All it takes is one molecule to reprogram an antibody-producing B cell into
a scavenging macrophage. This transformation is possible, new evidence shows,
because the molecule (C/EBPa, a transcription factor) "short-circuits" the cells
so that they re-express genes reserved for embryonic development. The findings
appear July 30 in Stem Cell Reports, the journal of the International Society
for Stem Cell Research.
Over the past 28 years, researchers have shown that a number of specialized
cell types can be forcibly converted into another, but the science of how this
change takes place is still emerging. Such transdifferentiations, as they're
called, include turning a skin cell into a muscle cell (or a muscle cell into a
brown fat cell) with the addition of just one or two transcription factors.
These are molecules that bind to a cell's DNA and cause other genes to be
expressed.
"For a long time it was unclear whether forcing cell fate decisions by
expressing transcription factors in the wrong cell type could teach us something
about what happens normally during physiological differentiation," says senior
study author Thomas Graf of the Center for Genomic Regulation in Spain. "What we
have now found is that the two processes are actually surprisingly similar."
Based on experiments led by the first author of the study, Chris van
Oevelen, B cell transdifferentiation takes place when C/EBPa binds to two
regions of DNA that act as gene expression enhancers. Whereas one of these
regions is normally active in immune cells, the other is only turned on when
macrophage precursors are ready to differentiate. This indicates that the
convergence of these two enhancer pathways can cause the B cell to act like a
macrophage precursor, thus triggering the unnatural transdifferentiation.
"This has taught us a great deal about how a transcription factor can
activate a new gene expression program (in our case, that of macrophages) but
has left us in the dark about the other part of the equation; namely, how the
factor silences the B cell program, something that must happen if
transdifferentiation is to work," Graf says. "This is one of the questions we
are focusing on now."
Graf is interested in this pathway because C/EBPa-induced, B
cell-to-macrophage transdifferentiation can convert both human B cell lymphoma
or leukemia cells into functional, non-cancerous macrophages. He believes that
induced transdifferentiation could become therapeutically relevant, if a drug
could be found that can replace the transcription factor--not to mention that
understanding the mechanisms of the process would help labs worldwide who use
this transdifferentiation approach to generate cells "a la carte" for
regenerative purposes.
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2015年7月29日星期三
Researchers design first artificial ribosome
Researchers at the University of Illinois at Chicago and Northwestern
University have engineered a tethered ribosome that works nearly as well as the
authentic cellular component, or organelle, that produces all the proteins and
enzymes within the cell. The engineered ribosome may enable the production of
new drugs and next-generation biomaterials and lead to a better understanding of
how ribosomes function.
The artificial ribosome, called Ribo-T, was created in the laboratories of Alexander Mankin, director of the UIC College of Pharmacy's Center for Biomolecular Sciences, and Northwestern's Michael Jewett, assistant professor of chemical and biological engineering. The human-made ribosome may be able to be manipulated in the laboratory to do things natural ribosomes cannot do.
When the cell makes a protein, mRNA (messenger RNA) is copied from DNA. The ribosomes' two subunits, one large and one small, unite on mRNA to form the functional unit that assembles the protein in a process called translation. Once the protein molecule is complete, the ribosome subunits -- both of which are themselves made up of RNA and protein -- separate from each other.
In a new study in the journal Nature, the researchers describe the design and properties of Ribo-T, a ribosome with subunits that will not separate. Ribo-T may be able to be tuned to produce unique and functional polymers for exploring ribosome functions or producing designer therapeutics -- and perhaps one day even non-biological polymers.
No one has ever developed something of this nature.
"We felt like there was a small -- very small -- chance Ribo-T could work, but we did not really know," Mankin said.
Mankin, Jewett and their colleagues were frustrated in their investigations by the ribosomes' subunits falling apart and coming together in every cycle of protein synthesis. Could the subunits be permanently linked together? The researchers devised a novel designer ribosome with tethered subunits -- Ribo-T.
"What we were ultimately able to do was show that by creating an engineered ribosome where the ribosomal RNA is shared between the two subunits and linked by these small tethers, we could actually create a dual translation system," Jewett said.
"It was surprising that our hybrid chimeric RNA could support assembly of a functional ribosome in the cell. It was also surprising that this tethered ribosome could support growth in the absence of wild-type ribosomes," he said.
Ribo-T worked even better than Mankin and Jewett believed it could. Not only did Ribo-T make proteins in a test-tube, it was able to make enough protein in bacterial cells that lacked natural ribosomes to keep the bacteria alive.
Jewett and Mankin were surprised by this. Scientists had previously believed that the ability of the two ribosomal subunits to separate was required for protein synthesis.
"Obviously this assumption was incorrect," Jewett said.
"Our new protein-making factory holds promise to expand the genetic code in a unique and transformative way, providing exciting opportunities for synthetic biology and biomolecular engineering," Jewett said.
"This is an exciting tool to explore ribosomal functions by experimenting with the most critical parts of the protein synthesis machine, which previously were 'untouchable,'" Mankin added.
Read more:http://www.cusabio.com/catalog-13-1.html
The artificial ribosome, called Ribo-T, was created in the laboratories of Alexander Mankin, director of the UIC College of Pharmacy's Center for Biomolecular Sciences, and Northwestern's Michael Jewett, assistant professor of chemical and biological engineering. The human-made ribosome may be able to be manipulated in the laboratory to do things natural ribosomes cannot do.
When the cell makes a protein, mRNA (messenger RNA) is copied from DNA. The ribosomes' two subunits, one large and one small, unite on mRNA to form the functional unit that assembles the protein in a process called translation. Once the protein molecule is complete, the ribosome subunits -- both of which are themselves made up of RNA and protein -- separate from each other.
In a new study in the journal Nature, the researchers describe the design and properties of Ribo-T, a ribosome with subunits that will not separate. Ribo-T may be able to be tuned to produce unique and functional polymers for exploring ribosome functions or producing designer therapeutics -- and perhaps one day even non-biological polymers.
No one has ever developed something of this nature.
"We felt like there was a small -- very small -- chance Ribo-T could work, but we did not really know," Mankin said.
Mankin, Jewett and their colleagues were frustrated in their investigations by the ribosomes' subunits falling apart and coming together in every cycle of protein synthesis. Could the subunits be permanently linked together? The researchers devised a novel designer ribosome with tethered subunits -- Ribo-T.
"What we were ultimately able to do was show that by creating an engineered ribosome where the ribosomal RNA is shared between the two subunits and linked by these small tethers, we could actually create a dual translation system," Jewett said.
"It was surprising that our hybrid chimeric RNA could support assembly of a functional ribosome in the cell. It was also surprising that this tethered ribosome could support growth in the absence of wild-type ribosomes," he said.
Ribo-T worked even better than Mankin and Jewett believed it could. Not only did Ribo-T make proteins in a test-tube, it was able to make enough protein in bacterial cells that lacked natural ribosomes to keep the bacteria alive.
Jewett and Mankin were surprised by this. Scientists had previously believed that the ability of the two ribosomal subunits to separate was required for protein synthesis.
"Obviously this assumption was incorrect," Jewett said.
"Our new protein-making factory holds promise to expand the genetic code in a unique and transformative way, providing exciting opportunities for synthetic biology and biomolecular engineering," Jewett said.
"This is an exciting tool to explore ribosomal functions by experimenting with the most critical parts of the protein synthesis machine, which previously were 'untouchable,'" Mankin added.
Read more:http://www.cusabio.com/catalog-13-1.html
Experimental MERS vaccine shows promise in animal studies
A two-step regimen of experimental vaccines against Middle East respiratory
syndrome (MERS) prompted immune responses in mice and rhesus macaques, report
National Institutes of Health scientists who designed the vaccines. Vaccinated
mice produced broadly neutralizing antibodies against multiple strains of the
MERS coronavirus (MERS-CoV), while vaccinated macaques were protected from
severe lung damage when later exposed to MERS-CoV. The findings suggest that the
current approach, in which vaccine design is guided by an understanding of
structure of viral components and their interactions with host cells, holds
promise for developing a similar human MERS vaccine regimen.
Currently, no licensed vaccines are available for MERS, a disease that first appeared in 2012. An outbreak in the Republic of Korea that began in May has caused more than 180 confirmed infections, including 36 deaths, through July 15 as well as widespread social disruption.
The research team was led by Barney S. Graham, M.D., Ph.D., Wing-Pui Kong, Ph.D., and colleagues at the National Institute of Allergy and Infectious Diseases' Vaccine Research Center. The investigators used structural information about a viral protein called the spike (S) glycoprotein, which MERS-CoV uses to enter cells, to design a number of experimental vaccines that they administered to mice in a two-step regimen involving an initial "priming" injection followed several weeks later by the same or a different "booster" vaccine.
The three prime-boost regimens that elicited the most robust immune responses in mice were then tested in groups of macaques and were found to elicit similar immune system responses. A separate group of 18 macaques (12 vaccinated, six unvaccinated) were exposed to MERS-CoV 19 weeks after the vaccinated animals received the boost injection. Although macaques do not develop overt MERS disease, the researchers observed that unvaccinated animals experienced lung abnormalities indicative of pneumonia that were more profound and longer lasting than those seen in the vaccinated animals. The team is now working on refining the vaccine candidates and may eventually test a second-generation vaccine candidate in clinical trials.
Read more:http://www.cusabio.com/catalog-13-1.html
Currently, no licensed vaccines are available for MERS, a disease that first appeared in 2012. An outbreak in the Republic of Korea that began in May has caused more than 180 confirmed infections, including 36 deaths, through July 15 as well as widespread social disruption.
The research team was led by Barney S. Graham, M.D., Ph.D., Wing-Pui Kong, Ph.D., and colleagues at the National Institute of Allergy and Infectious Diseases' Vaccine Research Center. The investigators used structural information about a viral protein called the spike (S) glycoprotein, which MERS-CoV uses to enter cells, to design a number of experimental vaccines that they administered to mice in a two-step regimen involving an initial "priming" injection followed several weeks later by the same or a different "booster" vaccine.
The three prime-boost regimens that elicited the most robust immune responses in mice were then tested in groups of macaques and were found to elicit similar immune system responses. A separate group of 18 macaques (12 vaccinated, six unvaccinated) were exposed to MERS-CoV 19 weeks after the vaccinated animals received the boost injection. Although macaques do not develop overt MERS disease, the researchers observed that unvaccinated animals experienced lung abnormalities indicative of pneumonia that were more profound and longer lasting than those seen in the vaccinated animals. The team is now working on refining the vaccine candidates and may eventually test a second-generation vaccine candidate in clinical trials.
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月27日星期一
new therapy slows spread of deadly brain tumor cells
The rapid spread of a common and deadly brain tumor has been slowed down
significantly in a mouse model by cutting off the way some cancer cells
communicate, according to a team of researchers that includes UF Health
faculty.
The technique improved the survival time for patients with glioblastoma by 50 percent when tested in a mouse model, said Loic P. Deleyrolle, Ph.D., a research assistant professor of neurosurgery in the UF College of Medicine.
Researchers focused on disrupting the cell-to-cell communication that allows cancer stem cells to spread. To do that, they targeted a channel that cancer cells use to transfer molecules. By cutting off their communications pathway, the deadly cells stay in check, Deleyrolle said.
Eight UF Health researchers took part in the study, which was co-authored by Deleyrolle and published recently in the journal Cell Reports. They collaborated with researchers at the Cleveland Clinic and the University of California, Berkeley.
Glioblastoma is the most common brain tumor in adults and there is no effective long-term treatment and patients usually live for 12 to 15 months after diagnosis, according to the National Cancer Institute. Glioblastoma tumors, which are highly malignant, typically start in the largest part of the brain and can spread rapidly.
The research focused on connexin 46, a protein that is an essential component of cancer stem cells. Connexin 46 is part of intercellular channels known as a gap junction. That intercellular channel, which allows cells to exchange molecules and ions, is crucial to the growth of a glioblastoma tumor, researchers found.
"When we shut down those channels in the cancer stem cells, we can significantly reduce the tumor-forming abilities of the cells," Deleyrolle said.
Tumor growth was significantly delayed in mouse models that were treated with a combination of the gap junction inhibitor 1-octanol and a chemotherapy drug, temozolomide. After 100 days, all of the mouse models that had the connexin 46 protein suppressed genetically were still alive. By comparison, all of the mouse models that didn't have the protein suppressed died within two months.
While the technique has yet to be tested in humans, Deleyrolle said the implications are clear and relevant. For now, a glioblastoma patient can expect to survive about 12 to 15 months. Patients can also develop a resistance to temozolomide when it is used for chemotherapy, further shortening their life expectancy.
"Any significant increase in survival time will be a meaningful improvement because the current treatments provide only weeks of efficacy" Deleyrolle said.
Another reason for optimism: All of the compounds that were tested as inhibitors are being used in humans or are in the clinical trial pipeline. Carbenoxolone is used in some European countries to treat ulcers, and 1-octanol is used as experimental treatment for tremor in the United States. That means that the amount of time needed to get the drugs into a clinical trial as a therapy for glioblastoma could be significantly shortened, Deleyrolle said.
Because gap junction inhibitors have ubiquitous functions in many organs and tissues, one of the next research steps is to determine the inhibitors' most effective and tolerable concentrations. It is also necessary to understand more about the mechanisms that make the inhibitors work, Deleyrolle said. Still, clinical trials could begin within a few years, he said.
Treating glioblastoma is especially difficult because its cells can vary drastically, even within a single tumor -- so breaking the chain of cell-to-cell communication is yet another potential weapon to fight the disease. If the new therapy is approved following a clinical trial, Deleyrolle said it would likely be put to use alongside traditional chemotherapy and radiation treatments.
Read more:http://www.cusabio.com/catalog-13-1.html
The technique improved the survival time for patients with glioblastoma by 50 percent when tested in a mouse model, said Loic P. Deleyrolle, Ph.D., a research assistant professor of neurosurgery in the UF College of Medicine.
Researchers focused on disrupting the cell-to-cell communication that allows cancer stem cells to spread. To do that, they targeted a channel that cancer cells use to transfer molecules. By cutting off their communications pathway, the deadly cells stay in check, Deleyrolle said.
Eight UF Health researchers took part in the study, which was co-authored by Deleyrolle and published recently in the journal Cell Reports. They collaborated with researchers at the Cleveland Clinic and the University of California, Berkeley.
Glioblastoma is the most common brain tumor in adults and there is no effective long-term treatment and patients usually live for 12 to 15 months after diagnosis, according to the National Cancer Institute. Glioblastoma tumors, which are highly malignant, typically start in the largest part of the brain and can spread rapidly.
The research focused on connexin 46, a protein that is an essential component of cancer stem cells. Connexin 46 is part of intercellular channels known as a gap junction. That intercellular channel, which allows cells to exchange molecules and ions, is crucial to the growth of a glioblastoma tumor, researchers found.
"When we shut down those channels in the cancer stem cells, we can significantly reduce the tumor-forming abilities of the cells," Deleyrolle said.
Tumor growth was significantly delayed in mouse models that were treated with a combination of the gap junction inhibitor 1-octanol and a chemotherapy drug, temozolomide. After 100 days, all of the mouse models that had the connexin 46 protein suppressed genetically were still alive. By comparison, all of the mouse models that didn't have the protein suppressed died within two months.
While the technique has yet to be tested in humans, Deleyrolle said the implications are clear and relevant. For now, a glioblastoma patient can expect to survive about 12 to 15 months. Patients can also develop a resistance to temozolomide when it is used for chemotherapy, further shortening their life expectancy.
"Any significant increase in survival time will be a meaningful improvement because the current treatments provide only weeks of efficacy" Deleyrolle said.
Another reason for optimism: All of the compounds that were tested as inhibitors are being used in humans or are in the clinical trial pipeline. Carbenoxolone is used in some European countries to treat ulcers, and 1-octanol is used as experimental treatment for tremor in the United States. That means that the amount of time needed to get the drugs into a clinical trial as a therapy for glioblastoma could be significantly shortened, Deleyrolle said.
Because gap junction inhibitors have ubiquitous functions in many organs and tissues, one of the next research steps is to determine the inhibitors' most effective and tolerable concentrations. It is also necessary to understand more about the mechanisms that make the inhibitors work, Deleyrolle said. Still, clinical trials could begin within a few years, he said.
Treating glioblastoma is especially difficult because its cells can vary drastically, even within a single tumor -- so breaking the chain of cell-to-cell communication is yet another potential weapon to fight the disease. If the new therapy is approved following a clinical trial, Deleyrolle said it would likely be put to use alongside traditional chemotherapy and radiation treatments.
Read more:http://www.cusabio.com/catalog-13-1.html
Clues to human molecular interactions
Scientists at Van Andel Research Institute (VARI) have revealed an
important molecular mechanism in plants that has significant similarities to
certain signaling mechanisms in humans, which are closely linked to early
embryonic development and to diseases such as cancer.
In plants as in animals and humans, intricate molecular networks regulate key biological functions, such as development and stress responses. The system can be likened to a massive switchboard--when the wrong switches are flipped, genes can be inappropriately turned on or off, leading to the onset of diseases.
Now, VARI scientists have unraveled how an important plant protein, known as TOPLESS, interacts with other molecules responsible for turning genes off. The findings in plants provide a general model across species for this type of gene silencing, which is linked to several vital biological functions in humans. The discovery was published today in Science Advances.
"This is really a fundamental discovery--our structure shows the corepressor TOPLESS interacting with key repressor motifs, which constitutes a major component of gene silencing in plants," said Van Andel Research Institute's Karsten Melcher, Ph.D., one of the study's corresponding authors. "Understanding this interaction in plants gives us unique insight into similar pathways in humans that involve these proteins, which are notoriously tough to investigate."
Using a method called X-ray crystallography, the team determined the three- dimensional structure of TOPLESS, both on its own and when linked with other molecules responsible for turning genes off, thereby regulating gene expression. Although these interacting molecules were chosen from different signaling pathways in plants, they all linked up with TOPLESS in the same manner
"This structure will allow us to take a more targeted approach to investigating TOPLESS's counterparts in humans and significantly expands our knowledge base," said VARI's H. Eric Xu, Ph.D., who also is a corresponding author. "We're extremely excited to continue this work to better understand these proteins and how they interact with other molecules in health and disease states."
The new paper is the third in a trio of publications that unveil key components of fundamental molecular processes. Although the new study provides further insight into human molecular pathways, the work also directly describes how components of the molecular switchboard in plants interact to regulate responses to a multitude of stressors, including temperature fluctuations. The new findings follow an earlier Nature paper, which was included in the top ten list of scientific breakthroughs of 2009 by Science magazine, and an earlier Science paper, both of which describe how plants respond to drought and temperature stress. Taken together, the papers not only have implications for developing hardier plants but also for determining molecular structures for components of entire pathways.
Authors include Jiyuan Ke, Honglei Ma, and Xin Gu of VARI and VARI-Shanghai Institute of Materia Medica; Jiayang Li of the Chinese Academy of Sciences; Joseph S. Brunzelle of Northwestern University; and Adam Thelen, now at Michigan State University.
Additional background information on TOPLESS and gene regulation:
Gene expression is regulated by both activators and repressors. Although gene repression is thought to be equally important as gene activation for this regulation, relatively little is known about the mechanisms of gene repressors and co-repressors.
TOPLESS functions as a co-repressor and interacts with repressors containing ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motifs. EAR motifs are the most common form of transcriptional repression motifs found in plants and are thought to facilitate stable epigenetic regulation of gene expression via recruitment of chromatin modifiers.
TOPLESS plays important roles in plant development; its name stems from the fact that mutations in TOPLESS can give rise to seedlings in which the shoot is transformed into a second root, hence "topless" seedlings.
In humans, similar proteins also are altered in many types of tumors, and control embryonic development and the development of neurons.
Read more:http://www.cusabio.com/catalog-15-1.html
In plants as in animals and humans, intricate molecular networks regulate key biological functions, such as development and stress responses. The system can be likened to a massive switchboard--when the wrong switches are flipped, genes can be inappropriately turned on or off, leading to the onset of diseases.
Now, VARI scientists have unraveled how an important plant protein, known as TOPLESS, interacts with other molecules responsible for turning genes off. The findings in plants provide a general model across species for this type of gene silencing, which is linked to several vital biological functions in humans. The discovery was published today in Science Advances.
"This is really a fundamental discovery--our structure shows the corepressor TOPLESS interacting with key repressor motifs, which constitutes a major component of gene silencing in plants," said Van Andel Research Institute's Karsten Melcher, Ph.D., one of the study's corresponding authors. "Understanding this interaction in plants gives us unique insight into similar pathways in humans that involve these proteins, which are notoriously tough to investigate."
Using a method called X-ray crystallography, the team determined the three- dimensional structure of TOPLESS, both on its own and when linked with other molecules responsible for turning genes off, thereby regulating gene expression. Although these interacting molecules were chosen from different signaling pathways in plants, they all linked up with TOPLESS in the same manner
"This structure will allow us to take a more targeted approach to investigating TOPLESS's counterparts in humans and significantly expands our knowledge base," said VARI's H. Eric Xu, Ph.D., who also is a corresponding author. "We're extremely excited to continue this work to better understand these proteins and how they interact with other molecules in health and disease states."
The new paper is the third in a trio of publications that unveil key components of fundamental molecular processes. Although the new study provides further insight into human molecular pathways, the work also directly describes how components of the molecular switchboard in plants interact to regulate responses to a multitude of stressors, including temperature fluctuations. The new findings follow an earlier Nature paper, which was included in the top ten list of scientific breakthroughs of 2009 by Science magazine, and an earlier Science paper, both of which describe how plants respond to drought and temperature stress. Taken together, the papers not only have implications for developing hardier plants but also for determining molecular structures for components of entire pathways.
Authors include Jiyuan Ke, Honglei Ma, and Xin Gu of VARI and VARI-Shanghai Institute of Materia Medica; Jiayang Li of the Chinese Academy of Sciences; Joseph S. Brunzelle of Northwestern University; and Adam Thelen, now at Michigan State University.
Additional background information on TOPLESS and gene regulation:
Gene expression is regulated by both activators and repressors. Although gene repression is thought to be equally important as gene activation for this regulation, relatively little is known about the mechanisms of gene repressors and co-repressors.
TOPLESS functions as a co-repressor and interacts with repressors containing ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motifs. EAR motifs are the most common form of transcriptional repression motifs found in plants and are thought to facilitate stable epigenetic regulation of gene expression via recruitment of chromatin modifiers.
TOPLESS plays important roles in plant development; its name stems from the fact that mutations in TOPLESS can give rise to seedlings in which the shoot is transformed into a second root, hence "topless" seedlings.
In humans, similar proteins also are altered in many types of tumors, and control embryonic development and the development of neurons.
Read more:http://www.cusabio.com/catalog-15-1.html
2015年7月23日星期四
New method to halt the advance of liver cancer found
A new study by researchers at Sanford Burnham Prebys Medical Discovery
Institute (SBP), the National Cancer Institute, and the Chulabhorn Research
Institute has found that blocking the activity of a key immune receptor, the
lymphotoxin-beta receptor (LTβR), reduces the progression of liver cancer. The
results, published in the online edition of Gut, could provide new treatment
strategies for the disease, which is the third leading cause of cancer-related
deaths worldwide.
"Our findings point to a new way to improve the treatment of liver cancer patients," said Carl Ware, Ph.D., professor and director in the Infectious and Inflammatory Disease Center at SBP and one of theauthors of the paper. "Combining drugs that are currently in clinical trials, which block the activity of the LTβR with drugs that target oncogene signals, may be a valuable new approach to improving patient outcomes."
The LTβR, originally discovered by Ware, is best known for controlling the development of lymphoid organs, supporting the body's immune response to pathogens, and regulating inflammation. His work has led to the understanding that blocking the activity of the receptor inhibits inflammation. This approach is currently studied as a treatment for chronic inflammatory diseases, including Sjögren's syndrome.
"For some time we have known about the interconnection between the receptor, inflammation -- including inflammation caused by hepatitis -- and liver cancer. Now, we have demonstrated how the receptor's signals create an environment that accelerates oncogenic activity and tumor growth," added Ware.
the research team introduced the liver cancer-causing AKT/β-catenin or AKT/Notch oncogenes to mice and then monitored liver cancer progression after administration of either a LTβR activator (agonist) or an inhibitor (antagonist). In mice that received the agonist, liver tumors rapidly proliferated and progressed. In contrast, mice that received the antagonist experienced reduced tumor progression and enhanced survival.
Importantly, the research team found that LTβR levels were elevated in human liver cancer cell lines, reflecting the need for enhanced receptor activity to maintain oncogene activity. Similarly, higher levels of the receptor correlated with poor survival in patients with intrahepatic cholangiocarcinoma, the second most common type of liver tumor.
"Cancers of the hepatobiliary system, including cholangiocarcinoma and hepatocellular carcinoma, typically present in advanced stages, with impaired liver function, respond poorly to chemotherapy, and have poor survival based on the lack of available treatment options," said Paul Timothy Fanta, M.D., associate clinical professor in the Division of Hematology and Oncology at UC San Diego's Moores Cancer Center."
"The present study describes interactions of the LTβR, a member of the tumor necrosis factor (TNF) superfamily of receptors and may play a key role in tumor formation through LTβR inflammation-mediated events and actions through AKT/Beta-catenin and Notch cellular pathways. The link between LTβR signaling and oncogenic activation suggests that drugs targeting LTβR signaling combined with AKT or Notch inhibitors may lead to rationally designed therapeutic trials in these underserved and lethal diseases," added Fanta.
Read more:http://www.cusabio.com/catalog-13-1.html
"Our findings point to a new way to improve the treatment of liver cancer patients," said Carl Ware, Ph.D., professor and director in the Infectious and Inflammatory Disease Center at SBP and one of theauthors of the paper. "Combining drugs that are currently in clinical trials, which block the activity of the LTβR with drugs that target oncogene signals, may be a valuable new approach to improving patient outcomes."
The LTβR, originally discovered by Ware, is best known for controlling the development of lymphoid organs, supporting the body's immune response to pathogens, and regulating inflammation. His work has led to the understanding that blocking the activity of the receptor inhibits inflammation. This approach is currently studied as a treatment for chronic inflammatory diseases, including Sjögren's syndrome.
"For some time we have known about the interconnection between the receptor, inflammation -- including inflammation caused by hepatitis -- and liver cancer. Now, we have demonstrated how the receptor's signals create an environment that accelerates oncogenic activity and tumor growth," added Ware.
the research team introduced the liver cancer-causing AKT/β-catenin or AKT/Notch oncogenes to mice and then monitored liver cancer progression after administration of either a LTβR activator (agonist) or an inhibitor (antagonist). In mice that received the agonist, liver tumors rapidly proliferated and progressed. In contrast, mice that received the antagonist experienced reduced tumor progression and enhanced survival.
Importantly, the research team found that LTβR levels were elevated in human liver cancer cell lines, reflecting the need for enhanced receptor activity to maintain oncogene activity. Similarly, higher levels of the receptor correlated with poor survival in patients with intrahepatic cholangiocarcinoma, the second most common type of liver tumor.
"Cancers of the hepatobiliary system, including cholangiocarcinoma and hepatocellular carcinoma, typically present in advanced stages, with impaired liver function, respond poorly to chemotherapy, and have poor survival based on the lack of available treatment options," said Paul Timothy Fanta, M.D., associate clinical professor in the Division of Hematology and Oncology at UC San Diego's Moores Cancer Center."
"The present study describes interactions of the LTβR, a member of the tumor necrosis factor (TNF) superfamily of receptors and may play a key role in tumor formation through LTβR inflammation-mediated events and actions through AKT/Beta-catenin and Notch cellular pathways. The link between LTβR signaling and oncogenic activation suggests that drugs targeting LTβR signaling combined with AKT or Notch inhibitors may lead to rationally designed therapeutic trials in these underserved and lethal diseases," added Fanta.
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月22日星期三
New smart drug targets, reduces site-specific inflammation
Ben-Gurion University of the Negev (BGU) and University of Colorado
researchers have developed a dynamic "smart" drug that targets inflammation in a
site-specific manner and could enhance the body's natural ability to fight
infection and reduce side effects.
The uniqueness of this novel anti-inflammatory molecule, reported in the current issue of Journal of Immunology, can be found in a singular property. When injected, it is as a non-active drug. However, a localized site with excessive inflammation will activate it. Most other anti-inflammatory agents effectively inhibit inflammatory processes, though in a non-specific manner and in areas that include sites of necessary normal inflammatory homeostasis.
"This development is important because inhibition of inflammation in a non-specific manner reduces the natural ability to fight infections and is a common side effect of anti-inflammatory biologic therapeutics," says Dr. Peleg Rider of BGU's Department of Clinical Biochemistry and Pharmacology.
When a non-specific agent is used, any patient who suffers from local inflammation might then be exposed to opportunistic infections at distant sites, such as lungs, risking, for example, tuberculosis. This risk is mainly of concern to immunosuppressed patients, as well as older patients and patients undergoing chemotherapy as part of an anti-cancer treatment course.
"The beauty of this invention lies in the use of a known natural biological code," Dr. Rider explains. "We mimicked a natural process that occurs during inflammation."
The protein molecule is actually a chimera comprised of two domains, both originating from the potent inflammatory cytokine family of IL-1. The first part of the protein holds the functional part of the molecule inactive, as occurs in normal living cells, and is connected to a potent natural inhibitor of IL-1. When it encounters inflammatory enzymes, the molecule is cleaved and the functional part becomes active.
Dr. Rider, along with BGU's Dr. Eli Lewis and Prof. Charles Dinarello of the University of Colorado, demonstrated their findings in a mouse model of local inflammation. They showed that leukocytes, which infiltrate inflammatory sites, indeed activate the chimeric protein, which in turn reduces local inflammation. The activation of the protein correlated with the amount of inflammatory stimuli.
"Thus, a point that is highly relevant to clinical practice arises. Upon resolution of inflammation, the activation of the protein is also reduced and side effects are avoided," Dr. Rider explains.
Read more:http://www.cusabio.com/catalog-13-1.html
The uniqueness of this novel anti-inflammatory molecule, reported in the current issue of Journal of Immunology, can be found in a singular property. When injected, it is as a non-active drug. However, a localized site with excessive inflammation will activate it. Most other anti-inflammatory agents effectively inhibit inflammatory processes, though in a non-specific manner and in areas that include sites of necessary normal inflammatory homeostasis.
"This development is important because inhibition of inflammation in a non-specific manner reduces the natural ability to fight infections and is a common side effect of anti-inflammatory biologic therapeutics," says Dr. Peleg Rider of BGU's Department of Clinical Biochemistry and Pharmacology.
When a non-specific agent is used, any patient who suffers from local inflammation might then be exposed to opportunistic infections at distant sites, such as lungs, risking, for example, tuberculosis. This risk is mainly of concern to immunosuppressed patients, as well as older patients and patients undergoing chemotherapy as part of an anti-cancer treatment course.
"The beauty of this invention lies in the use of a known natural biological code," Dr. Rider explains. "We mimicked a natural process that occurs during inflammation."
The protein molecule is actually a chimera comprised of two domains, both originating from the potent inflammatory cytokine family of IL-1. The first part of the protein holds the functional part of the molecule inactive, as occurs in normal living cells, and is connected to a potent natural inhibitor of IL-1. When it encounters inflammatory enzymes, the molecule is cleaved and the functional part becomes active.
Dr. Rider, along with BGU's Dr. Eli Lewis and Prof. Charles Dinarello of the University of Colorado, demonstrated their findings in a mouse model of local inflammation. They showed that leukocytes, which infiltrate inflammatory sites, indeed activate the chimeric protein, which in turn reduces local inflammation. The activation of the protein correlated with the amount of inflammatory stimuli.
"Thus, a point that is highly relevant to clinical practice arises. Upon resolution of inflammation, the activation of the protein is also reduced and side effects are avoided," Dr. Rider explains.
Read more:http://www.cusabio.com/catalog-13-1.html
Sound waves gently cull circulating tumor cells from blood samples
The capture and analysis of circulating tumor cells (CTCs) in the blood of
cancer patients is a valuable tool for treatment decisions and therapy
monitoring. Until recently, it was a huge challenge to capture these rare cells
in a blood sample. In a new approach, researchers funded by the National
Institute of Biomedical Imaging and Bioengineering have developed a system that
efficiently isolates CTCs using sound waves, without physical contact or damage
to the cells, assuring that their original characteristics are maintained. The
contact-free nature of the method offers the potential for more precise cancer
treatment and monitoring, and new discoveries on how cancer spreads.
"The group has developed gentle and efficient acoustic tweezers," explains Richard Conroy, Ph.D., Director of the NIBIB Program in Diagnostic and Interventional Ultrasound, "These tweezers can move and manipulate thousands of cells without touching them, preserving their characteristics. Development of tools like this will have a significant number of applications in both the research lab and the clinic."
The low-cost acoustic cell-separation device was developed by a research team led by Tony Jun Huang, Ph.D., at Pennsylvania State University, and his collaborators at the Massachusetts Institute of Technology, Notre Dame University, Penn State Hershey Cancer Center, and Carnegie Mellon University. The work is described in the April issue of the Proceedings of the National Academy of Sciences.
Advantages of acoustic separation
The potential for CTCs to provide valuable information about a patient's tumor has driven development of technologies to isolate these rare cells that travel through the blood after breaking off from the primary tumor. Current clinical techniques generally fall into two categories, each of which can damage or alter the characteristics of CTCs during isolation. The first depends on antibodies binding to a protein on the surface of the CTCs. One disadvantage of this technique is that the surface protein must be known ahead of time to determine which antibody should be used. This can cause CTCs to be missed, especially as the tumor evolves in response to chemotherapy and surface proteins change.
The second method separates CTCs based on their physical characteristics such as size and weight. Although this method does not rely on antibodies, it can change the CTCs' properties because of the physical stress caused by techniques such as rapid spinning in a centrifuge, which helps separate the larger cancer cells from smaller white blood cells. With these techniques, after they are isolated the captured CTCs may not still represent the characteristics of the parent tumor.
The new method uses sound, or acoustic waves, similar to the waves in an ultrasound imaging test, to gently separate CTCs from other blood cells without touching the CTCs. Blood samples from cancer patients are streamed across a microfluidic chip where only a fraction of a second of acoustic waves can separate the blood cells from the CTCs, based on their significant difference in size and weight. However, it is better than other size and weight-sorting methods because the brief acoustic exposure exerts little to no stress on the cells--maximizing the potential of CTCs to be maintained, and analyzed in their native state.
Optimizing the system
With the goal of moving this promising technology to the clinic, the group fine-tuned the system combining a mixture of cultured cancer cells and white blood cells (WBCs). Tests were done on this mixture to determine the parameters, including blood flow rates and acoustic wavelengths, that resulted in the most rapid and efficient cell separation. Their experiments resulted in a 20-fold increase in the efficiency of the separation system with a cancer cell recovery rate of more than 83%. The group then tested the optimized conditions on blood samples from three breast cancer patients, demonstrating their ability to successfully isolate CTCs from patients at a clinically useful rate.
"The current throughput is still far from ideal," explains Huang, "but it enables us to test the clinical utility of acoustic based separation, which has never been achieved before. We are working on improving the device design to allow acoustic separation processing at a rate of 7.5 mL of blood in one hour, which will exceed most of the current CTC separation methods."
The new method has many advantages: it is automated, biocompatible, does not change the properties of the cells, and is contained in an inexpensive and compact device. The improved efficiency of the acoustic separation of CTCs is expected to enhance performance in other applications as well, such as separating blood components, synchronizing cells for precise studies of cell division and growth, and separating bacteria from blood and other body fluids.
Read more:http://www.cusabio.com/catalog-13-1.html
"The group has developed gentle and efficient acoustic tweezers," explains Richard Conroy, Ph.D., Director of the NIBIB Program in Diagnostic and Interventional Ultrasound, "These tweezers can move and manipulate thousands of cells without touching them, preserving their characteristics. Development of tools like this will have a significant number of applications in both the research lab and the clinic."
The low-cost acoustic cell-separation device was developed by a research team led by Tony Jun Huang, Ph.D., at Pennsylvania State University, and his collaborators at the Massachusetts Institute of Technology, Notre Dame University, Penn State Hershey Cancer Center, and Carnegie Mellon University. The work is described in the April issue of the Proceedings of the National Academy of Sciences.
Advantages of acoustic separation
The potential for CTCs to provide valuable information about a patient's tumor has driven development of technologies to isolate these rare cells that travel through the blood after breaking off from the primary tumor. Current clinical techniques generally fall into two categories, each of which can damage or alter the characteristics of CTCs during isolation. The first depends on antibodies binding to a protein on the surface of the CTCs. One disadvantage of this technique is that the surface protein must be known ahead of time to determine which antibody should be used. This can cause CTCs to be missed, especially as the tumor evolves in response to chemotherapy and surface proteins change.
The second method separates CTCs based on their physical characteristics such as size and weight. Although this method does not rely on antibodies, it can change the CTCs' properties because of the physical stress caused by techniques such as rapid spinning in a centrifuge, which helps separate the larger cancer cells from smaller white blood cells. With these techniques, after they are isolated the captured CTCs may not still represent the characteristics of the parent tumor.
The new method uses sound, or acoustic waves, similar to the waves in an ultrasound imaging test, to gently separate CTCs from other blood cells without touching the CTCs. Blood samples from cancer patients are streamed across a microfluidic chip where only a fraction of a second of acoustic waves can separate the blood cells from the CTCs, based on their significant difference in size and weight. However, it is better than other size and weight-sorting methods because the brief acoustic exposure exerts little to no stress on the cells--maximizing the potential of CTCs to be maintained, and analyzed in their native state.
Optimizing the system
With the goal of moving this promising technology to the clinic, the group fine-tuned the system combining a mixture of cultured cancer cells and white blood cells (WBCs). Tests were done on this mixture to determine the parameters, including blood flow rates and acoustic wavelengths, that resulted in the most rapid and efficient cell separation. Their experiments resulted in a 20-fold increase in the efficiency of the separation system with a cancer cell recovery rate of more than 83%. The group then tested the optimized conditions on blood samples from three breast cancer patients, demonstrating their ability to successfully isolate CTCs from patients at a clinically useful rate.
"The current throughput is still far from ideal," explains Huang, "but it enables us to test the clinical utility of acoustic based separation, which has never been achieved before. We are working on improving the device design to allow acoustic separation processing at a rate of 7.5 mL of blood in one hour, which will exceed most of the current CTC separation methods."
The new method has many advantages: it is automated, biocompatible, does not change the properties of the cells, and is contained in an inexpensive and compact device. The improved efficiency of the acoustic separation of CTCs is expected to enhance performance in other applications as well, such as separating blood components, synchronizing cells for precise studies of cell division and growth, and separating bacteria from blood and other body fluids.
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月20日星期一
Novel monoclonal antibodies show promise for Alzheimer's disease treatment
Scientists at NYU Langone Medical Center's Center for Cognitive Neurology
have evidence that monoclonal antibodies they developed may provide the
blueprint for effective treatments for Alzheimer's disease and other
neurodegenerative diseases, such as Parkinson's disease.
A team led by Fernando Goni, PhD, an adjunct associate professor of Neurology, and Thomas Wisniewski MD, director of the Center for Cognitive Neurology at NYU Langone, showed that a novel class of monoclonal antibodies successfully targeted proteins that change shape and misfold, becoming toxic and triggering the hallmark beta-amyloid plaques and abnormal tau proteins that are known to accumulate in Alzheimer's and other neurodegenerative conditions. The monoclonal antibodies were also successful at targeting the proteins linked to Parkinson's development.
Monoclonal antibodies are antibodies produced by only one single, specific type of cell and all have the same activity. They can be purified and infused in any organism to produce a desired effect.
The new research suggests that monoclonal antibodies designed to specifically target these misfolding proteins in soluble, aggregated states, may be ideally suited to treating neurodegenerative diseases.
"There is a commonality underlying the misfolding in many neurodegenerative diseases and we are targeting it. We are confident this is the right strategy and our monoclonals are showing they are up to the task," says Dr Goni. "There is potential for specific therapeutic agents for neurodegenerative diseases."
Previous research has established that most neurodegenerative diseases including Alzheimer's, Lewy Body and other dementias, Parkinson's and prion diseases develop and progress along similar paths. In each disease, a particular protein undergoes a change in its shape from a soluble, physiologically functional protein to a protein that has lost the ability to perform its required tasks in the brain, starting off a chain reaction of binding to each other with little control. These aggregates become toxic to brain cells.
In previous studies, Drs. Goni and Wisniewski tested their theory that attacking an early form of these proteins when they change their shape could prevent their formation into aggregates that lead to plaques and tangles, or neutralize their capacity to spread throughout the brain, and stop the progression of a particular neurological disease. They found that their monoclonal antibodies reacted to an intermediate, or "oligomer" state of the amyloid and tau proteins seen in Alzheimer's disease, as well as to prion disease proteins.
In their new study, they determined the monoclonal antibodies' binding specificity to oligomeric forms of a protein called alpha-synuclein, which accumulates and presents in Lewy body containing neurons of Parkinson's disease patients.
Researchers tested three different monoclonal antibodies, each of which binds to amyloid and tau and also reverses Alzheimer's-like damage to brain tissue in animals. They found that all three monoclonal antibodies bind to the oligomeric forms of alpha-synuclein. Then, they confirmed the antibodies' affinity for these structures within neurons using brain tissue samples from people with Parkinson's disease and Alzheimer's.
"We have been developing this strategy for many years, and now we have results. Other labs are trying similar strategies," says Dr Wisniewski, the Lulu P. and David J. Levidow Professor of Neurology and a professor of Pathology and Psychiatry. "The importance of this concept is being increasingly recognized."
Researchers have plans for further animal tests of their monoclonal antibody regimen, on its own and in combination with other approaches, before proceeding to clinical trials.
Alzheimer's disease and other dementias affect 47 million people worldwide and 5.3 million Americans, numbers that are expected to triple by 2050, according to the Alzheimer's Association. This surge is expected to put a tremendous strain on the health care system unless better screening and treatment methods are identified.
Read more:http://www.cusabio.com/catalog-13-1.html
A team led by Fernando Goni, PhD, an adjunct associate professor of Neurology, and Thomas Wisniewski MD, director of the Center for Cognitive Neurology at NYU Langone, showed that a novel class of monoclonal antibodies successfully targeted proteins that change shape and misfold, becoming toxic and triggering the hallmark beta-amyloid plaques and abnormal tau proteins that are known to accumulate in Alzheimer's and other neurodegenerative conditions. The monoclonal antibodies were also successful at targeting the proteins linked to Parkinson's development.
Monoclonal antibodies are antibodies produced by only one single, specific type of cell and all have the same activity. They can be purified and infused in any organism to produce a desired effect.
The new research suggests that monoclonal antibodies designed to specifically target these misfolding proteins in soluble, aggregated states, may be ideally suited to treating neurodegenerative diseases.
"There is a commonality underlying the misfolding in many neurodegenerative diseases and we are targeting it. We are confident this is the right strategy and our monoclonals are showing they are up to the task," says Dr Goni. "There is potential for specific therapeutic agents for neurodegenerative diseases."
Previous research has established that most neurodegenerative diseases including Alzheimer's, Lewy Body and other dementias, Parkinson's and prion diseases develop and progress along similar paths. In each disease, a particular protein undergoes a change in its shape from a soluble, physiologically functional protein to a protein that has lost the ability to perform its required tasks in the brain, starting off a chain reaction of binding to each other with little control. These aggregates become toxic to brain cells.
In previous studies, Drs. Goni and Wisniewski tested their theory that attacking an early form of these proteins when they change their shape could prevent their formation into aggregates that lead to plaques and tangles, or neutralize their capacity to spread throughout the brain, and stop the progression of a particular neurological disease. They found that their monoclonal antibodies reacted to an intermediate, or "oligomer" state of the amyloid and tau proteins seen in Alzheimer's disease, as well as to prion disease proteins.
In their new study, they determined the monoclonal antibodies' binding specificity to oligomeric forms of a protein called alpha-synuclein, which accumulates and presents in Lewy body containing neurons of Parkinson's disease patients.
Researchers tested three different monoclonal antibodies, each of which binds to amyloid and tau and also reverses Alzheimer's-like damage to brain tissue in animals. They found that all three monoclonal antibodies bind to the oligomeric forms of alpha-synuclein. Then, they confirmed the antibodies' affinity for these structures within neurons using brain tissue samples from people with Parkinson's disease and Alzheimer's.
"We have been developing this strategy for many years, and now we have results. Other labs are trying similar strategies," says Dr Wisniewski, the Lulu P. and David J. Levidow Professor of Neurology and a professor of Pathology and Psychiatry. "The importance of this concept is being increasingly recognized."
Researchers have plans for further animal tests of their monoclonal antibody regimen, on its own and in combination with other approaches, before proceeding to clinical trials.
Alzheimer's disease and other dementias affect 47 million people worldwide and 5.3 million Americans, numbers that are expected to triple by 2050, according to the Alzheimer's Association. This surge is expected to put a tremendous strain on the health care system unless better screening and treatment methods are identified.
Read more:http://www.cusabio.com/catalog-13-1.html
Researchers discover a possible reason for drug resistance in breast tumors
HER2 membrane proteins play a special role in certain types of breast
cancer: amplified levels of HER2 drive unrestricted cell growth. HER2-tailored
antibody-based therapeutics aim to prevent cancer cell growth. However,
two-thirds of HER2 positive breast cancer patients develop resistance against
HER2-targeting drugs. The reason for this is not yet understood. Researchers now
found out, that HER2 dimers appeared to be absent from a small sub-population of
resting SKBR3 breast cancer cells. This small subpopulation may have
self-renewing properties that are resistant to HER2-antibody therapy and thus
able to seed new tumor growth.
For their studies researchers from the INM -- Leibniz-Institute for New Materials, Saarbrücken and from the German Cancer Research Center (DKFZ) in Heidelberg used a new electron microscopy method called Liquid STEM. It allows nanoscale studies of intact cells in their native liquid environment.
The scientists have studied the local variations of HER2 membrane protein and of its dimers. HER2 is a member of the human epidermal growth factor receptor (EGFR) family. These family members trigger cell growth signals, when two of the membrane proteins are bound into a protein complex (dimerization). This happens usually after the binding of a small protein, the epidermal growth factor, which circulates in the blood stream and serves as communicator to transmit signals that regulate cell growth. HER2 is special in the sense that it does not need the growth factor protein in order to form dimers. It is thus capable of triggering cell growth without external regulation. In certain types of breast cancer, amplified levels of HER2 and its dimerization are known to drive unrestricted cell growth. HER2-tailored antibody-based therapeutics entered clinical practice more than a decade ago. These drugs aim to prevent cell growth triggered by HER2 homo- and/or heterodimerization.
"We found out, that HER2 dimers appeared to be absent from a small sub-population of resting SKBR3 cells. Could such cells survive the therapy and then develop into a drug resistant cancer at a later stage? It thus seems to be of key significance to study this sub-population of cells with exceptional phenotype," says Niels de Jonge, head of the Innovative Electron Microscopy group.
HER2 dimerization processes were thus far mostly studied on the basis of cell population averages, for example, with biochemical methods using pooled cell material, and information about the localization of HER2 dimerization was lacking. Therefore, the researchers around de Jonge pioneered the electron microscopy method Liquid STEM to imaging these receptors on cancer cells. The cells were examined on a microchip placed in the electron microscope, and remained intact and in liquid. "Specimens cannot be studied in liquid with traditional electron microscopy," explains Professor de Jonge. "Cells are typically studied in dry state via thin sectioning of solid dried plastic embedded or frozen material. The role of HER proteins is a "hot" topic in cancer research but despite large research efforts using a wide range of techniques over the past decades this important information was not unveiled before. Our novel findings were obtained as a direct consequence of the high spatial resolution of Liquid STEM combined with its capability to study many intact cells in liquid," says de Jonge.
Read more:http://www.cusabio.com/catalog-13-1.html
For their studies researchers from the INM -- Leibniz-Institute for New Materials, Saarbrücken and from the German Cancer Research Center (DKFZ) in Heidelberg used a new electron microscopy method called Liquid STEM. It allows nanoscale studies of intact cells in their native liquid environment.
The scientists have studied the local variations of HER2 membrane protein and of its dimers. HER2 is a member of the human epidermal growth factor receptor (EGFR) family. These family members trigger cell growth signals, when two of the membrane proteins are bound into a protein complex (dimerization). This happens usually after the binding of a small protein, the epidermal growth factor, which circulates in the blood stream and serves as communicator to transmit signals that regulate cell growth. HER2 is special in the sense that it does not need the growth factor protein in order to form dimers. It is thus capable of triggering cell growth without external regulation. In certain types of breast cancer, amplified levels of HER2 and its dimerization are known to drive unrestricted cell growth. HER2-tailored antibody-based therapeutics entered clinical practice more than a decade ago. These drugs aim to prevent cell growth triggered by HER2 homo- and/or heterodimerization.
"We found out, that HER2 dimers appeared to be absent from a small sub-population of resting SKBR3 cells. Could such cells survive the therapy and then develop into a drug resistant cancer at a later stage? It thus seems to be of key significance to study this sub-population of cells with exceptional phenotype," says Niels de Jonge, head of the Innovative Electron Microscopy group.
HER2 dimerization processes were thus far mostly studied on the basis of cell population averages, for example, with biochemical methods using pooled cell material, and information about the localization of HER2 dimerization was lacking. Therefore, the researchers around de Jonge pioneered the electron microscopy method Liquid STEM to imaging these receptors on cancer cells. The cells were examined on a microchip placed in the electron microscope, and remained intact and in liquid. "Specimens cannot be studied in liquid with traditional electron microscopy," explains Professor de Jonge. "Cells are typically studied in dry state via thin sectioning of solid dried plastic embedded or frozen material. The role of HER proteins is a "hot" topic in cancer research but despite large research efforts using a wide range of techniques over the past decades this important information was not unveiled before. Our novel findings were obtained as a direct consequence of the high spatial resolution of Liquid STEM combined with its capability to study many intact cells in liquid," says de Jonge.
Read more:http://www.cusabio.com/catalog-13-1.html
Researchers discover a possible reason for drug resistance in breast tumors
HER2 membrane proteins play a special role in certain types of breast
cancer: amplified levels of HER2 drive unrestricted cell growth. HER2-tailored
antibody-based therapeutics aim to prevent cancer cell growth. However,
two-thirds of HER2 positive breast cancer patients develop resistance against
HER2-targeting drugs. The reason for this is not yet understood. Researchers now
found out, that HER2 dimers appeared to be absent from a small sub-population of
resting SKBR3 breast cancer cells. This small subpopulation may have
self-renewing properties that are resistant to HER2-antibody therapy and thus
able to seed new tumor growth.
For their studies researchers from the INM -- Leibniz-Institute for New Materials, Saarbrücken and from the German Cancer Research Center (DKFZ) in Heidelberg used a new electron microscopy method called Liquid STEM. It allows nanoscale studies of intact cells in their native liquid environment.
The scientists have studied the local variations of HER2 membrane protein and of its dimers. HER2 is a member of the human epidermal growth factor receptor (EGFR) family. These family members trigger cell growth signals, when two of the membrane proteins are bound into a protein complex (dimerization). This happens usually after the binding of a small protein, the epidermal growth factor, which circulates in the blood stream and serves as communicator to transmit signals that regulate cell growth. HER2 is special in the sense that it does not need the growth factor protein in order to form dimers. It is thus capable of triggering cell growth without external regulation. In certain types of breast cancer, amplified levels of HER2 and its dimerization are known to drive unrestricted cell growth. HER2-tailored antibody-based therapeutics entered clinical practice more than a decade ago. These drugs aim to prevent cell growth triggered by HER2 homo- and/or heterodimerization.
"We found out, that HER2 dimers appeared to be absent from a small sub-population of resting SKBR3 cells. Could such cells survive the therapy and then develop into a drug resistant cancer at a later stage? It thus seems to be of key significance to study this sub-population of cells with exceptional phenotype," says Niels de Jonge, head of the Innovative Electron Microscopy group.
HER2 dimerization processes were thus far mostly studied on the basis of cell population averages, for example, with biochemical methods using pooled cell material, and information about the localization of HER2 dimerization was lacking. Therefore, the researchers around de Jonge pioneered the electron microscopy method Liquid STEM to imaging these receptors on cancer cells. The cells were examined on a microchip placed in the electron microscope, and remained intact and in liquid. "Specimens cannot be studied in liquid with traditional electron microscopy," explains Professor de Jonge. "Cells are typically studied in dry state via thin sectioning of solid dried plastic embedded or frozen material. The role of HER proteins is a "hot" topic in cancer research but despite large research efforts using a wide range of techniques over the past decades this important information was not unveiled before. Our novel findings were obtained as a direct consequence of the high spatial resolution of Liquid STEM combined with its capability to study many intact cells in liquid," says de Jonge.
Read more:http://www.cusabio.com/catalog-13-1.html
For their studies researchers from the INM -- Leibniz-Institute for New Materials, Saarbrücken and from the German Cancer Research Center (DKFZ) in Heidelberg used a new electron microscopy method called Liquid STEM. It allows nanoscale studies of intact cells in their native liquid environment.
The scientists have studied the local variations of HER2 membrane protein and of its dimers. HER2 is a member of the human epidermal growth factor receptor (EGFR) family. These family members trigger cell growth signals, when two of the membrane proteins are bound into a protein complex (dimerization). This happens usually after the binding of a small protein, the epidermal growth factor, which circulates in the blood stream and serves as communicator to transmit signals that regulate cell growth. HER2 is special in the sense that it does not need the growth factor protein in order to form dimers. It is thus capable of triggering cell growth without external regulation. In certain types of breast cancer, amplified levels of HER2 and its dimerization are known to drive unrestricted cell growth. HER2-tailored antibody-based therapeutics entered clinical practice more than a decade ago. These drugs aim to prevent cell growth triggered by HER2 homo- and/or heterodimerization.
"We found out, that HER2 dimers appeared to be absent from a small sub-population of resting SKBR3 cells. Could such cells survive the therapy and then develop into a drug resistant cancer at a later stage? It thus seems to be of key significance to study this sub-population of cells with exceptional phenotype," says Niels de Jonge, head of the Innovative Electron Microscopy group.
HER2 dimerization processes were thus far mostly studied on the basis of cell population averages, for example, with biochemical methods using pooled cell material, and information about the localization of HER2 dimerization was lacking. Therefore, the researchers around de Jonge pioneered the electron microscopy method Liquid STEM to imaging these receptors on cancer cells. The cells were examined on a microchip placed in the electron microscope, and remained intact and in liquid. "Specimens cannot be studied in liquid with traditional electron microscopy," explains Professor de Jonge. "Cells are typically studied in dry state via thin sectioning of solid dried plastic embedded or frozen material. The role of HER proteins is a "hot" topic in cancer research but despite large research efforts using a wide range of techniques over the past decades this important information was not unveiled before. Our novel findings were obtained as a direct consequence of the high spatial resolution of Liquid STEM combined with its capability to study many intact cells in liquid," says de Jonge.
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月16日星期四
Cell division speeds up as part of antibody selection
In research published in Science on July 16, scientists led by Michel
Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman Professor and head of the
Laboratory of Molecular Immunology, uncovered a new mechanism by which the B
cells that produce the most finely tuned antibodies rise to dominance. This
discovery builds on earlier work published last year.
"Through a process called affinity maturation B cells compete, and those cells that produce the highest affinity antibodies win and come to dominate the B cell population. Our work so far has revealed two of the mechanisms that allow high affinity B cells to overwhelm the others," says Alex Gitlin, a graduate student in the lab and first author of the paper.
B cells have genes that code for antibodies, which latch onto foreign proteins, called antigens, as part of an immune response. During an infection, B cells and other immune cells form tiny structures called germinal centers in the spleen and lymph nodes.
Within germinal centers, B cells evolve in a Darwinian-like fashion. The gene responsible for producing their antibodies mutates rapidly, a million times faster than the normal rate of mutation in the human body, and the cells proliferate. B cells whose mutations increase the antibody's affinity for the antigen are selected, and these cells then continue to mutate and proliferate.
"Previously, we showed that high affinity cells spend more time dividing and mutating in between rounds of competition. We now show that these high affinity cells also use this additional time more effectively -- by dividing at faster rates," Gitlin says. In this manner, the germinal center produces the high affinity antibodies that are the basis of an effective immune response.
Vaccines initiate this process by exposing the body to pieces of a pathogen or to a weakened or dead version of it, prompting the immune system to develop protective antibodies. Because vaccines depend on effective antibody responses for protection, a better understanding of the antibody selection process in the germinal center might potentially be of use for developing more effective vaccines.
The team's research has focused on the dynamics inside the germinal center. Within it, B cells travel between two areas known as the dark zone and the light zone. In the dark zone, the B cells mutate and proliferate, before traveling to the light zone, where they pick up pieces of antigen. The higher the affinity of their antibodies, the more antigen they pick up.
Their previous experiments demonstrated that another type of immune cell, the T cell, operates in the light zone to recognize the higher affinity B cells based on the amount of antigen they display. The more antigen the B cells present to T cells, the stronger the signal the T cells send. As a result, the high affinity B cells spend more time in the dark zone in between visits to the light zone.
This time, the team, which also included collaborators at Memorial Sloan Kettering Cancer Center and Harvard Medical School, identified another reason the high affinity cells come to dominate: more rapid cell divisions. They induced the selection of an engineered set of B cells in mice, and used labels that the cells incorporate as they replicate their DNA in preparation for cell division. With these techniques they found that a signal from the T cell also prompts the high affinity B cells to divide more rapidly while in the dark zone. In effect, these cells have both more time and more speed with which to duplicate themselves.
By labeling DNA replication and following its progression, the team took a close look at how the S phase of the cell cycle, in which the cell copies its DNA in preparation for division, is sped up. They found that acceleration during this phase was due to the double-stranded DNA molecule being unzipped and copied more rapidly at the so-called replication fork.
Together, these studies describe two complementary ways in which signals from T cells empower the best equipped set of B cells to take over the immune response during affinity maturation. Other mechanisms, which are yet to be discovered, are also likely to be at play,The dynamics of germinal centers are crucial to this basic immunological process, and they may also have important implications for improving vaccines and understanding lymphomas, which often arise from germinal center B cells due to their high rates of proliferation and mutation.
Read more:http://www.cusabio.com/catalog-13-1.html
"Through a process called affinity maturation B cells compete, and those cells that produce the highest affinity antibodies win and come to dominate the B cell population. Our work so far has revealed two of the mechanisms that allow high affinity B cells to overwhelm the others," says Alex Gitlin, a graduate student in the lab and first author of the paper.
B cells have genes that code for antibodies, which latch onto foreign proteins, called antigens, as part of an immune response. During an infection, B cells and other immune cells form tiny structures called germinal centers in the spleen and lymph nodes.
Within germinal centers, B cells evolve in a Darwinian-like fashion. The gene responsible for producing their antibodies mutates rapidly, a million times faster than the normal rate of mutation in the human body, and the cells proliferate. B cells whose mutations increase the antibody's affinity for the antigen are selected, and these cells then continue to mutate and proliferate.
"Previously, we showed that high affinity cells spend more time dividing and mutating in between rounds of competition. We now show that these high affinity cells also use this additional time more effectively -- by dividing at faster rates," Gitlin says. In this manner, the germinal center produces the high affinity antibodies that are the basis of an effective immune response.
Vaccines initiate this process by exposing the body to pieces of a pathogen or to a weakened or dead version of it, prompting the immune system to develop protective antibodies. Because vaccines depend on effective antibody responses for protection, a better understanding of the antibody selection process in the germinal center might potentially be of use for developing more effective vaccines.
The team's research has focused on the dynamics inside the germinal center. Within it, B cells travel between two areas known as the dark zone and the light zone. In the dark zone, the B cells mutate and proliferate, before traveling to the light zone, where they pick up pieces of antigen. The higher the affinity of their antibodies, the more antigen they pick up.
Their previous experiments demonstrated that another type of immune cell, the T cell, operates in the light zone to recognize the higher affinity B cells based on the amount of antigen they display. The more antigen the B cells present to T cells, the stronger the signal the T cells send. As a result, the high affinity B cells spend more time in the dark zone in between visits to the light zone.
This time, the team, which also included collaborators at Memorial Sloan Kettering Cancer Center and Harvard Medical School, identified another reason the high affinity cells come to dominate: more rapid cell divisions. They induced the selection of an engineered set of B cells in mice, and used labels that the cells incorporate as they replicate their DNA in preparation for cell division. With these techniques they found that a signal from the T cell also prompts the high affinity B cells to divide more rapidly while in the dark zone. In effect, these cells have both more time and more speed with which to duplicate themselves.
By labeling DNA replication and following its progression, the team took a close look at how the S phase of the cell cycle, in which the cell copies its DNA in preparation for division, is sped up. They found that acceleration during this phase was due to the double-stranded DNA molecule being unzipped and copied more rapidly at the so-called replication fork.
Together, these studies describe two complementary ways in which signals from T cells empower the best equipped set of B cells to take over the immune response during affinity maturation. Other mechanisms, which are yet to be discovered, are also likely to be at play,The dynamics of germinal centers are crucial to this basic immunological process, and they may also have important implications for improving vaccines and understanding lymphomas, which often arise from germinal center B cells due to their high rates of proliferation and mutation.
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月15日星期三
HIV uses immune system's own tools to suppress it
A Canadian research team at the IRCM in Montreal, led by molecular
virologist Eric A. Cohen, PhD, made a significant discovery on how HIV escapes
the body's antiviral responses. The team uncovered how an HIV viral protein
known as Vpu tricks the immune system by using its own regulatory process to
evade the host's first line of defence.
The study's goal was to determine how HIV manages to compromise antiviral responses in the initial period of infection, also called the acute infection stage, during which the virus establishes itself in the body. The acute infection is considered a critical period in determining the complexity, extent and progression of the disease. It is also during this stage that HIV establishes latent infection in long-lasting cellular reservoirs. These viral reservoirs, which harbour the virus out of sight from the immune system and antiviral drugs, represent the primary barrier to a cure.
"An important component in this process is a group of proteins collectively called type 1 Interferons, which are the immune system's first line of defence against viral infections and are known to have a beneficial role in the early stages of HIV infection," says Dr. Cohen, Director of the Human Retrovirology research unit at the IRCM. "The problem is that HIV has developed mechanisms to suppress the Interferon response and, until now, little was known about how this was achieved."
Most of the Interferon is produced by a very small population of immune cells called pDCs (plasmacytoid dendritic cells), responsible for providing immediate defence against infections. PDCs patrol the body to detect invaders and, when they recognize the presence of a pathogen, they secrete Interferon. The Interferon then triggers a large array of defence mechanisms in nearby cells, creating an antiviral state that prevents the dissemination and, ultimately, the expansion of the virus.
"When pDCs encounter HIV-infected cells, the production of Interferon is regulated by a protein located on the infected cell's surface called BST2," explains Mariana Bego, PhD, first author of the study and research associate in Dr. Cohen's laboratory. "BST2 has the ability to bind to and activate a receptor called ILT7, found on the surface of pDCs, which, in turns, sends a signal that suppresses the production of Interferon and halts its defensive functions. Interestingly, BST2 is also responsible for restricting HIV production by trapping the virus at the cell surface before it can exit infected cells and disseminate. However, HIV uses the viral protein Vpu to counteract BST2 antiviral activity."
"With this study, we uncovered a unique mechanism whereby HIV exploits the regulatory process between BST2 and ILT7 to limit the body's antiviral response, which allows the virus to spread and leads to persistent infection," adds Dr. Bego. "We found that HIV, through Vpu, takes advantage of the role played by BST2 by maintaining its ability to activate ILT7 and limit the production of Interferon, all the while counteracting its direct antiviral activity on HIV production."
"The hope for a definitive cure and an effective vaccine has been frustrated by HIV's endless propensity to subvert the host's defences and persist in small populations of long-lasting reservoirs despite antiretroviral therapy," describes Dr. Cohen, who also leads CanCURE, a team of leading Canadian researchers working towards an HIV cure. "Our findings can provide tools to enhance antiviral responses during the early stages of infection. By blocking Vpu's action, we could prevent early viral expansion and dissemination, while also allowing pDCs to trigger effective antiviral responses. We believe that such interventions during primary infection have the potential to limit the establishment and complexity of viral reservoirs, a condition that seems required to achieve a sustained HIV remission."
"The discovery by Drs. Bego and Cohen, which explains how the virus can't be held down or wiped out during early periods of infection, will bring us closer to ending HIV/AIDS," says Robert Reinhard, CanCURE Community Liaison. "By filling an important gap in knowledge, this new study will advance research for an HIV cure."
Read more:http://www.cusabio.com/catalog-13-1.html
The study's goal was to determine how HIV manages to compromise antiviral responses in the initial period of infection, also called the acute infection stage, during which the virus establishes itself in the body. The acute infection is considered a critical period in determining the complexity, extent and progression of the disease. It is also during this stage that HIV establishes latent infection in long-lasting cellular reservoirs. These viral reservoirs, which harbour the virus out of sight from the immune system and antiviral drugs, represent the primary barrier to a cure.
"An important component in this process is a group of proteins collectively called type 1 Interferons, which are the immune system's first line of defence against viral infections and are known to have a beneficial role in the early stages of HIV infection," says Dr. Cohen, Director of the Human Retrovirology research unit at the IRCM. "The problem is that HIV has developed mechanisms to suppress the Interferon response and, until now, little was known about how this was achieved."
Most of the Interferon is produced by a very small population of immune cells called pDCs (plasmacytoid dendritic cells), responsible for providing immediate defence against infections. PDCs patrol the body to detect invaders and, when they recognize the presence of a pathogen, they secrete Interferon. The Interferon then triggers a large array of defence mechanisms in nearby cells, creating an antiviral state that prevents the dissemination and, ultimately, the expansion of the virus.
"When pDCs encounter HIV-infected cells, the production of Interferon is regulated by a protein located on the infected cell's surface called BST2," explains Mariana Bego, PhD, first author of the study and research associate in Dr. Cohen's laboratory. "BST2 has the ability to bind to and activate a receptor called ILT7, found on the surface of pDCs, which, in turns, sends a signal that suppresses the production of Interferon and halts its defensive functions. Interestingly, BST2 is also responsible for restricting HIV production by trapping the virus at the cell surface before it can exit infected cells and disseminate. However, HIV uses the viral protein Vpu to counteract BST2 antiviral activity."
"With this study, we uncovered a unique mechanism whereby HIV exploits the regulatory process between BST2 and ILT7 to limit the body's antiviral response, which allows the virus to spread and leads to persistent infection," adds Dr. Bego. "We found that HIV, through Vpu, takes advantage of the role played by BST2 by maintaining its ability to activate ILT7 and limit the production of Interferon, all the while counteracting its direct antiviral activity on HIV production."
"The hope for a definitive cure and an effective vaccine has been frustrated by HIV's endless propensity to subvert the host's defences and persist in small populations of long-lasting reservoirs despite antiretroviral therapy," describes Dr. Cohen, who also leads CanCURE, a team of leading Canadian researchers working towards an HIV cure. "Our findings can provide tools to enhance antiviral responses during the early stages of infection. By blocking Vpu's action, we could prevent early viral expansion and dissemination, while also allowing pDCs to trigger effective antiviral responses. We believe that such interventions during primary infection have the potential to limit the establishment and complexity of viral reservoirs, a condition that seems required to achieve a sustained HIV remission."
"The discovery by Drs. Bego and Cohen, which explains how the virus can't be held down or wiped out during early periods of infection, will bring us closer to ending HIV/AIDS," says Robert Reinhard, CanCURE Community Liaison. "By filling an important gap in knowledge, this new study will advance research for an HIV cure."
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月14日星期二
Scientific curiosity and preparedness for emerging pathogen outbreaks
An essay published in PLOS Pathogens' new "Research Matters" series
reflects on a career path that started with the study of a somewhat obscure
mouse virus mice and ended up at the frontline of the SARS and MERS coronavirus
epidemics.
His curiosity about basic cell biology and the desire to understand the devastating effects of viruses on the developing human brain led Stanley Perlman, from the University of Iowa's Carver School of Medicine, Iowa City, USA, to dedicate the work of his research group to the study of a virus that infects the mouse brain, murine hepatitis virus (MHV), a member of the coronavirus family, and the mammalian immune response to it.
Their work showed that while the immune response to MHV infection is essential to controlling the infection, it is also responsible for many of the clinical symptoms that occur, including the destruction of a certain type of nerve cell. Incidentally, these results from the mouse model studies stem turned out to be highly relevant to the human multiple sclerosis.
Perlman and colleagues also showed that the immune response to MHV involves an intricate interplay of different immune cells, and that unless it is dampened appropriately after the initial destructive attack on the invading virus, some of these cells will damage and even destroy the host's own tissues. A key role in controlling the immune response, they found, was played by so-called "regulatory T cells," a finding that is now well-established and central to many current approaches to prevent or treat autoimmune and other inflammatory diseases.
As Perlman states, while "until the early 2000s, coronaviruses were not considered important human pathogens," the main reason for "rapid progress in understanding SARS and MERS and in developing vaccines and therapies was existing knowledge gained from studies of MHV and other animal coronaviruses."
Besides MHV, Perlman's laboratory now also studies three human coronaviruses and has developed a mouse model for MERS. His "journey from studies of murine coronaviruses to those of serious human pathogens," he says, illustrates the importance of research driven initially by curiosity." "It is only through basic research into these pathogens," he concludes, "that we will be prepared for future outbreaks."
Read more:http://about.cusabio.com/m-219.html
His curiosity about basic cell biology and the desire to understand the devastating effects of viruses on the developing human brain led Stanley Perlman, from the University of Iowa's Carver School of Medicine, Iowa City, USA, to dedicate the work of his research group to the study of a virus that infects the mouse brain, murine hepatitis virus (MHV), a member of the coronavirus family, and the mammalian immune response to it.
Their work showed that while the immune response to MHV infection is essential to controlling the infection, it is also responsible for many of the clinical symptoms that occur, including the destruction of a certain type of nerve cell. Incidentally, these results from the mouse model studies stem turned out to be highly relevant to the human multiple sclerosis.
Perlman and colleagues also showed that the immune response to MHV involves an intricate interplay of different immune cells, and that unless it is dampened appropriately after the initial destructive attack on the invading virus, some of these cells will damage and even destroy the host's own tissues. A key role in controlling the immune response, they found, was played by so-called "regulatory T cells," a finding that is now well-established and central to many current approaches to prevent or treat autoimmune and other inflammatory diseases.
As Perlman states, while "until the early 2000s, coronaviruses were not considered important human pathogens," the main reason for "rapid progress in understanding SARS and MERS and in developing vaccines and therapies was existing knowledge gained from studies of MHV and other animal coronaviruses."
Besides MHV, Perlman's laboratory now also studies three human coronaviruses and has developed a mouse model for MERS. His "journey from studies of murine coronaviruses to those of serious human pathogens," he says, illustrates the importance of research driven initially by curiosity." "It is only through basic research into these pathogens," he concludes, "that we will be prepared for future outbreaks."
Read more:http://about.cusabio.com/m-219.html
2015年7月13日星期一
Chemotherapeutic coatings enhance tumor-frying nanoparticles
In a move akin to adding chemical weapons to a firebomb, researchers at
Duke University have devised a method for making a promising nanoscale cancer
treatment even more deadly to tumors.
The invention allows an extremely thin layer of hydrogels (think contact lenses) to be deposited on the surface of nanoshells -- particles about a hundred nanometers wide designed to absorb infrared light and generate heat. When heated, these special hydrogels lose their water content and release any molecules (such as drugs) trapped within.
By depositing the hydrogels on tumor-torching nanoshells and loading the new coating with chemotherapeutic drugs, a formidable one-two punch is formed.
The technique is described in a paper published in the journal ACS Biomaterials Science & Engineering on July 13, 2015, and was highlighted as an ACS Editor's Choice.
"The idea is to combine tumor-destroying heat therapy with localized drug delivery, so that you can hopefully have the most effective treatment possible," said Jennifer West, the Fitzpatrick Family University Professor of Engineering at Duke, who holds appointments in biomedical engineering, mechanical engineering and materials science, cell biology, and chemistry. "And many chemotherapeutic drugs have been shown to be more effective in heated tissue, so there's a potential synergy between the two approaches."
The photothermal therapy is already in clinical trials for several types of cancers being conducted by Nanospectra Biosciences, Inc., a company West founded. The nanoshells are tuned to absorb near-infrared light, which passes harmlessly through water and tissue. The nanoshells, however, quickly heat up enough to destroy cells, but only where the light shines.
Besides being able to accurately target specific locations in the body with the light, the treatment also hinges on the fact that nanoshells tend to accumulate within a tumor due to leaky vasculature.
"But you have to keep their size under about 500 nanometers," said West. "We had to come up with a new process to create a very thin polymer coating on the surface of these nanoparticles to keep them under that threshold."
In the new study, West and doctoral student Laura Strong loaded the newly coated nanoshells with a potent chemotherapeutic drug and delivered them to tumor cells in a laboratory setting. The treatment worked as planned; the nanoshells heated up and destroyed most of the tumor cells while releasing the drugs, which cleaned up the survivors. Completely eradicating every cancerous cell is extremely important, as the escape of even a single cell capable of metastasizing could prove deadly down the road.
The next step for the new cancer treatment is tests in live animals. While those experiments are in progress, human trials are still at least a couple years away.
But the technology need not be limited to cancer therapy.
"The hydrogels can release drugs just above body temperature, so you could potentially look at this for other drug-delivery applications where you don't necessarily want to destroy the tissue," said West. "You could do a milder warming and still trigger the drug release."
Read more:http://www.cusabio.com/catalog-15-1.html
The invention allows an extremely thin layer of hydrogels (think contact lenses) to be deposited on the surface of nanoshells -- particles about a hundred nanometers wide designed to absorb infrared light and generate heat. When heated, these special hydrogels lose their water content and release any molecules (such as drugs) trapped within.
By depositing the hydrogels on tumor-torching nanoshells and loading the new coating with chemotherapeutic drugs, a formidable one-two punch is formed.
The technique is described in a paper published in the journal ACS Biomaterials Science & Engineering on July 13, 2015, and was highlighted as an ACS Editor's Choice.
"The idea is to combine tumor-destroying heat therapy with localized drug delivery, so that you can hopefully have the most effective treatment possible," said Jennifer West, the Fitzpatrick Family University Professor of Engineering at Duke, who holds appointments in biomedical engineering, mechanical engineering and materials science, cell biology, and chemistry. "And many chemotherapeutic drugs have been shown to be more effective in heated tissue, so there's a potential synergy between the two approaches."
The photothermal therapy is already in clinical trials for several types of cancers being conducted by Nanospectra Biosciences, Inc., a company West founded. The nanoshells are tuned to absorb near-infrared light, which passes harmlessly through water and tissue. The nanoshells, however, quickly heat up enough to destroy cells, but only where the light shines.
Besides being able to accurately target specific locations in the body with the light, the treatment also hinges on the fact that nanoshells tend to accumulate within a tumor due to leaky vasculature.
"But you have to keep their size under about 500 nanometers," said West. "We had to come up with a new process to create a very thin polymer coating on the surface of these nanoparticles to keep them under that threshold."
In the new study, West and doctoral student Laura Strong loaded the newly coated nanoshells with a potent chemotherapeutic drug and delivered them to tumor cells in a laboratory setting. The treatment worked as planned; the nanoshells heated up and destroyed most of the tumor cells while releasing the drugs, which cleaned up the survivors. Completely eradicating every cancerous cell is extremely important, as the escape of even a single cell capable of metastasizing could prove deadly down the road.
The next step for the new cancer treatment is tests in live animals. While those experiments are in progress, human trials are still at least a couple years away.
But the technology need not be limited to cancer therapy.
"The hydrogels can release drugs just above body temperature, so you could potentially look at this for other drug-delivery applications where you don't necessarily want to destroy the tissue," said West. "You could do a milder warming and still trigger the drug release."
Read more:http://www.cusabio.com/catalog-15-1.html
2015年7月12日星期日
Gene therapy advance thwarts brain cancer in rats
Researchers funded by the National Institute of Biomedical Imaging and
Bioengineering have designed a nanoparticle transport system for gene delivery
that destroys deadly brain gliomas in a rat model, significantly extending the
lives of the treated animals. The nanoparticles are filled with genes for an
enzyme that converts a prodrug called ganciclovir into a potent destroyer of the
glioma cells.
Glioma is one of the most lethal human cancers, with a five year survival rate of just 12%, and no reliable treatment. Advances in the understanding of the molecular processes that cause these tumors has resulted in therapies aimed at delivering specific genes into tumors -- genes that make proteins to kill or suppress the growth of the tumor. Currently this approach relies heavily on using viruses to deliver the anti-tumor genes into the target cancer cells. Unfortunately, viral delivery poses significant safety risks including toxicity, activation of the patient's immune system against the virus, and the possibility of the virus itself encouraging tumors to develop.
Biodegradable nanoparticles have recently shown promise as a method to deliver genes into cells. Their use for delivery avoids many of the problems associated with viral gene delivery. To demonstrate virus free delivery, the first goal of the group was to develop a nanoparticle that could efficiently carry DNA encoding a gene known as HSVtk into cells. The HSVtk gene produces an enzyme that turns the compound ganciclovir--which by itself has no effect on cancer cells -- into a compound that is toxic to actively dividing brain cancer cells.
A number of polymer structures were tested for their ability to deliver DNA into two rat glioma cell lines. Among the many polymers tried, the one known as PBAE 447 was found to be the most efficient in delivering the HSVtk gene into the cultured rat glioma cells. Furthermore, when combined with ganciclovir, the HSVtk-encoding nanoparticles were 100% effective in killing both of the glioma cell lines grown in the laboratory.
Next, the gene therapy system was tested in live rats with brain gliomas. Because it is important that the nanoparticles spread throughout the entire tumor, they were infused into the rat gliomas using convection-enhanced delivery (CED). The method involves injection into the tumor and the application of a pressure gradient, which efficiently disperses the nanoparticles throughout the tumors.
To test the tumor-killing ability of the system, the tumor-bearing rats were given systemic administration of ganciclovir for two days, then CED was used to infuse the HSVtk-encoding nanoparticles into the rat gliomas, and systemic ganciclovir treatment continued for eight more days. The treatment resulted in shrinkage of the tumors and a significant increase in survival when compared with control glioma-bearing animals that did not receive the combination treatment.
In the future, the investigators envision that doctors would administer this therapy during the surgery commonly used to treat glioma in humans. They are also interested in testing the ability to deliver other cancer-killing genes and whether the nanoparticles could be successfully administered systemically -- which could broaden the use of the therapy for a wide range of solid tumors and systemic cancers.
Read more:http://www.cusabio.com/catalog-13-1.html
Glioma is one of the most lethal human cancers, with a five year survival rate of just 12%, and no reliable treatment. Advances in the understanding of the molecular processes that cause these tumors has resulted in therapies aimed at delivering specific genes into tumors -- genes that make proteins to kill or suppress the growth of the tumor. Currently this approach relies heavily on using viruses to deliver the anti-tumor genes into the target cancer cells. Unfortunately, viral delivery poses significant safety risks including toxicity, activation of the patient's immune system against the virus, and the possibility of the virus itself encouraging tumors to develop.
Biodegradable nanoparticles have recently shown promise as a method to deliver genes into cells. Their use for delivery avoids many of the problems associated with viral gene delivery. To demonstrate virus free delivery, the first goal of the group was to develop a nanoparticle that could efficiently carry DNA encoding a gene known as HSVtk into cells. The HSVtk gene produces an enzyme that turns the compound ganciclovir--which by itself has no effect on cancer cells -- into a compound that is toxic to actively dividing brain cancer cells.
A number of polymer structures were tested for their ability to deliver DNA into two rat glioma cell lines. Among the many polymers tried, the one known as PBAE 447 was found to be the most efficient in delivering the HSVtk gene into the cultured rat glioma cells. Furthermore, when combined with ganciclovir, the HSVtk-encoding nanoparticles were 100% effective in killing both of the glioma cell lines grown in the laboratory.
Next, the gene therapy system was tested in live rats with brain gliomas. Because it is important that the nanoparticles spread throughout the entire tumor, they were infused into the rat gliomas using convection-enhanced delivery (CED). The method involves injection into the tumor and the application of a pressure gradient, which efficiently disperses the nanoparticles throughout the tumors.
To test the tumor-killing ability of the system, the tumor-bearing rats were given systemic administration of ganciclovir for two days, then CED was used to infuse the HSVtk-encoding nanoparticles into the rat gliomas, and systemic ganciclovir treatment continued for eight more days. The treatment resulted in shrinkage of the tumors and a significant increase in survival when compared with control glioma-bearing animals that did not receive the combination treatment.
In the future, the investigators envision that doctors would administer this therapy during the surgery commonly used to treat glioma in humans. They are also interested in testing the ability to deliver other cancer-killing genes and whether the nanoparticles could be successfully administered systemically -- which could broaden the use of the therapy for a wide range of solid tumors and systemic cancers.
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月9日星期四
Multiple myeloma hides in bones like a wolf in sheep's clothing
Multiple myeloma uses a trick akin to a wolf in sheep's clothing to grow in
and spread to new bone sites. By overexpressing Runx2, a gene that normally is a
master regulator of bone formation, the cells of this largely incurable cancer
produce proteins that mimic the normal bone-resident cells, according to
research published in the journal Bloodby Yang Yang, M.D., Ph.D., associate
professor of pathology at the University of Alabama at Birmingham.
This is the first study of the Runx2 expression in multiple myeloma, a cancer of the white blood cells that causes an estimated 11,000 deaths a year in the U.S., says Yang, who is also a scientist in UAB's Comprehensive Cancer Center and Center for Metabolic Bone Disease. Runx2 has been linked to bone metastasis in several solid tumors, though researchers did not analyze the solid tumors for expression of bone-related genes.
"This new mechanism of Runx2 overexpression can give multiple myeloma cells a bone cell-like phenotype," Yang said of the work by her lab and collaborators. "When the multiple myeloma cells come to the new bone sites, the bone immune cells think, 'This is one of our neighbor cells,' and therefore do not eliminate them. The bone immune cells do not recognize these cells as strangers."
A series of experiments in the multiple myeloma study, with both animal models and cells from human patients, highlights the role of the transcription factor Runx2 to express bone-related genes in myeloma cells -- genes that normally exist in bone residential cells, such as bone-forming osteoblasts and osteocytes, and the bone-resorbing osteoclast cells. These changes make the multiple myeloma cells more aggressive.
For animal models, Yang and colleagues used molecular genetic techniques to either increase or decrease the expression of Runx2 in a mouse myeloma cell line. The increased expression cells are called "Runx2 knock-in" cells, and the decreased expression cells are called "Runx2 knock-down" cells.
In mice, the Runx2 knock-in myeloma cells produced greater tumor growth and a wider spread of disease compared with the original myeloma cells; conversely, the Runx2 knock-down cells had less tumor growth and disease spread. The researchers also tested a Runx2 knock-down variant of a human multiple myeloma cell line and found that it produced significantly less tumor growth in immunodeficient mice than the original human multiple myeloma cells.
The researchers used the Runx2 knock-in and knock-down cells to show that Runx2 overexpression activates the Akt/β-catenin/Survivin signaling system in the multiple myeloma cells. This is a different signaling system than the one activated by Runx2 in solid tumors.
Downstream of the signaling system, Runx2 overexpression led to overexpression of bone-related genes, including genes expressed by osteoblasts, osteoclasts and osteocytes. "Taken together, these results support the hypothesis that multiple myeloma cells express bone-related genes in a Runx2-dependent fashion that mimics bone marrow resident cells and likely contributes to tumor survival and growth in the bone microenvironment," Yang and colleagues wrote in the paper.
The overexpression of Runx2 also enhanced secretion of soluble factors that aid tumor progression and metastasis, including cytokines and growth factors.
In humans, a comparison of bone marrow from 14 normal bone marrow donors, 35 multiple myeloma patients and 11 patients with a noncancerous condition called monoclonal gammopathy of undetermined significance (MGUS) showed that Runx2 levels were significantly higher in the multiple myeloma cells.
Furthermore, the levels of Runx2 expression among a larger group of 351 newly diagnosed multiple myeloma patients were significantly higher in patients who had a high risk of early disease-related death, as compared with lower-risk patients. The risk levels were determined by an existing gene expression profile test.
"This suggests that Runx2 levels in myeloma cells may be a gene predictor of a patient's prognosis, good or bad," Yang said.
"Collectively, these Runx2-mediated effects have the potential to modify the tumor-bone microenvironment and support multiple myeloma cell growth in bone," Yang and colleagues concluded. "Therefore, the targeting of Runx2 expression in multiple myeloma cells may represent a new therapeutic strategy for the treatment of aggressive multiple myeloma."
Read more:http://about.cusabio.com/m-219.html
This is the first study of the Runx2 expression in multiple myeloma, a cancer of the white blood cells that causes an estimated 11,000 deaths a year in the U.S., says Yang, who is also a scientist in UAB's Comprehensive Cancer Center and Center for Metabolic Bone Disease. Runx2 has been linked to bone metastasis in several solid tumors, though researchers did not analyze the solid tumors for expression of bone-related genes.
"This new mechanism of Runx2 overexpression can give multiple myeloma cells a bone cell-like phenotype," Yang said of the work by her lab and collaborators. "When the multiple myeloma cells come to the new bone sites, the bone immune cells think, 'This is one of our neighbor cells,' and therefore do not eliminate them. The bone immune cells do not recognize these cells as strangers."
A series of experiments in the multiple myeloma study, with both animal models and cells from human patients, highlights the role of the transcription factor Runx2 to express bone-related genes in myeloma cells -- genes that normally exist in bone residential cells, such as bone-forming osteoblasts and osteocytes, and the bone-resorbing osteoclast cells. These changes make the multiple myeloma cells more aggressive.
For animal models, Yang and colleagues used molecular genetic techniques to either increase or decrease the expression of Runx2 in a mouse myeloma cell line. The increased expression cells are called "Runx2 knock-in" cells, and the decreased expression cells are called "Runx2 knock-down" cells.
In mice, the Runx2 knock-in myeloma cells produced greater tumor growth and a wider spread of disease compared with the original myeloma cells; conversely, the Runx2 knock-down cells had less tumor growth and disease spread. The researchers also tested a Runx2 knock-down variant of a human multiple myeloma cell line and found that it produced significantly less tumor growth in immunodeficient mice than the original human multiple myeloma cells.
The researchers used the Runx2 knock-in and knock-down cells to show that Runx2 overexpression activates the Akt/β-catenin/Survivin signaling system in the multiple myeloma cells. This is a different signaling system than the one activated by Runx2 in solid tumors.
Downstream of the signaling system, Runx2 overexpression led to overexpression of bone-related genes, including genes expressed by osteoblasts, osteoclasts and osteocytes. "Taken together, these results support the hypothesis that multiple myeloma cells express bone-related genes in a Runx2-dependent fashion that mimics bone marrow resident cells and likely contributes to tumor survival and growth in the bone microenvironment," Yang and colleagues wrote in the paper.
The overexpression of Runx2 also enhanced secretion of soluble factors that aid tumor progression and metastasis, including cytokines and growth factors.
In humans, a comparison of bone marrow from 14 normal bone marrow donors, 35 multiple myeloma patients and 11 patients with a noncancerous condition called monoclonal gammopathy of undetermined significance (MGUS) showed that Runx2 levels were significantly higher in the multiple myeloma cells.
Furthermore, the levels of Runx2 expression among a larger group of 351 newly diagnosed multiple myeloma patients were significantly higher in patients who had a high risk of early disease-related death, as compared with lower-risk patients. The risk levels were determined by an existing gene expression profile test.
"This suggests that Runx2 levels in myeloma cells may be a gene predictor of a patient's prognosis, good or bad," Yang said.
"Collectively, these Runx2-mediated effects have the potential to modify the tumor-bone microenvironment and support multiple myeloma cell growth in bone," Yang and colleagues concluded. "Therefore, the targeting of Runx2 expression in multiple myeloma cells may represent a new therapeutic strategy for the treatment of aggressive multiple myeloma."
Read more:http://about.cusabio.com/m-219.html
2015年7月8日星期三
Disrupting cells' 'powerhouses' can lead to tumor growth, study finds
Cancer cells defy the rules by which normal cells abide. They can divide
without cease, invade distant tissues and consume glucose at abnormal rates.
Now a study by University of Pennsylvania researchers implicates defects in mitochondria, the energy-production centers of cells, as playing a key role in the transition from normal to cancerous. When the Penn scientists disrupted a key component of mitochondria, otherwise normal cells took on characteristics of cancerous tumor cells.
The research is published in the journal Oncogene and was led by members of the lab of Narayan G. Avadhani, the Harriet Ellison Woodward Professor of Biochemistry in Penn's School of Veterinary Medicine's Department of Biomedical Sciences, in collaboration with the lab of Hiroshi Nakagawa from the Gastroenterology Division in Penn's Perelman School of Medicine. Satish Srinivasan, a research investigator in Avadhani's lab, was the lead author. Manti Guha, Dawei Dong and Gordon Ruthel of Penn Vet and Kelly A. Whelan of Penn Medicine also contributed, along with Yasuto Uchikado and Shoji Natsugoe of Japan's Kagoshima University.
In 1924, German biologist Otto Heinrich Warburg observed that cancerous cells consumed glucose at a higher rate than normal cells and had defects in their "grana," the organelles that are now known as mitochondria. He postulated that the mitochondrial defects led to problems in the process by which the cell produces energy, called oxidative phosphorylation, and that these defects contributed to the cells becoming cancerous.
"The first part of the Warburg hypothesis has held up solidly in that most proliferating tumors show high dependence on glucose as an energy source and they release large amounts of lactic acid," Avadhani said. "But the second part, about the defective mitochondrial function causing cells to be tumorigenic, has been highly contentious."
To see whether the second part of Warburg's postulation was correct, the Penn-led research team took cell lines from the skeleton, kidney, breast and esophagus and used RNA molecules to silence the expression of select components of the mitochondrias' cytochrome oxidase C, or CcO, a critical enzyme involved in oxidative phosphorylation. CcO uses oxygen to make water and set up a transmembrane potential that is used to synthesize ATP, the molecule used for energy by the body's cells.
The biologists observed that disrupting only a single protein subunit of cytochrome oxidase C led to major changes in the mitochondria and in the cells themselves.
"These cells showed all the characteristics of cancer cells," Avadhani said.
They displayed changes in their metabolism, becoming more reliant on glucose and reducing their synthesis of ATP. Instead of conducting oxidative phosphorylation, they largely switched over to conducting glycolysis, a less efficient means of making ATP that is common in cancer cells.
The cells lost contact inhibition and gained an increased ability to invade distant tissues, both "hallmarks of cancer cells," Avadhani noted. When they were grown in a 3D medium, which closely mimics the natural environment in which tumors grow in the body, the cells with disrupted mitochondria formed large, long-lived colonies, akin to tumors.
The researchers also silenced cytochrome oxidase C subunits in an already-tumorigenic breast and esophageal cancer cell lines.
"We found that the cells became even more invasive, heightening their malignant potency," Srinivasan said.
Finally the Penn team looked at actual tumors from human patients and found that the most oxygen-starved regions, which are common in tumors, contained defective versions of cytochrome oxidase.
"That result alone couldn't tell us whether that was the cause or effect of tumors, but our cell system clearly says that mitochondrial dysfunction is a driving force in tumorigenesis," Avadhani said.
The researchers observed that disrupting CcO triggered the mitochondria to activate a stress signal to the nucleus, akin to an "SOS" alerting the cell that something is amiss. Avadhani and his colleagues had previously seen a similar pathway activated in cells with depleted mitochondrial DNA, which is also linked to cancer.
Building on these findings, Avadhani and members of his lab will examine whether inhibiting components of this mitochondrial stress signaling pathway might be a strategy for preventing cancer progression.
"We are targeting the signaling pathway, developing a lot of small molecules and antibodies," Avadhani said. "Hopefully if you block the signaling the cells will not go into the so called oncogenic mode and instead would simply die."
In addition, they noted that looking for defects in cytochrome oxidase C could be a biomarker for cancer screening.
Read more:http://www.cusabio.com/catalog-13-1.html
Now a study by University of Pennsylvania researchers implicates defects in mitochondria, the energy-production centers of cells, as playing a key role in the transition from normal to cancerous. When the Penn scientists disrupted a key component of mitochondria, otherwise normal cells took on characteristics of cancerous tumor cells.
The research is published in the journal Oncogene and was led by members of the lab of Narayan G. Avadhani, the Harriet Ellison Woodward Professor of Biochemistry in Penn's School of Veterinary Medicine's Department of Biomedical Sciences, in collaboration with the lab of Hiroshi Nakagawa from the Gastroenterology Division in Penn's Perelman School of Medicine. Satish Srinivasan, a research investigator in Avadhani's lab, was the lead author. Manti Guha, Dawei Dong and Gordon Ruthel of Penn Vet and Kelly A. Whelan of Penn Medicine also contributed, along with Yasuto Uchikado and Shoji Natsugoe of Japan's Kagoshima University.
In 1924, German biologist Otto Heinrich Warburg observed that cancerous cells consumed glucose at a higher rate than normal cells and had defects in their "grana," the organelles that are now known as mitochondria. He postulated that the mitochondrial defects led to problems in the process by which the cell produces energy, called oxidative phosphorylation, and that these defects contributed to the cells becoming cancerous.
"The first part of the Warburg hypothesis has held up solidly in that most proliferating tumors show high dependence on glucose as an energy source and they release large amounts of lactic acid," Avadhani said. "But the second part, about the defective mitochondrial function causing cells to be tumorigenic, has been highly contentious."
To see whether the second part of Warburg's postulation was correct, the Penn-led research team took cell lines from the skeleton, kidney, breast and esophagus and used RNA molecules to silence the expression of select components of the mitochondrias' cytochrome oxidase C, or CcO, a critical enzyme involved in oxidative phosphorylation. CcO uses oxygen to make water and set up a transmembrane potential that is used to synthesize ATP, the molecule used for energy by the body's cells.
The biologists observed that disrupting only a single protein subunit of cytochrome oxidase C led to major changes in the mitochondria and in the cells themselves.
"These cells showed all the characteristics of cancer cells," Avadhani said.
They displayed changes in their metabolism, becoming more reliant on glucose and reducing their synthesis of ATP. Instead of conducting oxidative phosphorylation, they largely switched over to conducting glycolysis, a less efficient means of making ATP that is common in cancer cells.
The cells lost contact inhibition and gained an increased ability to invade distant tissues, both "hallmarks of cancer cells," Avadhani noted. When they were grown in a 3D medium, which closely mimics the natural environment in which tumors grow in the body, the cells with disrupted mitochondria formed large, long-lived colonies, akin to tumors.
The researchers also silenced cytochrome oxidase C subunits in an already-tumorigenic breast and esophageal cancer cell lines.
"We found that the cells became even more invasive, heightening their malignant potency," Srinivasan said.
Finally the Penn team looked at actual tumors from human patients and found that the most oxygen-starved regions, which are common in tumors, contained defective versions of cytochrome oxidase.
"That result alone couldn't tell us whether that was the cause or effect of tumors, but our cell system clearly says that mitochondrial dysfunction is a driving force in tumorigenesis," Avadhani said.
The researchers observed that disrupting CcO triggered the mitochondria to activate a stress signal to the nucleus, akin to an "SOS" alerting the cell that something is amiss. Avadhani and his colleagues had previously seen a similar pathway activated in cells with depleted mitochondrial DNA, which is also linked to cancer.
Building on these findings, Avadhani and members of his lab will examine whether inhibiting components of this mitochondrial stress signaling pathway might be a strategy for preventing cancer progression.
"We are targeting the signaling pathway, developing a lot of small molecules and antibodies," Avadhani said. "Hopefully if you block the signaling the cells will not go into the so called oncogenic mode and instead would simply die."
In addition, they noted that looking for defects in cytochrome oxidase C could be a biomarker for cancer screening.
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月7日星期二
Association between genetic condition, hormonal factors, and risk of endometrial cancer
For women with Lynch syndrome, an association was found between the risk of
endometrial cancer and the age of first menstrual cycle, having given birth, and
hormonal contraceptive use, according to a study in the July 7 issue of JAMA.
Lynch syndrome is a genetic condition that increases the risk for various
cancers.
Endometrial cancer is the most common type of gynecologic cancer in developed countries. Between 2 percent and 5 percent of all endometrial cancer cases are associated with a hereditary susceptibility to cancer, mainly Lynch syndrome, which is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Depending on the mutated gene, cumulative risk of developing endometrial cancer by age 70 years for women is thought to be between 15 percent and 30 percent. Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with an MMR gene mutation. Studies in the general population have shown that hormonal factors are associated with endometrial cancer risk, according to background information in the article.
For Lynch syndrome, the association between hormonal factors and endometrial cancer risk has not been clear. Aung Ko Win, M.B.B.S., Ph.D., M.P.H., of the University of Melbourne, Victoria, Australia, and colleagues conducted a study that included 1,128 women with an MMR gene mutation identified from the Colon Cancer Family Registry. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand.
Endometrial cancer was diagnosed in 133 women. The researchers found that later age at menarche (first menstrual cycle, age 13 or older), parity (has had one or more live births), and hormonal contraceptive use (for one year or longer) were associated with a lower risk of endometrial cancer. There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use.
"In this study, an inverse association was observed between the risk of endometrial cancer for women with an MMR gene mutation and later age of menarche, increased parity, and use of hormonal contraceptives. The directions of the observed associations are similar to those that have been reported for the general population, suggesting a possible protective effect of these factors," the authors write.
"If replicated, these findings suggest that women with an MMR gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk."
Read more:http://www.cusabio.com/catalog-15-1.html
Endometrial cancer is the most common type of gynecologic cancer in developed countries. Between 2 percent and 5 percent of all endometrial cancer cases are associated with a hereditary susceptibility to cancer, mainly Lynch syndrome, which is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Depending on the mutated gene, cumulative risk of developing endometrial cancer by age 70 years for women is thought to be between 15 percent and 30 percent. Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with an MMR gene mutation. Studies in the general population have shown that hormonal factors are associated with endometrial cancer risk, according to background information in the article.
For Lynch syndrome, the association between hormonal factors and endometrial cancer risk has not been clear. Aung Ko Win, M.B.B.S., Ph.D., M.P.H., of the University of Melbourne, Victoria, Australia, and colleagues conducted a study that included 1,128 women with an MMR gene mutation identified from the Colon Cancer Family Registry. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand.
Endometrial cancer was diagnosed in 133 women. The researchers found that later age at menarche (first menstrual cycle, age 13 or older), parity (has had one or more live births), and hormonal contraceptive use (for one year or longer) were associated with a lower risk of endometrial cancer. There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use.
"In this study, an inverse association was observed between the risk of endometrial cancer for women with an MMR gene mutation and later age of menarche, increased parity, and use of hormonal contraceptives. The directions of the observed associations are similar to those that have been reported for the general population, suggesting a possible protective effect of these factors," the authors write.
"If replicated, these findings suggest that women with an MMR gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk."
Read more:http://www.cusabio.com/catalog-15-1.html
2015年7月6日星期一
Scientists lead consensus guidelines for thyroid cancer molecular tests
University of Pittsburgh Cancer Institute (UPCI) scientists recently led a
panel of experts in revising national guidelines for thyroid cancer testing to
reflect newly available tests that better incorporate personalized medicine into
diagnosing the condition.
Their clinical explanation for when to use and how to
interpret thyroid cancer tests is published in the July issue of the scientific
journalThyroid. The American Thyroid Association is revising its 2015 Guidelines
for Thyroid Nodule and Thyroid Cancer Management to direct doctors to the
scientific publication.
"Minimally invasive molecular testing for thyroid cancer has improved by leaps and bounds in the last several years," said co-author Robert L. Ferris, M.D., Ph.D., professor and chief of the Division of Head and Neck Surgery in Pitt's School of Medicine. "But different tests perform differently and, therefore, need to be interpreted carefully to make the best decisions regarding extent of surgery for patients with thyroid nodules. Our goal with this analysis is to give clinicians a clear understanding of what each type of test can tell them and when to use them to determine the best course of treatment."
Cancer in the thyroid, which is located just below the "Adam's apple" area of the neck, is the fifth most common cancer diagnosed in women. Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.
UPCI, partner with UPMC CancerCenter, has been a national leader in developing personalized genetic tests for thyroid cancer that have spared patients repeat or unnecessary surgeries. A low-cost test called ThyroSeq, developed by a team led by Yuri Nikiforov, M.D., Ph.D., director of Pitt's Division of Molecular and Genomic Pathology, allows pathologists to simultaneously test for multiple genetic markers of thyroid cancer using just a few cells collected from the nodule.
This allows doctors to "rule-in" a specific cancer diagnosis with a high degree of certainty, without a biopsy to remove a large portion of the thyroid, which would then have to be followed with a second surgery if cancer is detected to remove the entire gland. As Dr. Nikiforov's group added more genetic sequences to the ThyroSeq test to create a larger and more sensitive version of the test, it is now also performing as a "rule-out" test that can tell doctors with a high degree of certainty that a patient does not have cancer.
Other available tests use different technology to serve as accurate "rule-out" tools, but do not have the high sensitivity needed to also reliably "rule-in" cancer. And, in some cases, the accuracy of the "rule out" tests depends on the prevalence of cancer in the patients seen by each individual cancer institute. This is critical because clinicians must know this rate at their institution to correctly calculate the accuracy of "rule-out" test results for each patient.
In addition to Dr. Ferris and co-author Sally E. Carty, M.D., who is professor and chief of the Division of Endocrine Surgery in Pitt's School of Medicine and co-director of the UPMC/UPCI Multidisciplinary Thyroid Center, the panel reviewing the tests was a multidisciplinary group from a dozen institutions in the U.S. and Canada.
"This was a very innovative and collegial initiative," said Dr. Carty. "Through an objective review of the existing tests and the scientific literature characterizing their performance, we are seeking to help clinicians make the best decisions for their patients."
Dr. Ferris agrees, noting that "this is an exciting time in personalized medicine, and these tests give us the ability to not only better diagnose and treat thyroid cancer, but also significantly reduce surgeries for people who don't have cancer."
Read more:http://www.cusabio.com/catalog-15-1.html
"Minimally invasive molecular testing for thyroid cancer has improved by leaps and bounds in the last several years," said co-author Robert L. Ferris, M.D., Ph.D., professor and chief of the Division of Head and Neck Surgery in Pitt's School of Medicine. "But different tests perform differently and, therefore, need to be interpreted carefully to make the best decisions regarding extent of surgery for patients with thyroid nodules. Our goal with this analysis is to give clinicians a clear understanding of what each type of test can tell them and when to use them to determine the best course of treatment."
Cancer in the thyroid, which is located just below the "Adam's apple" area of the neck, is the fifth most common cancer diagnosed in women. Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.
UPCI, partner with UPMC CancerCenter, has been a national leader in developing personalized genetic tests for thyroid cancer that have spared patients repeat or unnecessary surgeries. A low-cost test called ThyroSeq, developed by a team led by Yuri Nikiforov, M.D., Ph.D., director of Pitt's Division of Molecular and Genomic Pathology, allows pathologists to simultaneously test for multiple genetic markers of thyroid cancer using just a few cells collected from the nodule.
This allows doctors to "rule-in" a specific cancer diagnosis with a high degree of certainty, without a biopsy to remove a large portion of the thyroid, which would then have to be followed with a second surgery if cancer is detected to remove the entire gland. As Dr. Nikiforov's group added more genetic sequences to the ThyroSeq test to create a larger and more sensitive version of the test, it is now also performing as a "rule-out" test that can tell doctors with a high degree of certainty that a patient does not have cancer.
Other available tests use different technology to serve as accurate "rule-out" tools, but do not have the high sensitivity needed to also reliably "rule-in" cancer. And, in some cases, the accuracy of the "rule out" tests depends on the prevalence of cancer in the patients seen by each individual cancer institute. This is critical because clinicians must know this rate at their institution to correctly calculate the accuracy of "rule-out" test results for each patient.
In addition to Dr. Ferris and co-author Sally E. Carty, M.D., who is professor and chief of the Division of Endocrine Surgery in Pitt's School of Medicine and co-director of the UPMC/UPCI Multidisciplinary Thyroid Center, the panel reviewing the tests was a multidisciplinary group from a dozen institutions in the U.S. and Canada.
"This was a very innovative and collegial initiative," said Dr. Carty. "Through an objective review of the existing tests and the scientific literature characterizing their performance, we are seeking to help clinicians make the best decisions for their patients."
Dr. Ferris agrees, noting that "this is an exciting time in personalized medicine, and these tests give us the ability to not only better diagnose and treat thyroid cancer, but also significantly reduce surgeries for people who don't have cancer."
Read more:http://www.cusabio.com/catalog-15-1.html
2015年7月5日星期日
Lifelong learning is made possible by recycling of histones, study says
Neurons are a limited commodity; each of us goes through life with
essentially the same set we had at birth. But these cells, whose electrical
signals drive our thoughts, perceptions, and actions, are anything but static.
They change and adapt in response to experience throughout our lifetimes, a
process better known as learning.
Research conducted at The Rockefeller University and collaborating institutions has uncovered a new mechanism that makes this plasticity possible. This discovery centers on a specific type of histone, proteins that support DNA and help control its expression.
"Histones and their modifications can play an important role in switching genes on and off -- a type of epigenetic control. This research uncovers an epigenetic mechanism, involving one slightly-modified, "variant" histone, that makes learning possible by facilitating the genetic changes necessary for neurons to form connections," says study author C. David Allis, Joy and Jack Fishman Professor and head of the Laboratory of Chromatin Biology and Epigenetics. This research was published in Neuron on July 1.
Histones are proteins that act as spools to DNA's thread, giving the genetic code support, structure, and protection. Five major types of histone, including one called H3, are known, and researchers have become interested in the function of variants of these histones, which are often very similar to their standard counterparts. This new research focused on one such variant, H3.3, which closely resembles its main H3 counterpart.
In a series of experiments using a wide variety of techniques, first author Ian Maze, a former postdoc in Allis's lab and now an assistant professor at Icahn School of Medicine at Mount Sinai, and his colleagues linked plasticity and, as a result, learning with the destruction and replacement of H3.3 within the neurons of the hippocampus, a region of the brain associated with memory, among other things.
They began by looking at histones within the brains of mice and postmortem samples from humans. In both cases, they found levels of H3.3 increasing with age and finally coming to dominate. By feeding the animals food containing a chemical label, and following the decay of a radioactive signal naturally found in the human brain samples, the researchers determined that, rather than remaining in place on DNA throughout life, H3.3 is constantly recycled, with new H3.3 proteins replacing old ones, a process that slows down with age.
Next, they wanted to know what these changes meant. In cell culture, they linked H3.3 turnover with increased neural activity, and then in mice, they found that a mentally stimulating environment -- for mice this means a running wheel, toys, and plenty of space, among other things -- produced increased turnover of H3.3 in the hippocampus. These results suggested a link between H3.3 recycling and neuronal plasticity. When the researchers looked to gene expression, they found that following stimulation of a neuron, the expression of certain genes increased. The same genes turned out to be necessary for forming synapses, and they were accompanied by significant amounts of H3.3.
Their results so far led them to suspect a connection between H3.3 recycling and learning, by way of synapse formation. They then tested this hypothesis.
"When we put an end to histone turnover in adult mice, we found it disrupted normal gene expression patterns associated with plasticity, and as a result, impaired the animals' ability to learn new things. For instance, they had difficulty distinguishing objects they had previously encountered from new ones," Maze says. "Because some psychiatric diseases, such as schizophrenia, are associated with deficits in synapses, it would be interesting to investigate whether or not histone turnover is involved."
In additional experiments, the researchers reduced histone turnover in embryonic stem cells, which have the potential to become any type of cell in an organism, with little effect. However, reducing turnover did alter gene expression in glial cells, other brain cells involved in supporting neurons. However, turnover affected a different set of genes for glial cells and astrocytes than in the neurons.
"It appears the turnover of H3.3 may have implications beyond neurons, as a means for controlling plasticity in adult cells that have a set identity, but still must respond to their environment," says Allis, who is also a Tri-Institutional Professor. "Our experiments suggest this is the case for cells within the nervous system, and we suspect the same may be true elsewhere in the body."
Read more:http://www.cusabio.com/catalog-13-1.html
Research conducted at The Rockefeller University and collaborating institutions has uncovered a new mechanism that makes this plasticity possible. This discovery centers on a specific type of histone, proteins that support DNA and help control its expression.
"Histones and their modifications can play an important role in switching genes on and off -- a type of epigenetic control. This research uncovers an epigenetic mechanism, involving one slightly-modified, "variant" histone, that makes learning possible by facilitating the genetic changes necessary for neurons to form connections," says study author C. David Allis, Joy and Jack Fishman Professor and head of the Laboratory of Chromatin Biology and Epigenetics. This research was published in Neuron on July 1.
Histones are proteins that act as spools to DNA's thread, giving the genetic code support, structure, and protection. Five major types of histone, including one called H3, are known, and researchers have become interested in the function of variants of these histones, which are often very similar to their standard counterparts. This new research focused on one such variant, H3.3, which closely resembles its main H3 counterpart.
In a series of experiments using a wide variety of techniques, first author Ian Maze, a former postdoc in Allis's lab and now an assistant professor at Icahn School of Medicine at Mount Sinai, and his colleagues linked plasticity and, as a result, learning with the destruction and replacement of H3.3 within the neurons of the hippocampus, a region of the brain associated with memory, among other things.
They began by looking at histones within the brains of mice and postmortem samples from humans. In both cases, they found levels of H3.3 increasing with age and finally coming to dominate. By feeding the animals food containing a chemical label, and following the decay of a radioactive signal naturally found in the human brain samples, the researchers determined that, rather than remaining in place on DNA throughout life, H3.3 is constantly recycled, with new H3.3 proteins replacing old ones, a process that slows down with age.
Next, they wanted to know what these changes meant. In cell culture, they linked H3.3 turnover with increased neural activity, and then in mice, they found that a mentally stimulating environment -- for mice this means a running wheel, toys, and plenty of space, among other things -- produced increased turnover of H3.3 in the hippocampus. These results suggested a link between H3.3 recycling and neuronal plasticity. When the researchers looked to gene expression, they found that following stimulation of a neuron, the expression of certain genes increased. The same genes turned out to be necessary for forming synapses, and they were accompanied by significant amounts of H3.3.
Their results so far led them to suspect a connection between H3.3 recycling and learning, by way of synapse formation. They then tested this hypothesis.
"When we put an end to histone turnover in adult mice, we found it disrupted normal gene expression patterns associated with plasticity, and as a result, impaired the animals' ability to learn new things. For instance, they had difficulty distinguishing objects they had previously encountered from new ones," Maze says. "Because some psychiatric diseases, such as schizophrenia, are associated with deficits in synapses, it would be interesting to investigate whether or not histone turnover is involved."
In additional experiments, the researchers reduced histone turnover in embryonic stem cells, which have the potential to become any type of cell in an organism, with little effect. However, reducing turnover did alter gene expression in glial cells, other brain cells involved in supporting neurons. However, turnover affected a different set of genes for glial cells and astrocytes than in the neurons.
"It appears the turnover of H3.3 may have implications beyond neurons, as a means for controlling plasticity in adult cells that have a set identity, but still must respond to their environment," says Allis, who is also a Tri-Institutional Professor. "Our experiments suggest this is the case for cells within the nervous system, and we suspect the same may be true elsewhere in the body."
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月2日星期四
Viral protein in their sights
Viruses need us. In order to multiply, viruses have to invade a host cell
and copy their genetic information. To do so, viruses encode their own
replication machinery or components that subvert the host replication machinery
to their advantage.
Ebola virus and rabies virus, two of the most lethal pathogens known to humans, belong to an order of RNA viruses that share a common strategy for copying their genomes inside their hosts. Other relatives include Marburg virus, measles, mumps, respiratory syncytial virus and vesicular stomatitis virus (VSV). Scientists study VSV, which causes acute disease in livestock but typically does not lead to illness in people, as a model for viruses that are harmful to humans.
Now a team from Harvard Medical School, using electron cryomicroscopy (imaging frozen specimens to reduce damage from electron radiation), has for the first time revealed the structure of a VSV protein at the atomic level. Called polymerase protein L, it is required for viral replication in this group of RNA viruses. The findings are published in Cell.
"We now have a better understanding of how RNA synthesis works for these viruses," said Sean Whelan, HMS professor of microbiology and immunobiology and senior author of the paper. "I think if you were trying to develop a viral-specific target to block the replication of one of these viruses, having the structure of the polymerase protein would help."
Scientists already know how these RNA viruses infect cells. They start by delivering a large protein RNA complex, which is viral RNA enclosed in a protein coat. The protein that copies viral RNA is polymerase protein L, which conducts all the enzymatic activities needed to synthesize RNA and then add a cap structure to its end to ensure it doesn't get destroyed by the cell--and to ensure that it can be translated into protein.
While researchers have known the atomic structures of the protein that coats the viral RNA, there are no data on protein L's atomic structure.
Antiviral drugs that target polymerase molecules are based in part on knowing their structure. That approach has been successful against HIV and herpes and hepatitis C viruses. But for the class of viruses known as nonsegmented negative-strand RNA viruses, finding the structure of polymerase protein L has been challenging.
The "L" stands for large. Larger proteins are often difficult to produce and to purify, Whelan said. Protein L is also flexible, with many functional fragments that are hard to isolate. The viruses evolved to make only small quantities of this protein.
Five years ago, using a lower-resolution form of electron microscopy in which the protein is visualized in the presence of negative stain, Whelan's team was able to detect at low resolution a structure that looked like a doughnut with three globular domains. Those earlier studies were informative, but the approach could not provide the atomic level of resolution the team ultimately needed.
Advances in electron cryomicroscopy encouraged them to try again. A team from Whelan's lab, working with a group led by Stephen Harrison, Giovanni Armenise -- Harvard Professor of Basic Biomedical Science at HMS and a Howard Hughes Medical Institute (HHMI) investigator, was able to collect data from their viral samples that gave them much greater resolution. They also were able to align the images they collected into a three-dimensional model of polymerase protein L.
Into the density map obtained from these studies, members of the team built an atomic model of the polypeptide chain of VSV L protein. Solving this puzzle was a significant challenge and also involved the team of Nikolaus Grigorieff at HHMI's Janelia campus.
The result? An atomic level model of polymerase protein L's structure for VSV, which will form the basis for understanding the L protein of the other viruses in the order.
"The Ebola protein will look the same, the rabies protein will look the same, the other L proteins will look the same," Whelan said. "There will be some subtle differences reflecting the precise nature of amino acids, but we know that they're functionally and structurally the same."
Knowing the structure means scientists can explore how RNA synthesis is working in these viruses.
"It begins to suggest ways that we can perhaps pull apart other proteins that have not been so easy to express, such as the L protein in Ebola," Whelan said. "It doesn't mean we're going to have inhibitors immediately, but this is an important step, I think, towards that longer-term goal."
Read more:http://www.cusabio.com/catalog-13-1.html
Ebola virus and rabies virus, two of the most lethal pathogens known to humans, belong to an order of RNA viruses that share a common strategy for copying their genomes inside their hosts. Other relatives include Marburg virus, measles, mumps, respiratory syncytial virus and vesicular stomatitis virus (VSV). Scientists study VSV, which causes acute disease in livestock but typically does not lead to illness in people, as a model for viruses that are harmful to humans.
Now a team from Harvard Medical School, using electron cryomicroscopy (imaging frozen specimens to reduce damage from electron radiation), has for the first time revealed the structure of a VSV protein at the atomic level. Called polymerase protein L, it is required for viral replication in this group of RNA viruses. The findings are published in Cell.
"We now have a better understanding of how RNA synthesis works for these viruses," said Sean Whelan, HMS professor of microbiology and immunobiology and senior author of the paper. "I think if you were trying to develop a viral-specific target to block the replication of one of these viruses, having the structure of the polymerase protein would help."
Scientists already know how these RNA viruses infect cells. They start by delivering a large protein RNA complex, which is viral RNA enclosed in a protein coat. The protein that copies viral RNA is polymerase protein L, which conducts all the enzymatic activities needed to synthesize RNA and then add a cap structure to its end to ensure it doesn't get destroyed by the cell--and to ensure that it can be translated into protein.
While researchers have known the atomic structures of the protein that coats the viral RNA, there are no data on protein L's atomic structure.
Antiviral drugs that target polymerase molecules are based in part on knowing their structure. That approach has been successful against HIV and herpes and hepatitis C viruses. But for the class of viruses known as nonsegmented negative-strand RNA viruses, finding the structure of polymerase protein L has been challenging.
The "L" stands for large. Larger proteins are often difficult to produce and to purify, Whelan said. Protein L is also flexible, with many functional fragments that are hard to isolate. The viruses evolved to make only small quantities of this protein.
Five years ago, using a lower-resolution form of electron microscopy in which the protein is visualized in the presence of negative stain, Whelan's team was able to detect at low resolution a structure that looked like a doughnut with three globular domains. Those earlier studies were informative, but the approach could not provide the atomic level of resolution the team ultimately needed.
Advances in electron cryomicroscopy encouraged them to try again. A team from Whelan's lab, working with a group led by Stephen Harrison, Giovanni Armenise -- Harvard Professor of Basic Biomedical Science at HMS and a Howard Hughes Medical Institute (HHMI) investigator, was able to collect data from their viral samples that gave them much greater resolution. They also were able to align the images they collected into a three-dimensional model of polymerase protein L.
Into the density map obtained from these studies, members of the team built an atomic model of the polypeptide chain of VSV L protein. Solving this puzzle was a significant challenge and also involved the team of Nikolaus Grigorieff at HHMI's Janelia campus.
The result? An atomic level model of polymerase protein L's structure for VSV, which will form the basis for understanding the L protein of the other viruses in the order.
"The Ebola protein will look the same, the rabies protein will look the same, the other L proteins will look the same," Whelan said. "There will be some subtle differences reflecting the precise nature of amino acids, but we know that they're functionally and structurally the same."
Knowing the structure means scientists can explore how RNA synthesis is working in these viruses.
"It begins to suggest ways that we can perhaps pull apart other proteins that have not been so easy to express, such as the L protein in Ebola," Whelan said. "It doesn't mean we're going to have inhibitors immediately, but this is an important step, I think, towards that longer-term goal."
Read more:http://www.cusabio.com/catalog-13-1.html
2015年7月1日星期三
Regenerative medicine biologists discover a cellular structure that explains fate of stem cells
UT Southwestern Medical Center scientists collaborating with University of
Michigan researchers have found a previously unidentified mechanism that helps
explain why stem cells undergo self-renewing divisions but their offspring do
not.
Adult stem cells provide a ready supply of new cells needed for tissue homeostasis throughout the life of an organism. Specialized environments called "niches" help to maintain stem cells in an undifferentiated and self-renewing state. Cells that comprise the niche produce signals and growth factors essential for stem cell maintenance. The mechanisms that allow for reception of these signals exclusively by stem cells and not their more specialized progeny remain poorly understood.
"This finding stands to change the way we think about how stem cells and their neighbors communicate with one another," said Dr. Michael Buszczak, Associate Professor in the Department of Molecular Biology and with the Hamon Center for Regenerative Science and Medicine.
The findings are presented in the journal Nature.
Scientists have been working to understand how the signaling between niches and stem cells works.
"These signals act over a short range, so only stem cells ? but not their differentiating progeny ? receive the self-renewing signals," said Dr. Buszczak, E.E. and Greer Garson Fogelson Scholar in Medical Research. "The mechanics of this communication were not known. What we discovered was that the stem cells form microtubule-based nanotubes, which extend into the niche. These threadlike nanotubes act like straws to tap into the niche and allow signaling to occur specifically in the stem cell."
The findings emanate from an active collaboration between the Buszczak lab at UT Southwestern and the lab of Dr. Yukiko Yamashita at the University of Michigan. Dr. Yamashita is an Associate Professor of Cell and Developmental Biology at the University of Michigan Life Sciences Institute and a Howard Hughes Medical Institute (HHMI) Investigator.
First author Dr. Mayu Inaba, a Postdoctoral Research Fellow at the Life Sciences Institute and a visiting Senior Fellow in Molecular Biology at UT Southwestern in the Buszczak lab, noticed thin projections linking individual stem cells back to a central hub in the stem cell "niche." Dr. Yamashita looked through her old image files and identified the same connections in numerous images. "I had seen them, but I wasn't seeing them," Dr. Yamashita said. Dr. Inaba worked to further develop the project as a senior research fellow in the Buszczak lab over the last several years.
The findings are important groundwork for understanding how stem cells reproduce and how miscommunication between cells can result in diseases like cancer. Too much stem cell production, for example, can lead to cancerous growth. Too little reproduction can result in inadequate renewal of cells and underlies the aging process.
The long-term goal of Dr. Buszczak's lab is to determine the complete regulatory network that controls both the maintenance of Drosophila stem cells and the differentiation of their daughters. "We hope to use this information as a foundation for understanding how perturbations in normal gene expression programs cause disease," Dr. Buszczak said.
The mission of the Hamon Center for Regenerative Science and Medicine is to impact human health through discoveries of the fundamental mechanisms of tissue formation and repair, and to use this knowledge to develop transformative strategies and medicines to enhance tissue regeneration. The Center is led by Dr. Eric Olson, Chair of Molecular Biology at UT Southwestern.
The research was supported by the HHMI and the MacArthur Foundation.
Read more:http://www.cusabio.com/catalog-15-1.html
Adult stem cells provide a ready supply of new cells needed for tissue homeostasis throughout the life of an organism. Specialized environments called "niches" help to maintain stem cells in an undifferentiated and self-renewing state. Cells that comprise the niche produce signals and growth factors essential for stem cell maintenance. The mechanisms that allow for reception of these signals exclusively by stem cells and not their more specialized progeny remain poorly understood.
"This finding stands to change the way we think about how stem cells and their neighbors communicate with one another," said Dr. Michael Buszczak, Associate Professor in the Department of Molecular Biology and with the Hamon Center for Regenerative Science and Medicine.
The findings are presented in the journal Nature.
Scientists have been working to understand how the signaling between niches and stem cells works.
"These signals act over a short range, so only stem cells ? but not their differentiating progeny ? receive the self-renewing signals," said Dr. Buszczak, E.E. and Greer Garson Fogelson Scholar in Medical Research. "The mechanics of this communication were not known. What we discovered was that the stem cells form microtubule-based nanotubes, which extend into the niche. These threadlike nanotubes act like straws to tap into the niche and allow signaling to occur specifically in the stem cell."
The findings emanate from an active collaboration between the Buszczak lab at UT Southwestern and the lab of Dr. Yukiko Yamashita at the University of Michigan. Dr. Yamashita is an Associate Professor of Cell and Developmental Biology at the University of Michigan Life Sciences Institute and a Howard Hughes Medical Institute (HHMI) Investigator.
First author Dr. Mayu Inaba, a Postdoctoral Research Fellow at the Life Sciences Institute and a visiting Senior Fellow in Molecular Biology at UT Southwestern in the Buszczak lab, noticed thin projections linking individual stem cells back to a central hub in the stem cell "niche." Dr. Yamashita looked through her old image files and identified the same connections in numerous images. "I had seen them, but I wasn't seeing them," Dr. Yamashita said. Dr. Inaba worked to further develop the project as a senior research fellow in the Buszczak lab over the last several years.
The findings are important groundwork for understanding how stem cells reproduce and how miscommunication between cells can result in diseases like cancer. Too much stem cell production, for example, can lead to cancerous growth. Too little reproduction can result in inadequate renewal of cells and underlies the aging process.
The long-term goal of Dr. Buszczak's lab is to determine the complete regulatory network that controls both the maintenance of Drosophila stem cells and the differentiation of their daughters. "We hope to use this information as a foundation for understanding how perturbations in normal gene expression programs cause disease," Dr. Buszczak said.
The mission of the Hamon Center for Regenerative Science and Medicine is to impact human health through discoveries of the fundamental mechanisms of tissue formation and repair, and to use this knowledge to develop transformative strategies and medicines to enhance tissue regeneration. The Center is led by Dr. Eric Olson, Chair of Molecular Biology at UT Southwestern.
The research was supported by the HHMI and the MacArthur Foundation.
Read more:http://www.cusabio.com/catalog-15-1.html
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