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.
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