
SPIKE1 is a master regulator of many growth control pathways, including the protein signaling pathway that produces the cytoskeleton. Szymanski and his colleagues were able to demonstrate that one of SPIKE1's functions is to control production of actin filament, which defines localized cell regions for delivery and recycling of growth materials.
"Wall construction in plants, just as in a road project, is a coordinated effort," Szymanski said. "The supply and demand of the materials needed for growth must be coordinated. The question is, how do cells regulate this?"
The signaling pathway, headed by SPIKE1, is responsible for organizing activities during construction - delivering materials and recycling materials that are used during growth, he said. After SPIKE1 initiates communication among proteins along the pathway, actin filaments are produced and changes in cell shape and size occur.
Cells also must coordinate with the activities of surrounding cells that have different shapes and functions.
"Cell expansion occurs in a crowded, but accommodating environment," Szymanski said. "As neighboring cells expand, this growth intrudes upon a neighbor. SPIKE1 generates signals so that cells can coordinate with neighboring cells' activities to promote organized cell expansion and proper cell-to-cell adhesion."
Szymanski and his colleagues used an altered version of the mustard family laboratory plant Arabidopsis to study SPIKE1's function and find the proteins that it activates and to which it binds.
They found that when they created mutant plants by switching off the SPIKE1 gene so that the function is lost, one result was improper growth that manifested as holes in the leaf epidermis.
By studying the results of turning off various other protein complexes in the pathway, Szymanski's team was able to follow the sequence of events that occur during signaling.
They also found that plants in which the function of one of the pathway's signaling proteins was altered resulted in mutants that all looked alike, Szymanski said. This suggested that the three major protein complexes the scientists investigated all function in a common pathway. The Purdue research team confirmed this by making double mutants - plants in which two of the proteins had been switched off. One of the pathway's protein complexes, called "WAVE," functions the same way in both humans and Arabidopsis, and the SPIKE1 signaling pathway is likely to function in other plants including rice and corn.
However, in other organisms with SPIKE1-like genes, switching off the gene kills the organism. This lethality has made it difficult for scientists to understand the function of SPIKE1 and comparable genes in other organisms, including humans. Since Arabidopsis survives when SPIKE1 is disrupted, the Purdue team was able to determine the signaling pathway.
The scientists hypothesize that SPIKE1 may both generate and organize protein complex signaling, Szymanski said. They also need to discover what activates SPIKE1. When the researchers understand enough about the processes involved in plant cell growth and development, then they may be able to design plants that are bigger with more cell wall that can be processed into biofuel.
"Learning more about SPIKE1 likely will help us gain a better understanding of the mechanics and regulation involved with the pathways that control cell architecture and development in plants, and also may be relevant to animal and human growth and development," Szymanski said.
The other researchers involved with this study were graduate student Dipanwita Basu, postdoctoral students Jie Le and Taya Zakharova, and research technician Eileen Mallery. All are in the Purdue Department of Agronomy.
The National Science Foundation and the Purdue Agricultural Research Program funded this project.
purdue
The pathway moves materials that determine cell shape and size through a system of signaling proteins, said Dan Szymanski, a plant geneticist and cellular biologist. By learning more about the growth and development process, it may be possible to engineer plants with improved properties such as cell walls that are more massive or are more easily fermented in the biofuel process.
"We expect that cell wall material will to be a major source of biomass from plants designated for biofuel production," Szymanski said. "We need to learn more about how plant cells control the quality and amount of cell wall material."
He and his research team investigated plant growth and cell wall development from several scientific approaches in determining the cascade of events that leads to changes in the cell wall. They discovered that a protein called "SPIKE1" directs the protein signaling pathway. They report their findings in "Early Edition," the online publication of the journal Proceedings of the National Academy of Sciences. The study also will be published in the journal's March 11 print issue.
"Plant cells grow by expansion, which is cell wall synthesis coupled with an increase in cell size," Szymanski said. "The key questions we need to answer in trying to create plants more valuable for biofuel production center on understanding how plants integrate metabolism, cell growth and biomass production."
To answer those questions and be able to engineer plants for improved growth of biomass for alternative fuels, Szymanski and other scientists must investigate molecular function.
"Our research is focused on understanding signaling mechanisms," he said. "How does a cell interpret multiple types of information and then translate that information to a signal that says, 'Grow here, or modify or reinforce the cell wall here.' Or how does a cell know to make new cytoskeleton filaments at a certain time and place to define regions of growth that determine the cell's shape and size?"
Actin filaments comprise the cytoskeleton, which is the roadway for delivery and recycling of materials that drive plant growth and determine the cell shape and size. Actin is an abundant protein in organisms that have multiple cells with nuclei.
SPIKE1 is a master regulator of many growth control pathways, including the protein signaling pathway that produces the cytoskeleton. Szymanski and his colleagues were able to demonstrate that one of SPIKE1's functions is to control production of actin filament, which defines localized cell regions for delivery and recycling of growth materials.
"Wall construction in plants, just as in a road project, is a coordinated effort," Szymanski said. "The supply and demand of the materials needed for growth must be coordinated. The question is, how do cells regulate this?"
The signaling pathway, headed by SPIKE1, is responsible for organizing activities during construction - delivering materials and recycling materials that are used during growth, he said. After SPIKE1 initiates communication among proteins along the pathway, actin filaments are produced and changes in cell shape and size occur.
Cells also must coordinate with the activities of surrounding cells that have different shapes and functions.
"Cell expansion occurs in a crowded, but accommodating environment," Szymanski said. "As neighboring cells expand, this growth intrudes upon a neighbor. SPIKE1 generates signals so that cells can coordinate with neighboring cells' activities to promote organized cell expansion and proper cell-to-cell adhesion."
Szymanski and his colleagues used an altered version of the mustard family laboratory plant Arabidopsis to study SPIKE1's function and find the proteins that it activates and to which it binds.
They found that when they created mutant plants by switching off the SPIKE1 gene so that the function is lost, one result was improper growth that manifested as holes in the leaf epidermis.
By studying the results of turning off various other protein complexes in the pathway, Szymanski's team was able to follow the sequence of events that occur during signaling.
They also found that plants in which the function of one of the pathway's signaling proteins was altered resulted in mutants that all looked alike, Szymanski said. This suggested that the three major protein complexes the scientists investigated all function in a common pathway. The Purdue research team confirmed this by making double mutants - plants in which two of the proteins had been switched off. One of the pathway's protein complexes, called "WAVE," functions the same way in both humans and Arabidopsis, and the SPIKE1 signaling pathway is likely to function in other plants including rice and corn.
However, in other organisms with SPIKE1-like genes, switching off the gene kills the organism. This lethality has made it difficult for scientists to understand the function of SPIKE1 and comparable genes in other organisms, including humans. Since Arabidopsis survives when SPIKE1 is disrupted, the Purdue team was able to determine the signaling pathway.
The scientists hypothesize that SPIKE1 may both generate and organize protein complex signaling, Szymanski said. They also need to discover what activates SPIKE1. When the researchers understand enough about the processes involved in plant cell growth and development, then they may be able to design plants that are bigger with more cell wall that can be processed into biofuel.
"Learning more about SPIKE1 likely will help us gain a better understanding of the mechanics and regulation involved with the pathways that control cell architecture and development in plants, and also may be relevant to animal and human growth and development," Szymanski said.
The other researchers involved with this study were graduate student Dipanwita Basu, postdoctoral students Jie Le and Taya Zakharova, and research technician Eileen Mallery. All are in the Purdue Department of Agronomy.
The National Science Foundation and the Purdue Agricultural Research Program funded this project.
purdue
New Technique Detects Proteins That Make Us Age
Chemists and biologists from the University of Bath have developed a new technique that could be used to diagnose and develop treatments for age-related conditions like Alzheimer's disease, diabetes and cancer.
In these diseases, proteins in the body react with sugars in a process called glycation. This modifies the protein's function and can trigger complications such as inflammation and premature aging.
The team at Bath, led by Dr Jean van den Elsen and Dr Tony James, has developed a technique that can detect glycated proteins and could in the future be used for diagnosing a whole range of diseases in patients.
They used a technique called gel electrophoresis, where samples are put into a thin gel layer and an electric current is applied. The gel acts like a molecular sieve, sorting proteins from the samples according to their size and shape, allowing scientists to identify whether specific proteins are present in the blood.
For this study, the researchers have patented a new type of gel electrophoresis, which uses boronic acid to distinguish between the glycated and unmodified proteins.
Dr Tony James from the University's Department of Chemistry explained: "Not all sugars are 'bad' - in fact many proteins contain beneficial 'good' sugar units.
"However, some sugars can be 'bad' and cause complications in diseases such as Alzheimer's and diabetes.
Dr Jean van den Elsen, from the University's Department of Biology & Biochemistry, said: "Our method specifically recognises these 'bad' sugars in the presence of the 'good' sugars and as such is an excellent diagnostic tool."
PhD student Marta Pereira Morais added: "We believe our method will also aid the development of new drug based therapies for these diseases."
Whilst the technique has only been assessed in the lab at present, the researchers say it has the potential to be developed into a test for these conditions in patients.
Dr James added: "Currently there is no blood test for Alzheimer's disease.
"If we can develop this technique into a test, doctors could potentially diagnose patients at an early stage before their symptoms show up in a brain scan."
The method could also be used to diagnose diabetes, which also leads to elevated levels of glycated proteins in the blood.
Dr van den Elsen said: "Whilst there are other methods of detecting diabetes, this will be an excellent way to measure the level of this glycation damage."
The importance of the technique has been recognised by publication in the scientific journal Proteomics and by the University which has patented the method.
The project was funded from a number of sources including the University's Enterprise Development Fund (EDF), the Biotechnology & Biologcial Sciences Research Council and the Royal Society.
The team is now looking for industrial collaborators to help develop the technique further with the aid of the University's technology transfer centre, Bath Ventures.
Source: Bath University
In these diseases, proteins in the body react with sugars in a process called glycation. This modifies the protein's function and can trigger complications such as inflammation and premature aging.
The team at Bath, led by Dr Jean van den Elsen and Dr Tony James, has developed a technique that can detect glycated proteins and could in the future be used for diagnosing a whole range of diseases in patients.
They used a technique called gel electrophoresis, where samples are put into a thin gel layer and an electric current is applied. The gel acts like a molecular sieve, sorting proteins from the samples according to their size and shape, allowing scientists to identify whether specific proteins are present in the blood.
For this study, the researchers have patented a new type of gel electrophoresis, which uses boronic acid to distinguish between the glycated and unmodified proteins.
Dr Tony James from the University's Department of Chemistry explained: "Not all sugars are 'bad' - in fact many proteins contain beneficial 'good' sugar units.
"However, some sugars can be 'bad' and cause complications in diseases such as Alzheimer's and diabetes.
Dr Jean van den Elsen, from the University's Department of Biology & Biochemistry, said: "Our method specifically recognises these 'bad' sugars in the presence of the 'good' sugars and as such is an excellent diagnostic tool."
PhD student Marta Pereira Morais added: "We believe our method will also aid the development of new drug based therapies for these diseases."
Whilst the technique has only been assessed in the lab at present, the researchers say it has the potential to be developed into a test for these conditions in patients.
Dr James added: "Currently there is no blood test for Alzheimer's disease.
"If we can develop this technique into a test, doctors could potentially diagnose patients at an early stage before their symptoms show up in a brain scan."
The method could also be used to diagnose diabetes, which also leads to elevated levels of glycated proteins in the blood.
Dr van den Elsen said: "Whilst there are other methods of detecting diabetes, this will be an excellent way to measure the level of this glycation damage."
The importance of the technique has been recognised by publication in the scientific journal Proteomics and by the University which has patented the method.
The project was funded from a number of sources including the University's Enterprise Development Fund (EDF), the Biotechnology & Biologcial Sciences Research Council and the Royal Society.
The team is now looking for industrial collaborators to help develop the technique further with the aid of the University's technology transfer centre, Bath Ventures.
Source: Bath University
Evolution Of A Sperm Activator
The fusion of sperm and egg succeeds in mammals because the sperm cells hyperactivate as they swim into the increasingly alkaline female reproductive tract. One fast-moving sperm drives on through the egg's fertilization barrier.
Mammals have sperm with a tail that reacts when calcium ions enter a microscopic channel in the tail and make the sperm go into overdrive. In fact, four genes are needed to produce the so-called CatSper ion channel in the sperm tail that hypermotivates the sperm. The CatSper genes may someday be targeted in a male contraceptive: no calcium-ion channel gene = no sperm hyperactivity = no fertilization (infertility related to the gene blockage has been proven in mice).
The interesting thing is that mammals, reptiles, sea urchins, and even some primitive lower invertebrates, animals without backbones, have all of these four genes, while birds, insects, worms, frogs, and most fish species, do not, says co-author Xingjiang Cai, M.D., Ph.D., of the Duke Department of Cell Biology and the Duke Department of Medicine, in the Division of Cardiology.
He and co-author David E. Clapham, M.D., Ph.D., have worked to learn more about the evolution of the sperm-specific ion channels. Their genomics study was designed to address the physiological significance of the CatSper channels and sperm hyperactivation across animal species using genomic databases to track evolutionary paths of the genes that contribute to this channel.
"One of the important things about studying this particular ion channel (on the sperm) is that targeting these genes should not affect any other ion channel in the body. Other ion channels are important in heart function and in other organs," Cai said. "The idea that this sperm ion channel could be blocked for a human male contraceptive is interesting."
A contraceptive drug used specifically in men with no side effects would be very appealing, he said.
"We were surprised that some vertebrates and a lot of other species do not have this CatSper channel, so we thought there must be other mechanisms for sperm activation, besides this unique ion channel," Cai said. The comparative genomics conducted in the study showed extensive gene loss of all four CatSper genes through evolution, especially in the vertebrate animals. The study also showed unique evolutionary characteristics of sperm-specific calcium ion channels and their adaptation to sperm biology.
The paper on the evolution of the CatSper genes, published in the Oct. 30 edition of PLoS ONE, notes that birds and fish often have thin oocyte (egg) cell walls, so the sperm in these animals doesn't need extra speed, just the genes required for normal swimming.
The other author of this paper is David E. Clapham of the Howard Hughes Medical Institute, the Department of Cardiology of Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston. This research was funded by the Howard Hughes Medical Institute, the National Institutes of Health, and the American Heart Association. PLos ONE is an interactive, open-access journal for peer-reviewed research that encourages commentary from readers.
Source
Mary Jane Gore
Senior Science Writer
Duke Medicine News and Communications
duke
Mammals have sperm with a tail that reacts when calcium ions enter a microscopic channel in the tail and make the sperm go into overdrive. In fact, four genes are needed to produce the so-called CatSper ion channel in the sperm tail that hypermotivates the sperm. The CatSper genes may someday be targeted in a male contraceptive: no calcium-ion channel gene = no sperm hyperactivity = no fertilization (infertility related to the gene blockage has been proven in mice).
The interesting thing is that mammals, reptiles, sea urchins, and even some primitive lower invertebrates, animals without backbones, have all of these four genes, while birds, insects, worms, frogs, and most fish species, do not, says co-author Xingjiang Cai, M.D., Ph.D., of the Duke Department of Cell Biology and the Duke Department of Medicine, in the Division of Cardiology.
He and co-author David E. Clapham, M.D., Ph.D., have worked to learn more about the evolution of the sperm-specific ion channels. Their genomics study was designed to address the physiological significance of the CatSper channels and sperm hyperactivation across animal species using genomic databases to track evolutionary paths of the genes that contribute to this channel.
"One of the important things about studying this particular ion channel (on the sperm) is that targeting these genes should not affect any other ion channel in the body. Other ion channels are important in heart function and in other organs," Cai said. "The idea that this sperm ion channel could be blocked for a human male contraceptive is interesting."
A contraceptive drug used specifically in men with no side effects would be very appealing, he said.
"We were surprised that some vertebrates and a lot of other species do not have this CatSper channel, so we thought there must be other mechanisms for sperm activation, besides this unique ion channel," Cai said. The comparative genomics conducted in the study showed extensive gene loss of all four CatSper genes through evolution, especially in the vertebrate animals. The study also showed unique evolutionary characteristics of sperm-specific calcium ion channels and their adaptation to sperm biology.
The paper on the evolution of the CatSper genes, published in the Oct. 30 edition of PLoS ONE, notes that birds and fish often have thin oocyte (egg) cell walls, so the sperm in these animals doesn't need extra speed, just the genes required for normal swimming.
The other author of this paper is David E. Clapham of the Howard Hughes Medical Institute, the Department of Cardiology of Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston. This research was funded by the Howard Hughes Medical Institute, the National Institutes of Health, and the American Heart Association. PLos ONE is an interactive, open-access journal for peer-reviewed research that encourages commentary from readers.
Source
Mary Jane Gore
Senior Science Writer
Duke Medicine News and Communications
duke
Human Skin Cells Reprogammed Into Embryonic Stem Cells, UCLA Study
UCLA stem cell scientists have reprogrammed human skin cells into cells with the same unlimited properties as embryonic stem cells without using embryos or eggs.
Led by scientists Kathrin Plath and William Lowry, UCLA researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Four regulator genes were used to create the cells, called induced pluripotent stem cells or iPS cells.
The UCLA study confirms the work first reported in late November of researcher Shinya Yamanaka at Kyoto University and James Thompson at the University of Wisconsin. The UCLA research appeared Feb. 11, 2008, in an early online edition of the journal Proceedings of the National Academy of the Sciences.
The implications for disease treatment could be significant. Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine. A patient's skin cells, for example, could be reprogrammed into embryonic stem cells. Those embryonic stem cells could then be prodded into becoming various cells types - beta islet cells to treat diabetes, hematopoetic cells to create a new blood supply for a leukemia patient, motor neuron cells to treat Parkinson's disease.
"Our reprogrammed human skin cells were virtually indistinguishable from human embryonic stem cells," said Plath, an assistant professor of biological chemistry, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and lead author of the study. "Our findings are an important step towards manipulating differentiated human cells to generate an unlimited supply of patient specific pluripotent stem cells. We are very excited about the potential implications."
The UCLA work was completed at about the same time the Yamanaka and Thomson reports were published. Taken together, the studies demonstrate that human iPS cells can be easily created by different laboratories and are likely to mark a milestone in stem cell-based regenerative medicine, Plath said.
These new techniques to develop stem cells could potentially replace a controversial method used to reprogram cells, somatic cell nuclear transfer (SCNT), sometimes referred to as therapeutic cloning. To date, therapeutic cloning has not been successful in humans. However, top stem cell scientists worldwide stress that further research comparing these reprogrammed cells with stem cells derived from embryos, considered the gold standard, is necessary. Additionally, many technical problems, such as the use of viruses to deliver the four genes for reprogramming, need to be overcome to produce safe iPS cells that can be used in the clinic.
"Reprogramming normal human cells into cells with identical properties to those in embryonic stem cells without SCNT may have important therapeutic ramifications and provide us with another valuable method to develop human stem cell lines," said Lowry, an assistant professor of molecular, cell and developmental biology, a Broad Stem Cell Center researcher and first author of the study. "It is important to remember that our research does not eliminate the need for embryo-based human embryonic stem cell research, but rather provides another avenue of worthwhile investigation."
The combination of four genes used to reprogram the skin cells regulate expression of downstream genes and either activate or silence their expression. The reprogrammed cells were not just functionally identical to embryonic stem cells. They also had identical biological structure, expressed the same genes and could be coaxed into giving rise to the same cell types as human embryonic stem cells.
The UCLA research team included four young scientists recruited to UCLA's new stem cell center in the wake of the passage of Proposition 71 in 2004, which created $3 billion in funding for embryonic stem cell research. The scientists were drawn to UCLA in part because of California's stem cell research friendly atmosphere and the funding opportunities created by Proposition 71. In addition to Plath and Lowry, the team included Amander Clarke, an assistant professor of molecular, cell and developmental biology, and April Pyle, an assistant professor of microbiology, immunology and molecular genetics.
The creation of the human iPS cells is an extension of Plath's work on mouse stem cell reprogramming. Plath headed up one of three research teams that were able to successfully reprogram mouse skin cells into mouse embryonic stem cells. That work appeared in the inaugural June 2007 issue of the journal Cell Stem Cell.
The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 150 members, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The institute supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Comprehensive Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit stemcell.ucla/.
Source: Kim Irwin
University of California - Los Angeles
Led by scientists Kathrin Plath and William Lowry, UCLA researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Four regulator genes were used to create the cells, called induced pluripotent stem cells or iPS cells.
The UCLA study confirms the work first reported in late November of researcher Shinya Yamanaka at Kyoto University and James Thompson at the University of Wisconsin. The UCLA research appeared Feb. 11, 2008, in an early online edition of the journal Proceedings of the National Academy of the Sciences.
The implications for disease treatment could be significant. Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine. A patient's skin cells, for example, could be reprogrammed into embryonic stem cells. Those embryonic stem cells could then be prodded into becoming various cells types - beta islet cells to treat diabetes, hematopoetic cells to create a new blood supply for a leukemia patient, motor neuron cells to treat Parkinson's disease.
"Our reprogrammed human skin cells were virtually indistinguishable from human embryonic stem cells," said Plath, an assistant professor of biological chemistry, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and lead author of the study. "Our findings are an important step towards manipulating differentiated human cells to generate an unlimited supply of patient specific pluripotent stem cells. We are very excited about the potential implications."
The UCLA work was completed at about the same time the Yamanaka and Thomson reports were published. Taken together, the studies demonstrate that human iPS cells can be easily created by different laboratories and are likely to mark a milestone in stem cell-based regenerative medicine, Plath said.
These new techniques to develop stem cells could potentially replace a controversial method used to reprogram cells, somatic cell nuclear transfer (SCNT), sometimes referred to as therapeutic cloning. To date, therapeutic cloning has not been successful in humans. However, top stem cell scientists worldwide stress that further research comparing these reprogrammed cells with stem cells derived from embryos, considered the gold standard, is necessary. Additionally, many technical problems, such as the use of viruses to deliver the four genes for reprogramming, need to be overcome to produce safe iPS cells that can be used in the clinic.
"Reprogramming normal human cells into cells with identical properties to those in embryonic stem cells without SCNT may have important therapeutic ramifications and provide us with another valuable method to develop human stem cell lines," said Lowry, an assistant professor of molecular, cell and developmental biology, a Broad Stem Cell Center researcher and first author of the study. "It is important to remember that our research does not eliminate the need for embryo-based human embryonic stem cell research, but rather provides another avenue of worthwhile investigation."
The combination of four genes used to reprogram the skin cells regulate expression of downstream genes and either activate or silence their expression. The reprogrammed cells were not just functionally identical to embryonic stem cells. They also had identical biological structure, expressed the same genes and could be coaxed into giving rise to the same cell types as human embryonic stem cells.
The UCLA research team included four young scientists recruited to UCLA's new stem cell center in the wake of the passage of Proposition 71 in 2004, which created $3 billion in funding for embryonic stem cell research. The scientists were drawn to UCLA in part because of California's stem cell research friendly atmosphere and the funding opportunities created by Proposition 71. In addition to Plath and Lowry, the team included Amander Clarke, an assistant professor of molecular, cell and developmental biology, and April Pyle, an assistant professor of microbiology, immunology and molecular genetics.
The creation of the human iPS cells is an extension of Plath's work on mouse stem cell reprogramming. Plath headed up one of three research teams that were able to successfully reprogram mouse skin cells into mouse embryonic stem cells. That work appeared in the inaugural June 2007 issue of the journal Cell Stem Cell.
The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 150 members, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The institute supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Comprehensive Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit stemcell.ucla/.
Source: Kim Irwin
University of California - Los Angeles
New Small And Medium Sized Enterprises Join TI Pharma By Signing Two New Projects
Three new small and medium sized enterprises (SMEs) - Syncom, Synvolux Therapeutics and InteRNA Technologies - have joined public-private partnership TI Pharma by participating in two new projects. These projects, focusing on cancer and inflammatory diseases, have a total budget of nearly 6 million euros.
The new consortium, formed by Syncom, Synvolux Therapeutics, and University Medical Center Groningen, focuses on designing a versatile drug delivery system for inflammatory diseases and cancer. Another new consortium is formed by InteRNA Technologies, Utrecht University and VU University Medical Center, and focuses on the development of anti-angiogenic microRNA-based therapeutic products for the treatment of cancer.
Versatile drug delivery platform for inflammatory diseases and cancer
New molecular entities (NMEs) in the drug development pipeline comprise various classes of kinase inhibitors that cause unacceptable toxicity in humans. Proper formulation might circumvent side effects and improve their general therapeutic efficacy. However, currently, no appropriate formulation technology is available for these kinase inhibitors.
This project focuses on a systematic approach in which chemical modification of NMEs is combined with drug formulation studies. This will lead to a versatile drug delivery platform for future clinical application of kinase inhibitors in the treatment of cancer and chronic inflammatory diseases. "This approach is expected to make targeted drug delivery finally meet its expectations, as it will become available for a variety of drug classes that are under development in the pharmaceutical industry," according to the consortium members.
Development of novel anti-angiogenic miRNA based therapeutics
"Conventional cancer treatment such as surgery, radiation therapy and chemotherapy are far from sufficient, therefore, new strategies of cancer treatment are needed more than ever," says Roel Schaapveld, Chief Executive Officer, InteRNA. There is a large body of evidence indicating that tumor growth and metastasis formation are dependent on the formation of new blood vessels. Furthermore, angiogenesis is an early event in the development of tumors, being already switched on in pre-cancerous events and long before visible or clinically relevant tumor mass is present. Schaapveld: "These two features make angiogenesis an ideal target for the development of novel anti-cancer strategies."
The recent discovery that non-coding RNAs, called microRNAs (miRNAs), play a critical role in gene regulation provides new opportunities to discover RNAs that can control angiogenesis. The major aim of this project is to establish a technology platform for the development of (anti-cancer) therapeutics based on angiostatic miRNAs. miRNA is utilized as a therapeutic modality and advanced nanoparticle delivery systems accomplish intracellular delivery of nucleic acid agents. These will be combined with the identification of surface receptor targets on tumor blood vessels to allow for therapeutic intervention. Eventually, this will result in the development of anti-angiogenic miRNA-based therapeutic products for the treatment of cancer.
Source: TI Pharma
The new consortium, formed by Syncom, Synvolux Therapeutics, and University Medical Center Groningen, focuses on designing a versatile drug delivery system for inflammatory diseases and cancer. Another new consortium is formed by InteRNA Technologies, Utrecht University and VU University Medical Center, and focuses on the development of anti-angiogenic microRNA-based therapeutic products for the treatment of cancer.
Versatile drug delivery platform for inflammatory diseases and cancer
New molecular entities (NMEs) in the drug development pipeline comprise various classes of kinase inhibitors that cause unacceptable toxicity in humans. Proper formulation might circumvent side effects and improve their general therapeutic efficacy. However, currently, no appropriate formulation technology is available for these kinase inhibitors.
This project focuses on a systematic approach in which chemical modification of NMEs is combined with drug formulation studies. This will lead to a versatile drug delivery platform for future clinical application of kinase inhibitors in the treatment of cancer and chronic inflammatory diseases. "This approach is expected to make targeted drug delivery finally meet its expectations, as it will become available for a variety of drug classes that are under development in the pharmaceutical industry," according to the consortium members.
Development of novel anti-angiogenic miRNA based therapeutics
"Conventional cancer treatment such as surgery, radiation therapy and chemotherapy are far from sufficient, therefore, new strategies of cancer treatment are needed more than ever," says Roel Schaapveld, Chief Executive Officer, InteRNA. There is a large body of evidence indicating that tumor growth and metastasis formation are dependent on the formation of new blood vessels. Furthermore, angiogenesis is an early event in the development of tumors, being already switched on in pre-cancerous events and long before visible or clinically relevant tumor mass is present. Schaapveld: "These two features make angiogenesis an ideal target for the development of novel anti-cancer strategies."
The recent discovery that non-coding RNAs, called microRNAs (miRNAs), play a critical role in gene regulation provides new opportunities to discover RNAs that can control angiogenesis. The major aim of this project is to establish a technology platform for the development of (anti-cancer) therapeutics based on angiostatic miRNAs. miRNA is utilized as a therapeutic modality and advanced nanoparticle delivery systems accomplish intracellular delivery of nucleic acid agents. These will be combined with the identification of surface receptor targets on tumor blood vessels to allow for therapeutic intervention. Eventually, this will result in the development of anti-angiogenic miRNA-based therapeutic products for the treatment of cancer.
Source: TI Pharma
New Strategy Aims To Reduce Reliance On Animal Testing
Testing the safety of chemicals ranging from pesticides to household cleaners will benefit from new technologies and a plan for collaboration, according to federal scientists from the National Institutes of Health (NIH) and the U.S. Environmental Protection Agency (EPA), who have announced a new toxicity testing agreement. The concept behind this agreement is highlighted in the Feb. 15, 2008 issue of the journal Science.
Two NIH institutes have formed a collaboration with the EPA to use the NIH Chemical Genomics Center's (NCGC) high-speed, automated screening robots to test suspected toxic compounds using cells and isolated molecular targets instead of laboratory animals. This new, trans-agency collaboration is anticipated to generate data more relevant to humans; expand the number of chemicals that are tested; and reduce the time, money and number of animals involved in testing. Full implementation of the hoped-for paradigm shift in toxicity testing will require validation of the new approaches, a substantial effort that could consume many years.
This collaboration is being made possible through a newly signed, five-year Memorandum of Understanding (MOU), which leverages the strengths of each organization. The MOU builds on the experimental toxicology expertise at the National Toxicology Program (NTP), headquartered at the National Institute of Environmental and Health Sciences (NIEHS), NIH; the high-throughput technology at NCGC, managed by the National Human Genome Research Institute (NHGRI), NIH; and the computational toxicology capabilities at the EPA's recently formed National Center for Computational Toxicology (NCCT).
The MOU provides for sample and information sharing necessary to more rapidly and effectively identify chemicals that might pose possible risks to the health of humans and animals and to the environment. It addresses opportunities for coordination in four basic areas related to achieving the toxicant testing goals, including: identification of toxicity pathways; selection of chemicals for testing; analysis and interpretation of data; and outreach to scientific and regulatory communities. The collective budget is yet to be determined.
The MOU and the plans articulated in the Science article provide a framework to implement the long-range vision outlined in the 2007 National Research Council (NRC) report, Toxicity Testing in the 21st Century: A Vision and a Strategy, which calls for a collaborative effort across the toxicology community to rely less on animal studies and more on in vitro tests using human cells and cellular components to identify chemicals with toxic effects. Importantly, the strategy calls for improvements in dose-response research, which will help predict toxicity at exposures that humans may encounter.
The collaborative research program is outlined in the jointly authored Science paper.
The co-authors - Francis S. Collins, M.D., Ph.D., NHGRI director; George M. Gray, Ph.D., assistant administrator for EPA's Office of Research and Development which houses the NCCT; and John R. Bucher, Ph.D., NTP associate director - describe the possibility of shifting from reliance on animal testing to biochemical- and cell-based assays, as well as those using lower organisms, such as zebrafish and roundworms.
Data collection to determine chemical toxicity currently relies heavily on whole-animal tests. The growing number of new chemicals, high testing costs and public unease with animal testing led to the search for alternate toxicology testing methods. Quantitative high-throughput screening (qHTS), developed at NCGC, increases the rate at which chemicals are tested, and profiles compounds over a wide range of concentrations. These qualities make the new qHTS technology ideal for toxicology testing, with the potential for advancing the goal of more accurate and timely public health decisions.
"A central component of federal effort will explore the use of high-throughput screening assays in toxicology," NHGRI's Dr. Collins said. "Such assays allow for the testing of thousands to hundreds of thousands of chemicals a day to determine their possible toxic effect." NCGC is part of a larger Molecular Libraries Imaging Program within the NIH Roadmap for Medical Research. It was designed to advance research on molecules from which most medicines marketed today are derived.
"We now are seeing tools newly available to us for chemical genomics research deployed for greater refinement, speed and capacity in chemical toxicity screening," Dr. Collins said.
"The experimental and computational expertise required to transform toxicology is an enormous undertaking and too great for any of our existing organizations to accomplish alone," said NTP's Dr. Bucher. "This collaborative approach allows us to draw on our individual strengths and establishes a long-term, multiple U.S. federal agency commitment." NTP will contribute thousands of compounds for testing. NTP's animal toxicology expertise will be utilized, along with a large database of the chemicals' effects on animals, with which the new cell-based data will be compared.
"As our detailed research strategy continues to develop, we will welcome the participation of other federal partners, as well as interested public and private sector organizations, to make this vision of 21st century toxicology a reality" said EPA's Dr. Gray. The EPA's engagement in this collaboration is part of its ToxCast™ program - an initiative launched in 2007 to revolutionize the agency's chemical toxicity evaluation procedures. ToxCast™ will use advances in computers, genomics and cellular biology to speed up toxicity testing and enhance capacity to screen new compounds.
Link for full-resolution b-roll clips from the NCGC facility.
The National Human Genome Research Institute is part of the National Institutes of Health. For more about NHGRI, visit genome/.
The National Institute of Environmental Health Sciences (NIEHS), a component of the National Institutes of Health (NIH), supports research to understand the effects of the environment on human health. For more information on environmental health topics, please visit our website at niehs.nih/.
The National Institutes of Health - "The Nation's Medical Research Agency" - includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more, visit nih/.
The Environmental Protection Agency's National Center for Computational Toxicology (NCCT) is a part of EPA's Office of Research and Development (ORD). Located in Research Triangle Park, N. C., NCCT coordinates and implements EPA's research in the field of computational toxicology. Computational toxicology is simply defined as the blending of modern computer science with molecular biology. The Center's goal is to improve the ability of the Agency to assess chemical hazard and risk. The Center's goal is to make the process more effective and efficient, while increasing the numbers of chemicals that can be evaluated. For more information about NCCT and its programs, visit epa/ncct/.
Source: Raymond MacDougall
NIH/National Human Genome Research Institute
Two NIH institutes have formed a collaboration with the EPA to use the NIH Chemical Genomics Center's (NCGC) high-speed, automated screening robots to test suspected toxic compounds using cells and isolated molecular targets instead of laboratory animals. This new, trans-agency collaboration is anticipated to generate data more relevant to humans; expand the number of chemicals that are tested; and reduce the time, money and number of animals involved in testing. Full implementation of the hoped-for paradigm shift in toxicity testing will require validation of the new approaches, a substantial effort that could consume many years.
This collaboration is being made possible through a newly signed, five-year Memorandum of Understanding (MOU), which leverages the strengths of each organization. The MOU builds on the experimental toxicology expertise at the National Toxicology Program (NTP), headquartered at the National Institute of Environmental and Health Sciences (NIEHS), NIH; the high-throughput technology at NCGC, managed by the National Human Genome Research Institute (NHGRI), NIH; and the computational toxicology capabilities at the EPA's recently formed National Center for Computational Toxicology (NCCT).
The MOU provides for sample and information sharing necessary to more rapidly and effectively identify chemicals that might pose possible risks to the health of humans and animals and to the environment. It addresses opportunities for coordination in four basic areas related to achieving the toxicant testing goals, including: identification of toxicity pathways; selection of chemicals for testing; analysis and interpretation of data; and outreach to scientific and regulatory communities. The collective budget is yet to be determined.
The MOU and the plans articulated in the Science article provide a framework to implement the long-range vision outlined in the 2007 National Research Council (NRC) report, Toxicity Testing in the 21st Century: A Vision and a Strategy, which calls for a collaborative effort across the toxicology community to rely less on animal studies and more on in vitro tests using human cells and cellular components to identify chemicals with toxic effects. Importantly, the strategy calls for improvements in dose-response research, which will help predict toxicity at exposures that humans may encounter.
The collaborative research program is outlined in the jointly authored Science paper.
The co-authors - Francis S. Collins, M.D., Ph.D., NHGRI director; George M. Gray, Ph.D., assistant administrator for EPA's Office of Research and Development which houses the NCCT; and John R. Bucher, Ph.D., NTP associate director - describe the possibility of shifting from reliance on animal testing to biochemical- and cell-based assays, as well as those using lower organisms, such as zebrafish and roundworms.
Data collection to determine chemical toxicity currently relies heavily on whole-animal tests. The growing number of new chemicals, high testing costs and public unease with animal testing led to the search for alternate toxicology testing methods. Quantitative high-throughput screening (qHTS), developed at NCGC, increases the rate at which chemicals are tested, and profiles compounds over a wide range of concentrations. These qualities make the new qHTS technology ideal for toxicology testing, with the potential for advancing the goal of more accurate and timely public health decisions.
"A central component of federal effort will explore the use of high-throughput screening assays in toxicology," NHGRI's Dr. Collins said. "Such assays allow for the testing of thousands to hundreds of thousands of chemicals a day to determine their possible toxic effect." NCGC is part of a larger Molecular Libraries Imaging Program within the NIH Roadmap for Medical Research. It was designed to advance research on molecules from which most medicines marketed today are derived.
"We now are seeing tools newly available to us for chemical genomics research deployed for greater refinement, speed and capacity in chemical toxicity screening," Dr. Collins said.
"The experimental and computational expertise required to transform toxicology is an enormous undertaking and too great for any of our existing organizations to accomplish alone," said NTP's Dr. Bucher. "This collaborative approach allows us to draw on our individual strengths and establishes a long-term, multiple U.S. federal agency commitment." NTP will contribute thousands of compounds for testing. NTP's animal toxicology expertise will be utilized, along with a large database of the chemicals' effects on animals, with which the new cell-based data will be compared.
"As our detailed research strategy continues to develop, we will welcome the participation of other federal partners, as well as interested public and private sector organizations, to make this vision of 21st century toxicology a reality" said EPA's Dr. Gray. The EPA's engagement in this collaboration is part of its ToxCast™ program - an initiative launched in 2007 to revolutionize the agency's chemical toxicity evaluation procedures. ToxCast™ will use advances in computers, genomics and cellular biology to speed up toxicity testing and enhance capacity to screen new compounds.
Link for full-resolution b-roll clips from the NCGC facility.
The National Human Genome Research Institute is part of the National Institutes of Health. For more about NHGRI, visit genome/.
The National Institute of Environmental Health Sciences (NIEHS), a component of the National Institutes of Health (NIH), supports research to understand the effects of the environment on human health. For more information on environmental health topics, please visit our website at niehs.nih/.
The National Institutes of Health - "The Nation's Medical Research Agency" - includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more, visit nih/.
The Environmental Protection Agency's National Center for Computational Toxicology (NCCT) is a part of EPA's Office of Research and Development (ORD). Located in Research Triangle Park, N. C., NCCT coordinates and implements EPA's research in the field of computational toxicology. Computational toxicology is simply defined as the blending of modern computer science with molecular biology. The Center's goal is to improve the ability of the Agency to assess chemical hazard and risk. The Center's goal is to make the process more effective and efficient, while increasing the numbers of chemicals that can be evaluated. For more information about NCCT and its programs, visit epa/ncct/.
Source: Raymond MacDougall
NIH/National Human Genome Research Institute
New Research Results Show That Investigational Drug Phenoxodiol Targets Cancer Protein, Causing Cancer Cell Death
A new
study further supports the unique mechanism of action of phenoxodiol, an
investigational drug being studied for the treatment of ovarian cancer. The
drug appears to work by targeting a certain tumor-specific protein, which
triggers a series of events that selectively induce cancer cell death.
Phenoxodiol is currently being studied in patients with resistant ovarian
cancer, a disease that is estimated to kill more than 15,000 women this
year in the U.S. alone.
In studies conducted thus far, phenoxodiol has exhibited an excellent
safety profile, with few patients experiencing side effects attributed to
the drug.
The new research was conducted by a team headed by Research Professor
Michael Berridge Ph.D., at the Malaghan Institute of Medical Research - New
Zealand's leading medical research facility focused on finding cures for
cancer and other diseases.
Findings from the study, to be presented at the New Zealand Society of
Oncology meeting to be held May 9-11, help explain the mechanism by which
phenoxodiol induces cancer cell death. This new research supports previous
findings by Professor James Morre, Ph.D. at Purdue University, which showed
that phenoxodiol interacts with the tumor-specific protein, tNOX, to
selectively block cancerous cells from dividing by switching off a variety
of pro-survival signaling mechanisms within the cancer cell, causing it to
die.
In cases of late-stage ovarian cancer, standard chemotherapy drugs
often have a limited duration of use. The cancer can progressively lose its
sensitivity to chemotherapy until cancer cells become unresponsive causing
resistance, a major barrier to successful cancer treatment. In laboratory
studies and Phase II clinical trials, phenoxodiol showed promise in
restoring drug sensitivity to resistant cancer cells.
"Phenoxodiol has a unique mechanism of action not exhibited by other
anticancer drugs in current use.," said Dr. Berridge. "By inhibiting plasma
membrane electron transport selectively in cancer cells, phenoxodiol
subjects these cells to stress that leads to cell death. This novel drug
and its related analogues have the potential to enhance anticancer efficacy
by a different mechanism, promising a new approach to management of solid
tumors in a range of clinical settings. As the first compound to operate
via this pathway, confirmatory evidence to validate the mechanism of action
is very desirable."
Specific Findings Identify Specific Proteins Associated with Unlocking
the Mystery for Why Cancer Cells don't Die the Way Healthy Cells Do
Evidence from this new study indicates that phenoxodiol inhibits
proliferation of many cancer cell lines and some primary immune cells.
Phenoxodiol induces the destruction of cancer cells by disrupting a stress
pathway in the outer cell membrane, causing down regulation of the
FLICE-inhibitory protein, FLIP, and resulting in caspase-dependent and
independent degradation of the X-linked inhibitor of cell death, XIAP.
Phenoxodiol selectively limits plasma membrane electron transport in
cancer cells, by binding to a cancer specific surface plasma membrane
electron transport element on cancer cells thereby inhibiting their
proliferation, whereas the compound has no such effect on normal healthy
cells.
Multinational trial underway
Phenoxodiol in combination with carboplatin is currently being studied
in a multi-national Phase III clinical trial called OVATURE, following
positive findings of previous trials conducted at Yale-New Haven Hospital.
The OVATURE trial will take place in 60 sites in the United States, Europe,
and Australia. Preliminary results from the trial are expected within 18
months.
About phenoxodiol:
Phenoxodiol is being developed as a therapy for late-stage,
chemo-resistant prostate, ovarian and cervical cancers. Phenoxodiol is an
investigational drug and, as such, is not commercially available. It is a
novel-acting drug that inhibits key pro-survival signaling pathways
operating via sphingosine-1-phosphate and Akt. Inhibition of these pathways
leads to prevention of phosphorylation of key anti-apoptotic proteins such
as XIAP. Loss of activity of these proteins restores the ability of
chemoresistant tumor cells to undergo apoptosis in response to
chemotherapy. The putative molecular target for phenoxodiol is a
tumor-specific protein, accounting for the highly selective nature of the
drug.
About Marshall Edwards Inc:
Marshall Edwards, Inc. (Nasdaq: MSHL) is a specialist oncology company
focused on the clinical development of novel anti-cancer therapeutics.
These derive from a flavonoid technology platform which has generated a
number of novel compounds characterized by broad ranging efficacy against a
range of cancer targets with few side effects. The unique combination of
efficacy and safety has been explained by their ability to target an enzyme
present on the surface of cancer cells, thereby inhibiting the production
of pro-survival proteins within the cell. Marshall Edwards, Inc. has
licensed rights from Novogen Limited (Nasdaq: NVGN) to bring three oncology
drugs - phenoxodiol, NV-196 and NV-143 - to market globally. Marshall
Edwards, Inc. is majority owned by Novogen, an Australian biotechnology
company that is specializing in the development of therapeutics based on a
flavonoid technology platform. Novogen, based in Sydney, Australia, is
developing a range of therapeutics across the fields of oncology,
cardiovascular disease and inflammatory diseases. More information on
phenoxodiol and on the Novogen group of companies can be found at
marshalledwardsinc and novogen.
Under U.S. law, a new drug cannot be marketed until it has been
investigated in clinical trials and approved by the FDA as being safe and
effective for the intended use. Statements included in this press release
that are not historical in nature are "forward-looking statements" within
the meaning of the "safe harbor" provisions of the Private Securities
Litigation Reform Act of 1995. You should be aware that our actual results
could differ materially from those contained in the forward-looking
statements, which are based on management's current expectations and are
subject to a number of risks and uncertainties, including, but not limited
to, our failure to successfully commercialize our product candidates; costs
and delays in the development and/or FDA approval, or the failure to obtain
such approval, of our product candidates; uncertainties in clinical trial
results; our inability to maintain or enter into, and the risks resulting
from our dependence upon, collaboration or contractual arrangements
necessary for the development, manufacture, commercialization, marketing,
sales and distribution of any products; competitive factors; our inability
to protect our patents or proprietary rights and obtain necessary rights to
third arty patents and intellectual property to operate our business; our
inability to operate our business without infringing the patents and
proprietary rights of others; general economic conditions; the failure of
any products to gain market acceptance; our inability to obtain any
additional required financing; technological changes; government
regulation; changes in industry practice; and one-time events. We do not
intend to update any of these factors or to publicly announce the results
of any revisions to these forward-looking statements.
Marshall Edwards Inc.
marshalledwardsinc
study further supports the unique mechanism of action of phenoxodiol, an
investigational drug being studied for the treatment of ovarian cancer. The
drug appears to work by targeting a certain tumor-specific protein, which
triggers a series of events that selectively induce cancer cell death.
Phenoxodiol is currently being studied in patients with resistant ovarian
cancer, a disease that is estimated to kill more than 15,000 women this
year in the U.S. alone.
In studies conducted thus far, phenoxodiol has exhibited an excellent
safety profile, with few patients experiencing side effects attributed to
the drug.
The new research was conducted by a team headed by Research Professor
Michael Berridge Ph.D., at the Malaghan Institute of Medical Research - New
Zealand's leading medical research facility focused on finding cures for
cancer and other diseases.
Findings from the study, to be presented at the New Zealand Society of
Oncology meeting to be held May 9-11, help explain the mechanism by which
phenoxodiol induces cancer cell death. This new research supports previous
findings by Professor James Morre, Ph.D. at Purdue University, which showed
that phenoxodiol interacts with the tumor-specific protein, tNOX, to
selectively block cancerous cells from dividing by switching off a variety
of pro-survival signaling mechanisms within the cancer cell, causing it to
die.
In cases of late-stage ovarian cancer, standard chemotherapy drugs
often have a limited duration of use. The cancer can progressively lose its
sensitivity to chemotherapy until cancer cells become unresponsive causing
resistance, a major barrier to successful cancer treatment. In laboratory
studies and Phase II clinical trials, phenoxodiol showed promise in
restoring drug sensitivity to resistant cancer cells.
"Phenoxodiol has a unique mechanism of action not exhibited by other
anticancer drugs in current use.," said Dr. Berridge. "By inhibiting plasma
membrane electron transport selectively in cancer cells, phenoxodiol
subjects these cells to stress that leads to cell death. This novel drug
and its related analogues have the potential to enhance anticancer efficacy
by a different mechanism, promising a new approach to management of solid
tumors in a range of clinical settings. As the first compound to operate
via this pathway, confirmatory evidence to validate the mechanism of action
is very desirable."
Specific Findings Identify Specific Proteins Associated with Unlocking
the Mystery for Why Cancer Cells don't Die the Way Healthy Cells Do
Evidence from this new study indicates that phenoxodiol inhibits
proliferation of many cancer cell lines and some primary immune cells.
Phenoxodiol induces the destruction of cancer cells by disrupting a stress
pathway in the outer cell membrane, causing down regulation of the
FLICE-inhibitory protein, FLIP, and resulting in caspase-dependent and
independent degradation of the X-linked inhibitor of cell death, XIAP.
Phenoxodiol selectively limits plasma membrane electron transport in
cancer cells, by binding to a cancer specific surface plasma membrane
electron transport element on cancer cells thereby inhibiting their
proliferation, whereas the compound has no such effect on normal healthy
cells.
Multinational trial underway
Phenoxodiol in combination with carboplatin is currently being studied
in a multi-national Phase III clinical trial called OVATURE, following
positive findings of previous trials conducted at Yale-New Haven Hospital.
The OVATURE trial will take place in 60 sites in the United States, Europe,
and Australia. Preliminary results from the trial are expected within 18
months.
About phenoxodiol:
Phenoxodiol is being developed as a therapy for late-stage,
chemo-resistant prostate, ovarian and cervical cancers. Phenoxodiol is an
investigational drug and, as such, is not commercially available. It is a
novel-acting drug that inhibits key pro-survival signaling pathways
operating via sphingosine-1-phosphate and Akt. Inhibition of these pathways
leads to prevention of phosphorylation of key anti-apoptotic proteins such
as XIAP. Loss of activity of these proteins restores the ability of
chemoresistant tumor cells to undergo apoptosis in response to
chemotherapy. The putative molecular target for phenoxodiol is a
tumor-specific protein, accounting for the highly selective nature of the
drug.
About Marshall Edwards Inc:
Marshall Edwards, Inc. (Nasdaq: MSHL) is a specialist oncology company
focused on the clinical development of novel anti-cancer therapeutics.
These derive from a flavonoid technology platform which has generated a
number of novel compounds characterized by broad ranging efficacy against a
range of cancer targets with few side effects. The unique combination of
efficacy and safety has been explained by their ability to target an enzyme
present on the surface of cancer cells, thereby inhibiting the production
of pro-survival proteins within the cell. Marshall Edwards, Inc. has
licensed rights from Novogen Limited (Nasdaq: NVGN) to bring three oncology
drugs - phenoxodiol, NV-196 and NV-143 - to market globally. Marshall
Edwards, Inc. is majority owned by Novogen, an Australian biotechnology
company that is specializing in the development of therapeutics based on a
flavonoid technology platform. Novogen, based in Sydney, Australia, is
developing a range of therapeutics across the fields of oncology,
cardiovascular disease and inflammatory diseases. More information on
phenoxodiol and on the Novogen group of companies can be found at
marshalledwardsinc and novogen.
Under U.S. law, a new drug cannot be marketed until it has been
investigated in clinical trials and approved by the FDA as being safe and
effective for the intended use. Statements included in this press release
that are not historical in nature are "forward-looking statements" within
the meaning of the "safe harbor" provisions of the Private Securities
Litigation Reform Act of 1995. You should be aware that our actual results
could differ materially from those contained in the forward-looking
statements, which are based on management's current expectations and are
subject to a number of risks and uncertainties, including, but not limited
to, our failure to successfully commercialize our product candidates; costs
and delays in the development and/or FDA approval, or the failure to obtain
such approval, of our product candidates; uncertainties in clinical trial
results; our inability to maintain or enter into, and the risks resulting
from our dependence upon, collaboration or contractual arrangements
necessary for the development, manufacture, commercialization, marketing,
sales and distribution of any products; competitive factors; our inability
to protect our patents or proprietary rights and obtain necessary rights to
third arty patents and intellectual property to operate our business; our
inability to operate our business without infringing the patents and
proprietary rights of others; general economic conditions; the failure of
any products to gain market acceptance; our inability to obtain any
additional required financing; technological changes; government
regulation; changes in industry practice; and one-time events. We do not
intend to update any of these factors or to publicly announce the results
of any revisions to these forward-looking statements.
Marshall Edwards Inc.
marshalledwardsinc
Grasping Bacterial 'Friending' Paves The Way To Disrupt Biofilm Creation
Finding a biological mechanism much like an online social network, scientists have identified the bacterial protein VpsT as the master regulator in Vibrio, the cause of cholera and other enteric diseases. This discovery, now published in the journal Science, provides a major tool to combat enteric disease.
For decades, it has been observed that bacteria engage in biofilm formation in nature and the lab. Like the online social network Facebook, free-swimming bacteria ditch the solitary lifestyle to form a biofilm community, but only after they've signaled their intention to do so to others. The protein VpsT receives the invitation and accepts it by starting a cellular program facilitating the process. "We have the parts list now," said Holger Sondermann, professor at Cornell University's College of Veterinary Medicine. "The next step will be to develop a clear understanding of the triggers and processes that regulate biofilm formation. With this data, we can find opportunities to disrupt the process and find entry points for therapeutic interventions."
Thus, bacteria hunker down with millions of other bacteria to form a biofilm community powerful enough to fog your contacts, rot your teeth, corrode metal and cause a host of human and animal diseases. Biofilms have been implicated in numerous chronic infections including cystic fibrosis, otitis media and prostatitis. Through interactions within a biofilm, the resident population of bacteria is likely to benefit from increased metabolic efficiency, substrate accessibility, enhanced resistance to environmental stress and antibiotics and an increased ability to cause infection and disease, says Sondermann.
This new research, "Vibrio cholerae VpsT Regulates Matrix Production and Motility by Directly Sensing Cyclic di-GMP," was published in the latest journal Science, Feb. 12, 2010. In addition to Sondermann, it was also authored by Petya Krasteva, first author, a graduate student in biochemistry, molecular and cellular biology, and by Marcos V. A. S. Navarro, a postdoctoral fellow in the Sondermann group. The work is a close collaboration with Fitnat H. Yildiz's laboratory at the University of California at Santa Cruz, and her a postdoctoral fellow Jiunn C. N. Fong, and her graduate students Nicholas J. Shikuma and Sinem Beyhan.
The project was funded by grants from the National Institutes of Health and the Pew Foundation.
Source:
Blaine Friedlander
Cornell University
For decades, it has been observed that bacteria engage in biofilm formation in nature and the lab. Like the online social network Facebook, free-swimming bacteria ditch the solitary lifestyle to form a biofilm community, but only after they've signaled their intention to do so to others. The protein VpsT receives the invitation and accepts it by starting a cellular program facilitating the process. "We have the parts list now," said Holger Sondermann, professor at Cornell University's College of Veterinary Medicine. "The next step will be to develop a clear understanding of the triggers and processes that regulate biofilm formation. With this data, we can find opportunities to disrupt the process and find entry points for therapeutic interventions."
Thus, bacteria hunker down with millions of other bacteria to form a biofilm community powerful enough to fog your contacts, rot your teeth, corrode metal and cause a host of human and animal diseases. Biofilms have been implicated in numerous chronic infections including cystic fibrosis, otitis media and prostatitis. Through interactions within a biofilm, the resident population of bacteria is likely to benefit from increased metabolic efficiency, substrate accessibility, enhanced resistance to environmental stress and antibiotics and an increased ability to cause infection and disease, says Sondermann.
This new research, "Vibrio cholerae VpsT Regulates Matrix Production and Motility by Directly Sensing Cyclic di-GMP," was published in the latest journal Science, Feb. 12, 2010. In addition to Sondermann, it was also authored by Petya Krasteva, first author, a graduate student in biochemistry, molecular and cellular biology, and by Marcos V. A. S. Navarro, a postdoctoral fellow in the Sondermann group. The work is a close collaboration with Fitnat H. Yildiz's laboratory at the University of California at Santa Cruz, and her a postdoctoral fellow Jiunn C. N. Fong, and her graduate students Nicholas J. Shikuma and Sinem Beyhan.
The project was funded by grants from the National Institutes of Health and the Pew Foundation.
Source:
Blaine Friedlander
Cornell University
DNA In Sperm Altered By Cigarette Smoke, Genetic Damage Could Pass To Offspring
The science has long been clear that smoking causes cancer, but new research shows that children could inherit genetic damage from a father who smokes.
Canadian researchers have demonstrated in mice that smoking can cause changes in the DNA sequence of sperm cells, alterations that could potentially be inherited by offspring. The results of their study are published in the June 1 issue of Cancer Research, a journal of the American Association for Cancer Research.
"Here we are looking at male germline mutations, which are mutations in the DNA of sperm. If inherited, these mutations persist as irreversible changes in the genetic composition of off-spring." said Carole Yauk, Ph.D., lead author of the study and research scientist in the Mutagenesis Section of Health Canada's Environmental and Occupational Toxicology Division. "We have known that mothers who smoke can harm their fetuses, and here we show evidence that fathers can potentially damage offspring long before they may even meet their future mate."
Males, whether they are mouse or man, generate a constant supply of new sperm from self-renewing spermatogonial stem cells. Yauk, along with colleagues at Health Canada and McMaster University, studied the spermatogonial stem cells of mature mice that had been exposed to cigarette smoke for either six or 12 weeks to look for alterations in a specific stretch of repeated portions of DNA, called Ms6-hm, which does not contain any known genes. The "smoking" mice were exposed to two cigarettes per day, the equivalent - based on blood levels of tobacco by-products - of an average human smoker, according to research previously published by one of the study's co-authors.
Yauk and her colleagues found that the rate of Ms6-hm mutations in the smoking mice were 1.4 times higher than that of non-smoking mice at six weeks, and 1.7 times that of non-smoking mice at 12 weeks. "This suggests that damage is related to the duration of exposure, so the longer you smoke the more mutations accumulate and the more likely a potential effect may arise in the offspring," Yauk said.
According to Yauk, previous studies have shown that Ms6-hm and similar locations of non-coding DNA are sensitive to damage from radiation, mutagenic chemicals and intense industrial air particulate pollution. While the researchers did not specifically study the protein-coding regions of DNA where genes reside, Yauk notes that previous studies correlate mutations in non-coding regions with those in coding regions, and that some repetitive regions of DNA (not exam-ined in this study) are associated with genes.
"It stands to reason that mutations could also interfere with genes, but our ongoing research looks to clarify the severity of DNA damage throughout the genome," said Yauk. "So, while some men say they'll quit smoking after their child is born, this represents a good reason to quit well in advance of trying to conceive."
Among the next steps in gaining a better understanding of the germline genetic health conse-quences of smoking, Yauk and her colleagues plan to study how altered DNA manifests itself in the children and grandchildren of male mice that are exposed to firsthand smoke. They also plan to study the effects of secondhand smoke on male mice as well the possibility that the eggs of females are affected by smoke.
Yauk's colleagues include fellow researchers from Health Canada and Martin Stämpfli, Ph.D., and his laboratory team at McMaster University. Funding for this research was provided by grants from the Canadian Regulatory System for Biotechnology and the Canadian Institutes of Health Research.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.
Contact: Greg Lester
American Association for Cancer Research
Canadian researchers have demonstrated in mice that smoking can cause changes in the DNA sequence of sperm cells, alterations that could potentially be inherited by offspring. The results of their study are published in the June 1 issue of Cancer Research, a journal of the American Association for Cancer Research.
"Here we are looking at male germline mutations, which are mutations in the DNA of sperm. If inherited, these mutations persist as irreversible changes in the genetic composition of off-spring." said Carole Yauk, Ph.D., lead author of the study and research scientist in the Mutagenesis Section of Health Canada's Environmental and Occupational Toxicology Division. "We have known that mothers who smoke can harm their fetuses, and here we show evidence that fathers can potentially damage offspring long before they may even meet their future mate."
Males, whether they are mouse or man, generate a constant supply of new sperm from self-renewing spermatogonial stem cells. Yauk, along with colleagues at Health Canada and McMaster University, studied the spermatogonial stem cells of mature mice that had been exposed to cigarette smoke for either six or 12 weeks to look for alterations in a specific stretch of repeated portions of DNA, called Ms6-hm, which does not contain any known genes. The "smoking" mice were exposed to two cigarettes per day, the equivalent - based on blood levels of tobacco by-products - of an average human smoker, according to research previously published by one of the study's co-authors.
Yauk and her colleagues found that the rate of Ms6-hm mutations in the smoking mice were 1.4 times higher than that of non-smoking mice at six weeks, and 1.7 times that of non-smoking mice at 12 weeks. "This suggests that damage is related to the duration of exposure, so the longer you smoke the more mutations accumulate and the more likely a potential effect may arise in the offspring," Yauk said.
According to Yauk, previous studies have shown that Ms6-hm and similar locations of non-coding DNA are sensitive to damage from radiation, mutagenic chemicals and intense industrial air particulate pollution. While the researchers did not specifically study the protein-coding regions of DNA where genes reside, Yauk notes that previous studies correlate mutations in non-coding regions with those in coding regions, and that some repetitive regions of DNA (not exam-ined in this study) are associated with genes.
"It stands to reason that mutations could also interfere with genes, but our ongoing research looks to clarify the severity of DNA damage throughout the genome," said Yauk. "So, while some men say they'll quit smoking after their child is born, this represents a good reason to quit well in advance of trying to conceive."
Among the next steps in gaining a better understanding of the germline genetic health conse-quences of smoking, Yauk and her colleagues plan to study how altered DNA manifests itself in the children and grandchildren of male mice that are exposed to firsthand smoke. They also plan to study the effects of secondhand smoke on male mice as well the possibility that the eggs of females are affected by smoke.
Yauk's colleagues include fellow researchers from Health Canada and Martin Stämpfli, Ph.D., and his laboratory team at McMaster University. Funding for this research was provided by grants from the Canadian Regulatory System for Biotechnology and the Canadian Institutes of Health Research.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.
Contact: Greg Lester
American Association for Cancer Research
Potential Leap Forward In Electron Microscopy
MIT electrical engineers have proposed a new scheme that can overcome a critical limitation of high-resolution electron microscopes: they cannot be used to image living cells because the electrons destroy the samples. The researchers suggest using a quantum mechanical measurement technique that allows electrons to sense objects remotely without ever hitting the imaged objects, thus avoiding damage.
Why it matters: A non-invasive electron microscope could shed light on fundamental questions about life and matter, allowing researchers to observe molecules inside a living cell without disturbing them. If successful, such microscopes would surmount what Nobel laureate Dennis Gabor concluded in 1956 was the fundamental limitation of electron microscopy: "The destruction of the object by the exploring agent."
How it works: Traditional electron microscopes use a particle beam of electrons, instead of light, to image specimens. These beams offer extremely high resolution, up to 0.2 to 10 nanometers - 10 to 1,000 times greater than a traditional light microscope.
In contrast, with the new proposed quantum mechanical setup, electrons would not directly strike the object being imaged. Instead, an electron would flow around one of two rings, arranged one above the other. The rings would be close enough together that the electron could hop easily between them. However, if an object (such as a cell) were placed between the rings, it would prevent the electron from hopping, and the electron would be trapped in one ring.
This setup would scan one "pixel" of the specimen at a time, putting them all together to create the full image. Whenever the electron is trapped, the system would know that there is a dark pixel in that spot.
Next steps: Assistant Professor Mehmet Fatih Yanik, senior author of the paper, says he expects the work "will likely ignite experimental efforts around the world for its realization, with perhaps the first prototype appearing in five years or so."
Though technical challenges need to be overcome (such as preventing the charged electron from interacting with other metals in the microscope), Yanik believes that eventually such a microscope could achieve single-nanometer resolution. That level of resolution would allow scientists to view molecules such as enzymes and nucleic acids inside living cells.
"Non-destructive Electron Microscopy and Interaction-free Quantum Measurements," William Putnan and Mehmet Fatih Yanik. Physical Review A - Rapid Communications, October issue.
Source:
Jen Hirsch
Massachusetts Institute of Technology
Why it matters: A non-invasive electron microscope could shed light on fundamental questions about life and matter, allowing researchers to observe molecules inside a living cell without disturbing them. If successful, such microscopes would surmount what Nobel laureate Dennis Gabor concluded in 1956 was the fundamental limitation of electron microscopy: "The destruction of the object by the exploring agent."
How it works: Traditional electron microscopes use a particle beam of electrons, instead of light, to image specimens. These beams offer extremely high resolution, up to 0.2 to 10 nanometers - 10 to 1,000 times greater than a traditional light microscope.
In contrast, with the new proposed quantum mechanical setup, electrons would not directly strike the object being imaged. Instead, an electron would flow around one of two rings, arranged one above the other. The rings would be close enough together that the electron could hop easily between them. However, if an object (such as a cell) were placed between the rings, it would prevent the electron from hopping, and the electron would be trapped in one ring.
This setup would scan one "pixel" of the specimen at a time, putting them all together to create the full image. Whenever the electron is trapped, the system would know that there is a dark pixel in that spot.
Next steps: Assistant Professor Mehmet Fatih Yanik, senior author of the paper, says he expects the work "will likely ignite experimental efforts around the world for its realization, with perhaps the first prototype appearing in five years or so."
Though technical challenges need to be overcome (such as preventing the charged electron from interacting with other metals in the microscope), Yanik believes that eventually such a microscope could achieve single-nanometer resolution. That level of resolution would allow scientists to view molecules such as enzymes and nucleic acids inside living cells.
"Non-destructive Electron Microscopy and Interaction-free Quantum Measurements," William Putnan and Mehmet Fatih Yanik. Physical Review A - Rapid Communications, October issue.
Source:
Jen Hirsch
Massachusetts Institute of Technology
RNA Molecules, Delivery System Improve Vaccine Responses, Effectiveness
A novel delivery system that could lead to more efficient and more disease-specific vaccines against infectious diseases has been developed by biomedical engineers at The University of Texas at Austin.
The findings use specific ribonucleic acid (RNA) molecules to significantly bolster a vaccine's effectiveness while tailoring it based on the type of immune response that is most desirable for a particular disease, says Krishnendu Roy, associate professor of biomedical engineering and lead investigator on the study.
Roy and his team, which included his graduate student Ankur Singh and collaborators at M.D. Anderson Cancer Center in Houston, achieved their results during a two-year study primarily working with a DNA-based hepatitis B vaccine. Their work was recently published in Molecular Therapy, the official journal of the American Society of Gene Therapy.
In their studies using mice, immune responses were five to 50 times stronger than with traditional vaccine delivery. The stronger the immune response to a vaccine, the better protection the vaccinated person should have.
Their research uses a novel polymer-based delivery system that consists of micron-sized particles carrying both the vaccine and the RNA to immune cells.
"What we've achieved is a delivery system that provides DNA-based vaccines along with RNA which allows us to significantly enhance the immune response and drive them into a certain direction that is effective against the disease," Roy says.
The team worked with what are called "silencing RNA," which shut down specific proteins in the body.
"By silencing certain proteins in the cells that process your vaccine, we can direct the immune response one way or the other," says Roy, who holds the General Dynamics Endowed Faculty Fellowship.
Physicians want to tailor the immune response because, Singh says, vaccines for parasitic infections may need more of an antibody response, while vaccines for viral infections need more of a cellular response, one that kills the infected cells.
The team's delivery system would work for a wide range of diseases, making it a broad platform for infectious disease vaccines, Roy says.
Roy says mice studies will continue for the next four to five years. If the tests continue to prove successful, testing could begin on primates and eventually humans within six to 10 years.
"Eventually, we want to try it with (vaccines for) cancer and other auto-immune diseases," Singh says.
Other collaborators include research fellow Hui Nie and graduate student Bilal Ghosn of the university, and Hong Qin and Dr. Larry W. Kwak of M.D. Anderson Cancer Center.
Funding was provided by the National Institute for Allergy and Infectious Diseases and the Coulter Foundation.
Source: Krishnendu Roy
University of Texas at Austin
The findings use specific ribonucleic acid (RNA) molecules to significantly bolster a vaccine's effectiveness while tailoring it based on the type of immune response that is most desirable for a particular disease, says Krishnendu Roy, associate professor of biomedical engineering and lead investigator on the study.
Roy and his team, which included his graduate student Ankur Singh and collaborators at M.D. Anderson Cancer Center in Houston, achieved their results during a two-year study primarily working with a DNA-based hepatitis B vaccine. Their work was recently published in Molecular Therapy, the official journal of the American Society of Gene Therapy.
In their studies using mice, immune responses were five to 50 times stronger than with traditional vaccine delivery. The stronger the immune response to a vaccine, the better protection the vaccinated person should have.
Their research uses a novel polymer-based delivery system that consists of micron-sized particles carrying both the vaccine and the RNA to immune cells.
"What we've achieved is a delivery system that provides DNA-based vaccines along with RNA which allows us to significantly enhance the immune response and drive them into a certain direction that is effective against the disease," Roy says.
The team worked with what are called "silencing RNA," which shut down specific proteins in the body.
"By silencing certain proteins in the cells that process your vaccine, we can direct the immune response one way or the other," says Roy, who holds the General Dynamics Endowed Faculty Fellowship.
Physicians want to tailor the immune response because, Singh says, vaccines for parasitic infections may need more of an antibody response, while vaccines for viral infections need more of a cellular response, one that kills the infected cells.
The team's delivery system would work for a wide range of diseases, making it a broad platform for infectious disease vaccines, Roy says.
Roy says mice studies will continue for the next four to five years. If the tests continue to prove successful, testing could begin on primates and eventually humans within six to 10 years.
"Eventually, we want to try it with (vaccines for) cancer and other auto-immune diseases," Singh says.
Other collaborators include research fellow Hui Nie and graduate student Bilal Ghosn of the university, and Hong Qin and Dr. Larry W. Kwak of M.D. Anderson Cancer Center.
Funding was provided by the National Institute for Allergy and Infectious Diseases and the Coulter Foundation.
Source: Krishnendu Roy
University of Texas at Austin
The Up Side Of Prions
Prions, the infamous agents behind mad cow disease and its human variation, Creutzfeldt-Jakob Disease, also have a helpful side. According to new findings from Gerald Zamponi and colleagues, normally functioning prions prevent neurons from working themselves to death. The findings appear in the Journal of Cell Biology.
Diseases such as mad cow result when the prion protein adopts an abnormal conformation. This infectious form creates a template that induces normal copies of the protein to misfold as well. Scientists have long assumed that prions must also have a beneficial side but have been unable to pinpoint any such favorable traits.
In the new work, the authors found that mice lacking the prion protein had overactive brain cells. Their neurons responded longer and more vigorously to electrical or drug-induced stimulation than did neurons that had normal prion protein. This hyperactivity eventually led to the neurons' death. The results might help explain why misfolded prions cause dementia: in the wrong conformation, the prion can no longer protect brain cells from deadly overexcitement.
Click below to:
View the full article
Listen to an interview with Gerald Zamponi
Read a Comment on the article
Read JCB "In This Issue" summary of the article
Source: Greg Boustead
Rockefeller University
Diseases such as mad cow result when the prion protein adopts an abnormal conformation. This infectious form creates a template that induces normal copies of the protein to misfold as well. Scientists have long assumed that prions must also have a beneficial side but have been unable to pinpoint any such favorable traits.
In the new work, the authors found that mice lacking the prion protein had overactive brain cells. Their neurons responded longer and more vigorously to electrical or drug-induced stimulation than did neurons that had normal prion protein. This hyperactivity eventually led to the neurons' death. The results might help explain why misfolded prions cause dementia: in the wrong conformation, the prion can no longer protect brain cells from deadly overexcitement.
Click below to:
View the full article
Listen to an interview with Gerald Zamponi
Read a Comment on the article
Read JCB "In This Issue" summary of the article
Source: Greg Boustead
Rockefeller University
How Histone Gene Expression Is Differentially Regulated During Drosophila Development
In their upcoming G&D paper, Dr. Robert Tjian (UC Berkeley) and colleagues reveal how histone gene expression is differentially regulated during Drosophila development. The researchers demonstrate that different basal transcription factors drive expression of the histone gene cluster, lending new insight into the regulation of metazoan transcription.
"This study surprised us on 2 levels; one was the preponderance of TRF2 dependent promoters; the other was the differential usage of TRF2 versus TBP within a gene cluster generally thought to be coordinately regulated. Just goes to show that dogma shifts constantly in this field of transcriptional control," explains Dr. Tjian.
In eukaryotic cells, gene transcription is initiated when the RNA polymerase II machinery recognizes and binds to specific core promoter sequences in the gene. While some genes contain a TATA box core promoter element that is recognized by TBP (the TATA-box binding polypeptide), the majority of core promoters fall into various TATA-less categories. A family of TBP-related factors (called TRFs) have been identified, but their core promoter recognition functions have not yet been elucidated.
In this paper, Dr. Tjian and colleagues identify novel TRF2 target promoters, effectively distinguishing between three classes of genes: TBP-dependent ones, TRF2-dependent ones and a small class genes that utilize both TBP and TRF2. They show that TRF2 is used as an alternative core promoter recognition factor to drive transcription of the TATA-less Histone H1 gene, while the other core Histone genes (H2A, H2B, H3 and H4) are dependent upon TBP. Furthermore, depletion of TRF2 in Drosophila cells resulted in reduced ribosomal gene transcription, abnormal cell changes and chromosomal defects.
Source: Heather Cosel
Cold Spring Harbor Laboratory
"This study surprised us on 2 levels; one was the preponderance of TRF2 dependent promoters; the other was the differential usage of TRF2 versus TBP within a gene cluster generally thought to be coordinately regulated. Just goes to show that dogma shifts constantly in this field of transcriptional control," explains Dr. Tjian.
In eukaryotic cells, gene transcription is initiated when the RNA polymerase II machinery recognizes and binds to specific core promoter sequences in the gene. While some genes contain a TATA box core promoter element that is recognized by TBP (the TATA-box binding polypeptide), the majority of core promoters fall into various TATA-less categories. A family of TBP-related factors (called TRFs) have been identified, but their core promoter recognition functions have not yet been elucidated.
In this paper, Dr. Tjian and colleagues identify novel TRF2 target promoters, effectively distinguishing between three classes of genes: TBP-dependent ones, TRF2-dependent ones and a small class genes that utilize both TBP and TRF2. They show that TRF2 is used as an alternative core promoter recognition factor to drive transcription of the TATA-less Histone H1 gene, while the other core Histone genes (H2A, H2B, H3 and H4) are dependent upon TBP. Furthermore, depletion of TRF2 in Drosophila cells resulted in reduced ribosomal gene transcription, abnormal cell changes and chromosomal defects.
Source: Heather Cosel
Cold Spring Harbor Laboratory
A Sticky Solution For Identifying Effective Probiotics
A sticky solution for identifying effective probiotics
Scientists have crystallised a protein that may help gut bacteria bind to the gastrointestinal tract. The protein could be used by probiotic producers to identify strains that are likely to be of real benefit to people.
"Probiotics need to interact with cells lining the gut to have a beneficial effect, and if they attach to surfaces in the gut they are more likely to stick around long enough to exert their activity," says Dr Nathalie Juge from the Institute of Food Research. IFR is an Institute of the Biotechnology and Biological Sciences Research Council, which funded the research.
The gut is the largest immune system organ in the body. The cells lining the gut are covered in a protective layer of mucus that is continuously renewed by specialised cells. As well as protecting the gut lining, mucus provides an attachment site for beneficial bacteria that help maintain normal gut function.
Mucus adhesion has been well studied for pathogenic bacteria, but precisely what enables commensal (our gut bacteria) bacteria to stick is not known. In a paper published in the Journal of Biological Chemistry, IFR and UEA scientists have obtained the first crystal structure of a mucus-binding protein.
The protein was obtained from a strain of Lactobacillus reuteri, a lactic acid bacterium naturally found in the gastrointestinal tract. Lactic acid bacteria are the most common microorganisms used as probiotics.
These mucus-binding proteins are more abundant in lactic acid bacteria than other types and particularly in strains that inhabit the gut. The presence of the proteins may contribute to the ability of lactic acid bacteria to interact with the host.
The team of scientists found that these mucus-binding proteins also recognise human immunoglobulin proteins. These are an integral part of the immune system. Mucus-binding proteins may therefore also play a wider role in gut health as a site of attachment for bacteria.
"The strain-specificity of these proteins demonstrates the need for the careful molecular design and selection of probiotics," says Dr Juge. "This also opens new avenues of research to study the fundamental roles bacteria play in the gastrointestinal tract."
Source: Institute of Food Research
Scientists have crystallised a protein that may help gut bacteria bind to the gastrointestinal tract. The protein could be used by probiotic producers to identify strains that are likely to be of real benefit to people.
"Probiotics need to interact with cells lining the gut to have a beneficial effect, and if they attach to surfaces in the gut they are more likely to stick around long enough to exert their activity," says Dr Nathalie Juge from the Institute of Food Research. IFR is an Institute of the Biotechnology and Biological Sciences Research Council, which funded the research.
The gut is the largest immune system organ in the body. The cells lining the gut are covered in a protective layer of mucus that is continuously renewed by specialised cells. As well as protecting the gut lining, mucus provides an attachment site for beneficial bacteria that help maintain normal gut function.
Mucus adhesion has been well studied for pathogenic bacteria, but precisely what enables commensal (our gut bacteria) bacteria to stick is not known. In a paper published in the Journal of Biological Chemistry, IFR and UEA scientists have obtained the first crystal structure of a mucus-binding protein.
The protein was obtained from a strain of Lactobacillus reuteri, a lactic acid bacterium naturally found in the gastrointestinal tract. Lactic acid bacteria are the most common microorganisms used as probiotics.
These mucus-binding proteins are more abundant in lactic acid bacteria than other types and particularly in strains that inhabit the gut. The presence of the proteins may contribute to the ability of lactic acid bacteria to interact with the host.
The team of scientists found that these mucus-binding proteins also recognise human immunoglobulin proteins. These are an integral part of the immune system. Mucus-binding proteins may therefore also play a wider role in gut health as a site of attachment for bacteria.
"The strain-specificity of these proteins demonstrates the need for the careful molecular design and selection of probiotics," says Dr Juge. "This also opens new avenues of research to study the fundamental roles bacteria play in the gastrointestinal tract."
Source: Institute of Food Research
Minuscule Molecules Pack A Powerful Punch In Immune Defence
Scientists have shown that a tiny microRNA molecule called miR-155, plays a critical role in immune defence and may be a lynchpin in the immune system. The findings reported today in Science reveal that mice lacking the bic/miR-155 gene, one of the world's first microRNA 'knockout' mice, have compromised immune systems and are less able to resist infection and mount an immune response to bacteria like Salmonella typhimurium, a leading cause of human gastroenteritis. They also develop symptoms similar to those of human autoimmune disorders.
The researchers from the Wellcome Trust Sanger Institute, The Babraham Institute, The Gurdon Institute and University of Cambridge, suggest that the corresponding human gene will have a similar role. This discovery provides insights into what makes our immune systems tick, what underpins diseases of the immune system like lymphoma development or autoimmunity, and how these minuscule molecules may be harnessed as effective therapeutic agents.
MicroRNAs, also known as short interfering (si) RNAs, are copied from DNA but do not contain code for protein. Rather they control gene activity by binding to specific related sequences, thereby interfering with a gene's ability to produce the proteins that co-ordinate cellular activities.
Previous research showed that miR-155 was active in cells of the immune system and over-activity of miR-155 has been reported in B-cell lymphomas and solid tumours, implicating this region of the genome in cancer. The research team, led by the Wellcome Trust Sanger Institute, targeted the Bic/microRNA-155 gene in embryonic stem cells, which they used to transfer the mutation into mice.
"Very little is known about the function of the hundreds of microRNA genes," said Dr Antony Rodriguez, lead author on the paper from the Wellcome Trust Sanger Institute. "Although plentiful, this class of gene had never before been knocked out in mice, the best model for human disease. But we simply did not know whether microRNA knockouts would have an effect in mice: previous knockout studies in nematode worms suggested that most microRNAs were not essential. Our findings were dramatically different."
The effects of the miR-155 knockout swept across the immune system; although knockout of miR-155 did not appear to affect normal growth and development of cells in the immune system, three critical components that normally orchestrate the immune response, T-cells, B-cells and dendritic cells, performed less well. The ability of T-cells to produce chemical signals called cytokines, regulators of the immune response, was disrupted. Antibody production by B cells was dramatically reduced and dendritic cells, which normally 'present' foreign proteins to the immune system to activate a response in T-cells, were unable to do so.
"These findings demonstrate the importance of this level of control in the immune system and will lead immunologists to rethink how the immune system works," said Dr Martin Turner, Head of the Laboratory of Lymphocyte Signalling and Development at the Babraham Institute.
To uncover how miR-155 might cause such widespread disruption, the team used microarray analysis to spot the genes whose activity was altered in the immune cells of the knockouts. The activity of over 150 genes with a large range of biological functions was reduced by miR-155, of particular note the gene c-Maf, which normally increases cytokine production and is critical for T-cell function. The team showed that miR-155 interacted directly with c-Maf, reducing its activity with consequences for activation of other genes, production of an effective immune response and susceptibility to autoimmunity and infection.
The knockout mice also develop changes to lung tissue, with scarring that is similar to some human systemic autoimmune disorders. The human Bic/miRNA-155 gene, which is 96% identical with the mature mouse microRNA, is located in a region of chromosome 21 associated with asthma, pollen sensitivity and atopic dermatitis. Hence it is thought that the equivalent human microRNA may be linked with the onset of some immune diseases.
"This dramatic finding reflects a large amount of work by collaborating groups," said Professor Allan Bradley, Director of the Wellcome Trust Sanger Institute. "Showing that knocking out a microRNA has such dramatic effects opens new doors to understanding this novel class of gene regulation, with consequences for human health and disease. Our work builds upon the sequences of the human and mouse genomes, the power of computer analysis and microarray work and exemplifies why whole-organism research can bring understanding that cannot be developed in any other way."
The study emphasises the value of the ES cell based knockout technology, currently being pursued on a large scale through the KOMP and EUCOMM programmes at the Wellcome Trust Sanger Institute. This success illustrates the power of the mouse to reveal function and indicates a wider role for microRNAs in animals with large genomes.
BABRAHAM INSTITUTE
Cambridge
CB2 4AT
babraham.ac.uk
The researchers from the Wellcome Trust Sanger Institute, The Babraham Institute, The Gurdon Institute and University of Cambridge, suggest that the corresponding human gene will have a similar role. This discovery provides insights into what makes our immune systems tick, what underpins diseases of the immune system like lymphoma development or autoimmunity, and how these minuscule molecules may be harnessed as effective therapeutic agents.
MicroRNAs, also known as short interfering (si) RNAs, are copied from DNA but do not contain code for protein. Rather they control gene activity by binding to specific related sequences, thereby interfering with a gene's ability to produce the proteins that co-ordinate cellular activities.
Previous research showed that miR-155 was active in cells of the immune system and over-activity of miR-155 has been reported in B-cell lymphomas and solid tumours, implicating this region of the genome in cancer. The research team, led by the Wellcome Trust Sanger Institute, targeted the Bic/microRNA-155 gene in embryonic stem cells, which they used to transfer the mutation into mice.
"Very little is known about the function of the hundreds of microRNA genes," said Dr Antony Rodriguez, lead author on the paper from the Wellcome Trust Sanger Institute. "Although plentiful, this class of gene had never before been knocked out in mice, the best model for human disease. But we simply did not know whether microRNA knockouts would have an effect in mice: previous knockout studies in nematode worms suggested that most microRNAs were not essential. Our findings were dramatically different."
The effects of the miR-155 knockout swept across the immune system; although knockout of miR-155 did not appear to affect normal growth and development of cells in the immune system, three critical components that normally orchestrate the immune response, T-cells, B-cells and dendritic cells, performed less well. The ability of T-cells to produce chemical signals called cytokines, regulators of the immune response, was disrupted. Antibody production by B cells was dramatically reduced and dendritic cells, which normally 'present' foreign proteins to the immune system to activate a response in T-cells, were unable to do so.
"These findings demonstrate the importance of this level of control in the immune system and will lead immunologists to rethink how the immune system works," said Dr Martin Turner, Head of the Laboratory of Lymphocyte Signalling and Development at the Babraham Institute.
To uncover how miR-155 might cause such widespread disruption, the team used microarray analysis to spot the genes whose activity was altered in the immune cells of the knockouts. The activity of over 150 genes with a large range of biological functions was reduced by miR-155, of particular note the gene c-Maf, which normally increases cytokine production and is critical for T-cell function. The team showed that miR-155 interacted directly with c-Maf, reducing its activity with consequences for activation of other genes, production of an effective immune response and susceptibility to autoimmunity and infection.
The knockout mice also develop changes to lung tissue, with scarring that is similar to some human systemic autoimmune disorders. The human Bic/miRNA-155 gene, which is 96% identical with the mature mouse microRNA, is located in a region of chromosome 21 associated with asthma, pollen sensitivity and atopic dermatitis. Hence it is thought that the equivalent human microRNA may be linked with the onset of some immune diseases.
"This dramatic finding reflects a large amount of work by collaborating groups," said Professor Allan Bradley, Director of the Wellcome Trust Sanger Institute. "Showing that knocking out a microRNA has such dramatic effects opens new doors to understanding this novel class of gene regulation, with consequences for human health and disease. Our work builds upon the sequences of the human and mouse genomes, the power of computer analysis and microarray work and exemplifies why whole-organism research can bring understanding that cannot be developed in any other way."
The study emphasises the value of the ES cell based knockout technology, currently being pursued on a large scale through the KOMP and EUCOMM programmes at the Wellcome Trust Sanger Institute. This success illustrates the power of the mouse to reveal function and indicates a wider role for microRNAs in animals with large genomes.
BABRAHAM INSTITUTE
Cambridge
CB2 4AT
babraham.ac.uk
Prognostic Significance Of Multidrug-Resistance Protein (MDR-1) In Renal Clear Cell Carcinomas: A Five Year Follow-Up Analysis
- Renal cell carcinoma (RCC) is notoriously resistant to a wide spectrum of treatment modalities such as radiation and chemotherapy. This has forced clinical researchers to look elsewhere for effective therapies for patients, such as immunotherapy and now, targeted therapy approaches. Little is known about the mechanism of chemoresistance by which RCC can escape the cytotoxic effects of chemotherapy. Here, Mignona and colleagues examine the multi-drug resistance gene (MDR-1) as a marker of prognosis and potential mechanism for chemoresistance in RCC.
Thirty tumor specimens of clear cell RCC from 30 patients were examined for MDR-1 expression using immunohistochemical techniques. MDR-1 is a membrane protein that is thought to facilitate excretion of chemotherapy molecules out of the cell. It was found to be expressed normally on the proximal renal tubule. With a mean follow-up of 69.8 months, 9 patients have died of RCC. The authors found that elevated MDR-1 expression was associated with a worse prognosis and increased likelihood of death from RCC (p
Thirty tumor specimens of clear cell RCC from 30 patients were examined for MDR-1 expression using immunohistochemical techniques. MDR-1 is a membrane protein that is thought to facilitate excretion of chemotherapy molecules out of the cell. It was found to be expressed normally on the proximal renal tubule. With a mean follow-up of 69.8 months, 9 patients have died of RCC. The authors found that elevated MDR-1 expression was associated with a worse prognosis and increased likelihood of death from RCC (p
Baxter Receives Approval To Process ARALAST NP
Baxter received Food
and Drug Administration approval to transfer ARALAST processing from a
third party to Baxter. ARALAST NP is a brand name referring to the therapy
completely processed by Baxter. It is biologically equivalent to currently
marketed ARALAST.
ARALAST is a human alpha1 -- proteinase inhibitor (A1PI) indicated for
chronic augmentation therapy in patients with hereditary emphysema, which
is a genetic condition caused by a deficiency of A1PI in the lungs. People
with this deficiency have reduced serum levels of A1PI, an important blood
protein processed in the liver that can protect lung tissue from damage
caused by enzymes that are released by white blood cells.
Alpha1-Antitrypsin deficiency affects an estimated 60,000 to 100,000 people
in the United States. It is estimated more than 95 percent of those with
AAT deficiency are undiagnosed. Without sufficient quantities of A1PI,
patients develop lung damage. If untreated, A1PI deficiency can result in
emphysema and premature death.
Important Safety Information
ARALAST is contraindicated in individuals with selective IgA
deficiencies (IgA level less than 15mg/dL) who have known antibody against
IgA, since they may experience severe reactions, including a severe,
potentially life-threatening allergic reaction to IgA, which may be
present. The most common symptoms during the clinical study were headache
(0.3%) and sleepiness (0.3%). Post-market adverse event data have indicated
reports of infusion site pain associated with the administration of
ARALAST. Pregnancy Category C, reproduction studies have not been conducted
with ARALAST. As with all plasma-derived therapeutics, the potential to
transmit infectious agents cannot be totally eliminated. Please see
accompanying ARALAST Prescribing Information for full prescribing details.
For more information on ARALAST, including full prescribing
information, please visit aralast.
About Baxter
Baxter Healthcare Corporation is the principal U.S. operating
subsidiary of Baxter International Inc. (NYSE: BAX). Baxter International
Inc., through its subsidiaries, assists healthcare professionals and their
patients with the treatment of complex medical conditions, including
cancer, hemophilia, immune disorders, kidney disease and trauma. The
company applies its expertise in medical devices, pharmaceuticals and
biotechnology to make a meaningful difference in patients' lives.
Baxter International Inc.
baxter
and Drug Administration approval to transfer ARALAST processing from a
third party to Baxter. ARALAST NP is a brand name referring to the therapy
completely processed by Baxter. It is biologically equivalent to currently
marketed ARALAST.
ARALAST is a human alpha1 -- proteinase inhibitor (A1PI) indicated for
chronic augmentation therapy in patients with hereditary emphysema, which
is a genetic condition caused by a deficiency of A1PI in the lungs. People
with this deficiency have reduced serum levels of A1PI, an important blood
protein processed in the liver that can protect lung tissue from damage
caused by enzymes that are released by white blood cells.
Alpha1-Antitrypsin deficiency affects an estimated 60,000 to 100,000 people
in the United States. It is estimated more than 95 percent of those with
AAT deficiency are undiagnosed. Without sufficient quantities of A1PI,
patients develop lung damage. If untreated, A1PI deficiency can result in
emphysema and premature death.
Important Safety Information
ARALAST is contraindicated in individuals with selective IgA
deficiencies (IgA level less than 15mg/dL) who have known antibody against
IgA, since they may experience severe reactions, including a severe,
potentially life-threatening allergic reaction to IgA, which may be
present. The most common symptoms during the clinical study were headache
(0.3%) and sleepiness (0.3%). Post-market adverse event data have indicated
reports of infusion site pain associated with the administration of
ARALAST. Pregnancy Category C, reproduction studies have not been conducted
with ARALAST. As with all plasma-derived therapeutics, the potential to
transmit infectious agents cannot be totally eliminated. Please see
accompanying ARALAST Prescribing Information for full prescribing details.
For more information on ARALAST, including full prescribing
information, please visit aralast.
About Baxter
Baxter Healthcare Corporation is the principal U.S. operating
subsidiary of Baxter International Inc. (NYSE: BAX). Baxter International
Inc., through its subsidiaries, assists healthcare professionals and their
patients with the treatment of complex medical conditions, including
cancer, hemophilia, immune disorders, kidney disease and trauma. The
company applies its expertise in medical devices, pharmaceuticals and
biotechnology to make a meaningful difference in patients' lives.
Baxter International Inc.
baxter
According To Animal Study, Variant Of Mad Cow Disease May Be Transmitted By Blood Transfusions,
Blood transfusions are a valuable treatment mechanism in modern medicine, but can come with the risk of donor disease transmission. Researchers are continually studying the biology of blood products to understand how certain diseases are transmitted in an effort to reduce this risk during blood transfusions. According to a study in sheep prepublished online in Blood, the official journal of the American Society of Hematology, the risk of transmitting bovine spongiform encephalopathy (BSE, commonly known as "mad cow disease") by blood transfusion is surprisingly high.
BSE is one of a group of rare neurodegenerative disorders called transmissible spongiform encephalopathies (TSEs), and there is no reliable non-invasive test for detecting infection before the onset of clinical disease. In addition to BSE, these diseases include scrapie, a closely related disease in sheep, and Creutzfeld-Jakob disease (CJD) in humans, which causes neurological symptoms such as unsteadiness and involuntary movements that develop as the illness progresses, rendering late-stage sufferers completely immobile at the time of death.
A new variant of CJD (termed vCJD) was recognized in the United Kingdom in the mid-1990s, apparently as a result of the transmission of BSE to humans. Because the symptoms of this disease can take many years to appear, it was not known how many people might have been infected, and without a reliable test for identifying these individuals, clinicians were very concerned that the infection could be transmitted between people by blood transfusion or contaminated surgical and dental instruments. As a result, costly control measures were introduced as a precautionary measure to reduce the risk of disease transmission, although at the time it was unclear whether there really was a significant risk or whether the control measures would be effective. This sheep study sought to better understand how readily TSEs could be transmitted by blood transfusion in order to help develop more targeted controls.
"It is vitally important that we better understand the mechanisms of disease transmission during blood transfusions so we can develop the most effective control measures and minimize human-to-human infections," said Dr. Fiona Houston, now a Faculty of Veterinary Medicine, University of Glasgow, UK, and lead author of the study.
The nine-year study conducted at the University of Edinburgh compared rates of disease transmission by examining blood transfusions from sheep infected with BSE or scrapie; the BSE donors were experimentally infected, while the scrapie donors had naturally acquired the disease. While scrapie is not thought to transmit to humans, it was included as an infection acquired under field conditions, which could possibly give different results than those obtained from experimentally infected animals. Because of the similarity in size of sheep and humans, the team was able to collect and transfuse volumes of blood equivalent to those taken from human blood donors.
The outcome of the experiment showed that both BSE and scrapie could be effectively transmitted between sheep by blood transfusion. Importantly, the team noted that transmission could occur when blood was collected from donors before they developed signs of disease, but was more likely when they were in the later stages of infection. Of the 22 sheep who received infected blood from the BSE donor group, five showed signs of TSEs and three others showed evidence of infection without clinical signs, yielding an overall transmission rate of 36 percent. Of the 21 infected scrapie recipients, nine developed clinical scrapie, yielding an overall transmission rate of 43 percent.
Investigators noted that the results were consistent with what is known about the four recorded cases of vCJD acquired by blood transfusion in humans. In addition to the stage of infection in the donor, factors such as genetic variation in disease susceptibility and the blood component transfused may influence the transmission rate by transfusion in both sheep and humans.
"The study shows that, for sheep infected with BSE or scrapie, transmission rates via blood transfusion can be high, particularly when donors are in the later stages of infection. This suggests that blood transfusion represents an efficient route of transmission for these diseases," said Dr. Houston. "Since the results are consistent with what we know about human transmission, the work helps justify the control measures put in place to safeguard human blood supplies. It also shows that blood from BSE- and scrapie-infected sheep could be used effectively in non-human experiments to answer important questions, such as which blood components are most heavily infected, and to develop much-needed diagnostic tests."
The American Society of Hematology (hematology/) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.
Source: Becka Livesay
American Society of Hematology
BSE is one of a group of rare neurodegenerative disorders called transmissible spongiform encephalopathies (TSEs), and there is no reliable non-invasive test for detecting infection before the onset of clinical disease. In addition to BSE, these diseases include scrapie, a closely related disease in sheep, and Creutzfeld-Jakob disease (CJD) in humans, which causes neurological symptoms such as unsteadiness and involuntary movements that develop as the illness progresses, rendering late-stage sufferers completely immobile at the time of death.
A new variant of CJD (termed vCJD) was recognized in the United Kingdom in the mid-1990s, apparently as a result of the transmission of BSE to humans. Because the symptoms of this disease can take many years to appear, it was not known how many people might have been infected, and without a reliable test for identifying these individuals, clinicians were very concerned that the infection could be transmitted between people by blood transfusion or contaminated surgical and dental instruments. As a result, costly control measures were introduced as a precautionary measure to reduce the risk of disease transmission, although at the time it was unclear whether there really was a significant risk or whether the control measures would be effective. This sheep study sought to better understand how readily TSEs could be transmitted by blood transfusion in order to help develop more targeted controls.
"It is vitally important that we better understand the mechanisms of disease transmission during blood transfusions so we can develop the most effective control measures and minimize human-to-human infections," said Dr. Fiona Houston, now a Faculty of Veterinary Medicine, University of Glasgow, UK, and lead author of the study.
The nine-year study conducted at the University of Edinburgh compared rates of disease transmission by examining blood transfusions from sheep infected with BSE or scrapie; the BSE donors were experimentally infected, while the scrapie donors had naturally acquired the disease. While scrapie is not thought to transmit to humans, it was included as an infection acquired under field conditions, which could possibly give different results than those obtained from experimentally infected animals. Because of the similarity in size of sheep and humans, the team was able to collect and transfuse volumes of blood equivalent to those taken from human blood donors.
The outcome of the experiment showed that both BSE and scrapie could be effectively transmitted between sheep by blood transfusion. Importantly, the team noted that transmission could occur when blood was collected from donors before they developed signs of disease, but was more likely when they were in the later stages of infection. Of the 22 sheep who received infected blood from the BSE donor group, five showed signs of TSEs and three others showed evidence of infection without clinical signs, yielding an overall transmission rate of 36 percent. Of the 21 infected scrapie recipients, nine developed clinical scrapie, yielding an overall transmission rate of 43 percent.
Investigators noted that the results were consistent with what is known about the four recorded cases of vCJD acquired by blood transfusion in humans. In addition to the stage of infection in the donor, factors such as genetic variation in disease susceptibility and the blood component transfused may influence the transmission rate by transfusion in both sheep and humans.
"The study shows that, for sheep infected with BSE or scrapie, transmission rates via blood transfusion can be high, particularly when donors are in the later stages of infection. This suggests that blood transfusion represents an efficient route of transmission for these diseases," said Dr. Houston. "Since the results are consistent with what we know about human transmission, the work helps justify the control measures put in place to safeguard human blood supplies. It also shows that blood from BSE- and scrapie-infected sheep could be used effectively in non-human experiments to answer important questions, such as which blood components are most heavily infected, and to develop much-needed diagnostic tests."
The American Society of Hematology (hematology/) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.
Source: Becka Livesay
American Society of Hematology
Report By Genetic Engineering & Biotechnology News On Clinical Trials In Developing Countries
Biotechnology companies are increasingly turning to developing nations as sites for clinical trials, reports Genetic Engineering and Biotechnology News (GEN). Increasing competition for clinical trial patients in the industrialized world is one of the major reasons for the offshore move, according to an article in the March 15 issue of GEN
"A ready supply of patients and large potential markets are other key drivers for the decision to conduct clinical trials in developing countries," notes John Sterling, Editor-in-Chief of GEN.
Developing nations also offer less competition from other ongoing clinical trials and patients and investigators are often eager to participate. In addition, biotech and pharma companies usually conduct trials in cities, as opposed to rural areas, since many developing world cities have doctors, staff, and equipment similar to conditions that are found in the West.
Nevertheless, there are cultural issues that must be addressed in some developing nations. For example, companies need to ascertain that the disease to be studied in a trial is actually recognized as a local morbidity. In many countries, mental illness, insomnia, and depression are seen as character weaknesses rather than as illnesses.
In the GEN article, insights on conducting clinical trials in developing countries are provided by Peregrine Pharmaceuticals, Integrated Clinical Trials Services, PharmaNet, Advaxis, and Pharm-Olam International.
Genetic Engineering and Biotechnology News (genengnews/), which is published 21 times a year by Mary Ann Liebert, Inc., is the most widely read biotechnology news magazine worldwide. It includes articles on Drug Discovery, Bioprocessing, OMICS, Biobusiness, and Clinical Research and Diagnostics.
Source: John Sterling
Mary Ann Liebert, Inc./Genetic Engineering News
"A ready supply of patients and large potential markets are other key drivers for the decision to conduct clinical trials in developing countries," notes John Sterling, Editor-in-Chief of GEN.
Developing nations also offer less competition from other ongoing clinical trials and patients and investigators are often eager to participate. In addition, biotech and pharma companies usually conduct trials in cities, as opposed to rural areas, since many developing world cities have doctors, staff, and equipment similar to conditions that are found in the West.
Nevertheless, there are cultural issues that must be addressed in some developing nations. For example, companies need to ascertain that the disease to be studied in a trial is actually recognized as a local morbidity. In many countries, mental illness, insomnia, and depression are seen as character weaknesses rather than as illnesses.
In the GEN article, insights on conducting clinical trials in developing countries are provided by Peregrine Pharmaceuticals, Integrated Clinical Trials Services, PharmaNet, Advaxis, and Pharm-Olam International.
Genetic Engineering and Biotechnology News (genengnews/), which is published 21 times a year by Mary Ann Liebert, Inc., is the most widely read biotechnology news magazine worldwide. It includes articles on Drug Discovery, Bioprocessing, OMICS, Biobusiness, and Clinical Research and Diagnostics.
Source: John Sterling
Mary Ann Liebert, Inc./Genetic Engineering News
Researchers Discover Master Metabolism Regulator With Profound Effect On Fat Metabolism
Two biologists at Penn State have discovered a master regulator that controls metabolic responses to a deficiency of essential amino acids in the diet. They also discovered that this regulatory substance, an enzyme named GCN2 eIF2alpha kinase, has an unexpectedly profound impact on fat metabolism. "Some results of our experiments suggest interventions that might help treat obesity, prevent Type II diabetes and heart attacks, or ameliorate protein malnutrition," said Douglas Cavener, professor and head of the Department of Biology, who led the research along with Feifan Guo, a research assistant professor. Their research appears in the scientific journal Cell Metabolism.
Organisms adapt metabolically to episodes of malnutrition and starvation by shutting down the synthesis of new proteins and fats and by using stores of these nutrients from muscle, fat, and the liver in order to continue vital functions. Cavener and Guo found that the removal of a single amino acid, leucine, from the diet is sufficient to provoke a starvation response that affects fat metabolism. "These findings are important for treating two major problems in the world," Cavener says. "The starvation response we discovered can repress fat synthesis and induce the body to consume virtually all of its stored fat within a few weeks of leucine deprivation. Because this response causes a striking loss of fatty tissue, we may be able to formulate a powerful new treatment for obesity."
The second problem is not excess food intake but insufficient protein intake, which plagues the populations of the poorer nations of Asia and Africa. The Food and Agriculture Organization of the United Nations estimates that 850 million people were malnourished between 1999 and 2005.[1] Those who eat a diet with sufficient calories that is lacking in an essential amino acid may suffer from stunted growth, developmental disorders, or even death. On the other hand, obesity is reaching near-epidemic proportions in wealthier nations. According to the Centers for Disease Control, 30 percent of U.S. adults over the age of 20 are obese.[2]
Rather than working with cells in culture, Guo and Cavener examined metabolic processes in a special strain of mice that lacks the GCN2 kinase and compared them with those of normal mice. "Organisms are remarkably sensitive to dietary intake," Cavener says. "Being deprived of even one essential amino acid is enough for the GCN2 kinase to switch the metabolism into an emergency mode. Despite the fact that these mice are consuming normal amounts of carbohydrates and fats, they rapidly shut down fat synthesis in the liver and mobilize their stored fat deposits. Their bodies are literally tricked into a starvation mode."
The experiments conducted by Guo and Cavener had striking and unexpected results. After 17 days of a leucine-deficient diet, the normal mice lost 48 percent of their liver mass and 97 percent of the adipose or fatty tissue from their abdomens. This response is very similar to what happens during starvation. In contrast, the mice without the GCN2 kinase kept a steady liver mass and lost only 69 percent of the adipose tissue on their abdomens.
One of the especially encouraging aspects of the research by Guo and Cavener was the short time frame in which dramatic changes could be induced. Even after only 7 days of leucine deprivation, the normal mice lost 50 percent of their fatty tissue. They also produced fewer lipids (fats) and showed a small drop in serum triglyceride levels. The mice lacking the GCN2 kinase did not lose as much fat as the normal mice did and, in addition, they developed very pale, fatty livers with unusually high levels of stored triglycerides because they continued to synthesize fatty acids. The remarkable rapidity of the weight change in the normal mice occurred because the repressed synthesis of new fats was coupled with the depletion of stored fats in the body.
These findings about the crucial regulatory role of GCN2 kinase in the metabolism have major implications for the treatment or prevention of obesity, which is associated with increased risk for heart disease, diabetes, hypertension, and osteoarthritis. "Most of all," Cavener says, "we hope to be able to devise dietary interventions that will significantly improve the health of millions of children all over the world who suffer from amino acid deprivation associated with protein malnutrition."
MORE INFORMATION:
[1] Reference: Michael Wines, 2006. nytimes/2006/12/28/world/africa/28malnutrition.html "Malnutrition Is Cheating Its Survivors, and Africa's Future" en.wikipedia/wiki/New_York_Times New York Times, December 28, 2006.
[2] Reference: cdc/od/oc/media/pressrel/r991026.htm citing October 27, 1999 article published in JAMA, and cdc/nccdphp/dnpa/obesity/.
Contact: Barbara K. Kennedy
Penn State
Organisms adapt metabolically to episodes of malnutrition and starvation by shutting down the synthesis of new proteins and fats and by using stores of these nutrients from muscle, fat, and the liver in order to continue vital functions. Cavener and Guo found that the removal of a single amino acid, leucine, from the diet is sufficient to provoke a starvation response that affects fat metabolism. "These findings are important for treating two major problems in the world," Cavener says. "The starvation response we discovered can repress fat synthesis and induce the body to consume virtually all of its stored fat within a few weeks of leucine deprivation. Because this response causes a striking loss of fatty tissue, we may be able to formulate a powerful new treatment for obesity."
The second problem is not excess food intake but insufficient protein intake, which plagues the populations of the poorer nations of Asia and Africa. The Food and Agriculture Organization of the United Nations estimates that 850 million people were malnourished between 1999 and 2005.[1] Those who eat a diet with sufficient calories that is lacking in an essential amino acid may suffer from stunted growth, developmental disorders, or even death. On the other hand, obesity is reaching near-epidemic proportions in wealthier nations. According to the Centers for Disease Control, 30 percent of U.S. adults over the age of 20 are obese.[2]
Rather than working with cells in culture, Guo and Cavener examined metabolic processes in a special strain of mice that lacks the GCN2 kinase and compared them with those of normal mice. "Organisms are remarkably sensitive to dietary intake," Cavener says. "Being deprived of even one essential amino acid is enough for the GCN2 kinase to switch the metabolism into an emergency mode. Despite the fact that these mice are consuming normal amounts of carbohydrates and fats, they rapidly shut down fat synthesis in the liver and mobilize their stored fat deposits. Their bodies are literally tricked into a starvation mode."
The experiments conducted by Guo and Cavener had striking and unexpected results. After 17 days of a leucine-deficient diet, the normal mice lost 48 percent of their liver mass and 97 percent of the adipose or fatty tissue from their abdomens. This response is very similar to what happens during starvation. In contrast, the mice without the GCN2 kinase kept a steady liver mass and lost only 69 percent of the adipose tissue on their abdomens.
One of the especially encouraging aspects of the research by Guo and Cavener was the short time frame in which dramatic changes could be induced. Even after only 7 days of leucine deprivation, the normal mice lost 50 percent of their fatty tissue. They also produced fewer lipids (fats) and showed a small drop in serum triglyceride levels. The mice lacking the GCN2 kinase did not lose as much fat as the normal mice did and, in addition, they developed very pale, fatty livers with unusually high levels of stored triglycerides because they continued to synthesize fatty acids. The remarkable rapidity of the weight change in the normal mice occurred because the repressed synthesis of new fats was coupled with the depletion of stored fats in the body.
These findings about the crucial regulatory role of GCN2 kinase in the metabolism have major implications for the treatment or prevention of obesity, which is associated with increased risk for heart disease, diabetes, hypertension, and osteoarthritis. "Most of all," Cavener says, "we hope to be able to devise dietary interventions that will significantly improve the health of millions of children all over the world who suffer from amino acid deprivation associated with protein malnutrition."
MORE INFORMATION:
[1] Reference: Michael Wines, 2006. nytimes/2006/12/28/world/africa/28malnutrition.html "Malnutrition Is Cheating Its Survivors, and Africa's Future" en.wikipedia/wiki/New_York_Times New York Times, December 28, 2006.
[2] Reference: cdc/od/oc/media/pressrel/r991026.htm citing October 27, 1999 article published in JAMA, and cdc/nccdphp/dnpa/obesity/.
Contact: Barbara K. Kennedy
Penn State
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