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UT Southwestern Medical Center chemists have successfully used synthetic nanoparticles to deliver tumor-suppressing therapies to diseased livers with cancer, an important hurdle scientists have been struggling to conquer. Late-stage liver cancer is a major challenge for therapeutic intervention. Drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers explain. UT Southwestern scientists crafted synthetic “dendrimer” nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the journal Proceedings of the National Academy of Sciences. “We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease,” says Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center. “We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development.” Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17 percent, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. Critical to understanding this problem, and developing the new therapy, was a close collaboration between Siegwart and Dr. Hao Zhu, Assistant Professor at the Children’s Medical Center Research Institute at UT Southwestern, and a practicing oncologist. “Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers,” says Zhu, also Assistant Professor of Internal Medicine and Pediatrics at UT Southwestern. The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma — the most common form of liver cancer — prompted the authors to develop non-toxic carriers and explore “miRNA” therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect. To address this problem, UTSW scientists chemically synthesized more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Siegwart says. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity. The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival. The multidisciplinary UTSW research team included Dr. Kejin Zhou, Liem Nguyen, Jason Miller, Dr. Yunfeng Yan, Dr. Petra Kos, Dr. Hu Xiong, Lin Li, Dr. Jing Hao, and Jonathan Minnig. The Siegwart Research Group uses a materials chemistry approach to tackle challenges in cancer therapy and diagnosis. The lab is currently focused on the development of improved materials for effective delivery of siRNA, miRNA, mRNA, and CRISPR strategies to manipulate gene expression in tumors and develop the next generation of cancer therapies. The research was supported by the Cancer Prevention and Research Institute of Texas (CPRIT), the Welch Foundation, the American Cancer Society, and the Mary Kay Foundation. Additional support for individual researchers included the Howard Hughes Medical Institute (HHMI), the Pollack Foundation, the National Institutes of Health, and the Burroughs Wellcome Fund.


Home > Press > Scientists synthesize nanoparticles that can deliver tumor suppressors to damaged livers Abstract: UT Southwestern Medical Center chemists have successfully used synthetic nanoparticles to deliver tumor-suppressing therapies to diseased livers with cancer, an important hurdle scientists have been struggling to conquer. Late-stage liver cancer is a major challenge for therapeutic intervention. Drugs that show promise in healthy functioning livers can cause devastating toxicity in cirrhotic livers with cancer, the researchers explained. UT Southwestern scientists crafted synthetic "dendrimer" nanoparticles that are able to provide the tumor-suppressing effect without further damaging the liver or neighboring tissue. The findings appear in the journal, Proceedings of the National Academy of Sciences. "We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease," said Dr. Daniel Siegwart, Assistant Professor of Biochemistry and with the Harold C. Simmons Comprehensive Cancer Center. "We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development." Primary liver cancer, a chronic consequence of liver disease, is a leading cause of cancer death and a major global health problem. Each year in the United States, about 20,000 men and 8,000 women get liver cancer, and the 5-year survival rate is only 17 percent, according to the Centers for Disease Control and Prevention. The percentage of Americans who get liver cancer has been rising slowly for several decades, with higher rates in Asians and in Hispanic and African-American men. Critical to understanding this problem, and developing the new therapy, was a close collaboration between Dr. Siegwart and Dr. Hao Zhu, Assistant Professor at the Children's Medical Center Research Institute at UT Southwestern, and a practicing oncologist. "Early-stage disease can be cured with surgery, but there are few options for cirrhotic patients with advanced liver cancers," said Dr. Zhu, also Assistant Professor of Internal Medicine and Pediatrics at UT Southwestern. The recent failure of five phase III human clinical trials of small-molecule drugs to treat hepatocellular carcinoma - the most common form of liver cancer - prompted the authors to develop non-toxic carriers and explore "miRNA" therapies as a promising alternative. MicroRNAs (miRNAs) are short nucleic acids that can function as natural tumor suppressors, but require delivery strategies to transport these large, anionic drugs into cells. To date, no existing carrier has been able to provide effective delivery to late-stage liver cancer without amplified toxicity, which negates the desired effect. To address this problem, UTSW scientists chemically synthesized more than 1,500 different types of nanoparticles, which allowed discovery of lead compounds that could function in the heavily compromised cancerous liver. Synthetic, man-made nanoscale compounds called dendrimers provided an opportunity to screen different combinations of chemical groups, physical properties, and molecular size, Dr. Siegwart said. This approach led to the identification of dendrimers to deliver miRNA to late-stage liver tumors with low liver toxicity. The study, conducted in genetic mouse models with a highly aggressive form of liver cancer, demonstrated that the miRNA nanoparticles inhibited tumor growth and dramatically extended survival. The multidisciplinary UTSW research team included Dr. Kejin Zhou, Liem Nguyen, Jason Miller, Dr. Yunfeng Yan, Dr. Petra Kos, Dr. Hu Xiong, Lin Li, Dr. Jing Hao, and Jonathan Minnig. The Siegwart Research Group uses a materials chemistry approach to tackle challenges in cancer therapy and diagnosis. The lab is currently focused on the development of improved materials for effective delivery of siRNA, miRNA, mRNA, and CRISPR strategies to manipulate gene expression in tumors and develop the next generation of cancer therapies. ### The research was supported by the Cancer Prevention and Research Institute of Texas (CPRIT), the Welch Foundation, the American Cancer Society, and the Mary Kay Foundation. Additional support for individual researchers included the Howard Hughes Medical Institute (HHMI), the Pollack Foundation, the National Institutes of Health, and the Burroughs Wellcome Fund. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 45 NCI-designated Comprehensive Cancer Centers in the nation. The Simmons Cancer Center includes 13 major cancer care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevention of cancer worldwide. The Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Participating Site by the NCI, and the only cancer center in North Texas to be so designated. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


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Site: http://phys.org/biology-news/

This image shows how individual cells respond to recruitment of EED, one of four chromatin regulators tested by the group that silence, or turn off, gene expression. The targeted gene codes for a fluorescent protein. Cells with active genes appear green. EED recruitment leads to complete silencing in all cells. However, the delay before silencing varies widely between individual cells, leading to the "salt-and-pepper" expression pattern seen at this intermediate time point. Credit: L. Bintu, J. Yong, and M.B. Elowitz / Caltech What if we could program living cells to do what we would like them to do in the body? Having such control—a major goal of synthetic biology—could allow for the development of cell-based therapies that might one day replace traditional drugs for diseases such as cancer. In order to reach this long-term goal, however, scientists must first learn to program many of the key things that cells do, such as communicate with one another, change their fate to become a particular cell type, and remember the chemical signals they have encountered. Now a team of researchers led by Caltech biologists Michael Elowitz, Lacramioara Bintu, and John Yong (PhD '15) have taken an important step toward being able to program that kind of cellular memory using tools that cells have evolved naturally. By combining synthetic biology approaches with time-lapse movies that track the behaviors of individual cells, they determined how four members of a class of proteins known as chromatin regulators establish and control a cell's ability to maintain a particular state of gene expression—to remember it—even once the signal that established that state is gone. The researchers reported their findings in the February 12 issue of the journal Science. "We took some of the most important chromatin regulators for a test-drive to understand not just how they are used naturally, but also what special capabilities each one provides," says Elowitz, a professor of biology and bioengineering at Caltech and an investigator with the Howard Hughes Medical Institute (HHMI). "We're playing with them to find out what we can get them to do for us." Rather than relying on a single protein to program all "memories" of gene expression, animal cells use hundreds of different chromatin regulators. These proteins each do basically the same thing—they modify a region of DNA to alter gene expression. That raises the question, why does the cell need all of these different chromatin regulators? Either there is a lot of redundancy built into the system or each regulator actually does something unique. And if the latter is the case, synthetic biologists would like to know how best to use these regulators as tools—how to select the ideal protein to achieve a certain effect or a specific type of cellular memory. Looking for answers, the researchers turned to an approach that Elowitz calls "build to understand." Rather than starting with a complex process and trying to pick apart its component pieces, the researchers build the targeted biological system in cells from the bottom up, giving themselves a chance to actually watch what happens with each change they introduce. In this case, that meant sticking different chromatin regulators—four gene-silencing proteins—down onto a specific section of DNA and seeing how each behaved. In order to do that the researchers engineered cells so that adding a small molecule would cause one of the gene-silencing regulators to bind to DNA near a particular gene that codes for a fluorescent protein. By tracking fluorescence in individual cells, the researchers could readily determine whether the regulator had turned off the gene. The researchers could also release the regulator from the DNA and see how long the gene remembered its effect. Although there are hundreds of chromatin regulators, they can be categorized into about a dozen broader classes. For this study, the researchers tested regulators from four biochemically diverse classes. "We tried a variety to see if different ones give you different types of behavior," explains Bintu. "It turns out they do." For a month at a time, the researchers used microscopy or flow cytometry to observe the living cells, using cell-tracking software that they wrote and time-lapse movies to watch individual cells grow and divide. In some cases, after a regulator was released, the cells and their daughter cells remained dark for days and then lit back up, indicating that they remembered the modification transiently. In other cases, the cells never lit back up, indicating more permanent memory. After modification, the genes were always in one of three states—"awake" and actively making protein, "asleep" and inactive but able to wake up in a matter of days, or "in a coma" and unable to be awakened within 30 days. Within an individual cell, the genes were always either completely on or off. That led the researchers to the surprising finding that the regulators control not the level or degree of expression of a particular gene in an individual cell, but rather how many cells in a population have that gene on or off. "You're controlling the probability that something is on or off," says Elowitz. "We think that this is something that's very useful generally in a multicellular organism—that in many cases, the organism may want to tell cells, 'I just want 30 percent of you to differentiate. You don't all need to do it.' This chromatin regulation system seems ready-made for orders like those." In addition, the researchers found that the type of memory imparted by each of the four chromatin regulators was different. One produced permanent memory, turning off the gene and putting a fraction of cells into a coma for the full 30 days. One yielded short-term memory, with the cells immediately waking up. "The really interesting thing we found is that some of the regulators give this type of hybrid memory where some of the cells awaken while a fraction of the cells remain in a deep coma," says Bintu. "How many are in the coma depends on how long you gave the signal—how long the chromatin regulator stayed attached." Going forward, the group plans to study additional chromatin regulators in the same manner, developing a better sense of the many ways they are used in the cell and also how they might work in combination. In the longer term they want to put these proteins together with other cellular components and begin programming more complex developmental behavior in synthetic circuits. "This is a step toward realizing this emerging vision of programmable cell-based therapies," says Elowitz. "But we are also answering more basic research questions. We see these as two sides of the same coin. We're not going to be able to program cells effectively until we understand what capabilities their core pathways provide." Explore further: Cause or consequence? Scientists help to settle an epigenetic debate More information: L. Bintu et al. Dynamics of epigenetic regulation at the single-cell level, Science (2016). DOI: 10.1126/science.aab2956


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Site: http://phys.org/biology-news/

Like a jungle cat, this parasite sports a long tail. But until now, little was known about what role that tail plays in this dangerous jumping. Today, scientists report that without a tail, this parasitic gene can't jump efficiently. The findings could help lead to new strategies for inhibiting the movement of the parasite, called a LINE-1 retrotransposon. The research, published in Molecular Cell by a team from the University of Michigan Medical School and the Howard Hughes Medical Institute, answers a key question about how "jumping genes" move to new DNA locations. The parasite in question isn't a foreign beast, but rather a piece of DNA that carries its own instructions for making a piece of "rogue" genetic material and two proteins that can help it jump. "Jumping" allows this rogue copy to land anywhere in the DNA of a cell, causing a change called a mutation. Jumping LINE-1s - and other genetic parasites like it - are responsible for about one in every 250 disease producing mutations in humans. They've been blamed for causing a number of diseases, including hemophilia, Duchenne muscular dystrophy, and cancer. Copies of this parasite litter our DNA, though most of them can no longer jump and cause damage. For these reasons, scientists want to understand as much as possible about how this process works. Perhaps someday, this new understanding could help fight the effects of these jumps - or prevent the parasites from leaping in the first place. "Now, we have a mechanism to explain how sequences that comprise one-third of our genome have moved," says John Moran, Ph.D., senior author of the new paper and a longtime U-M and HHMI researcher studying jumping genes. "By understanding how LINE-1 jumps, we can understand how it contributes to disease." The gene that's responsible for LINE-1 jumping does its damage by first creating an RNA copy of itself. That RNA copy tells the cell to make two proteins that help make it possible for the LINE-1 RNA itself to jump into a new spot. Each copy of LINE-1 RNA has a long tail at its end that's made up of multiple copies of a substance called adenosine. Known as a "poly(A) tail", it's long been suspected of playing a role in LINE-1 jumping. But it was impossible to figure this role out because removing the tail also eliminates another key function it serves, in getting the RNA to the location where proteins are made. Like the Cheshire Cat of Alice in Wonderland, if the tail vanished, the rest of the "cat" would too. So, a postdoctoral fellow, Aurélien Doucet, Ph.D., now a research associate at the Institute for Research on Cancer and Aging in Nice, or CNRS, in France, collaborated with Jeremy Wilusz, Ph.D., now an assistant professor at the University of Pennsylvania Perelman School of Medicine, to figure out a way to delete the LINE-1 poly(A) tail to determine if it affected LINE-1 jumping. They succeeded in making a LINE-1 RNA, without a poly(A) tail, that got where it needed to in the cell to make proteins. The substitute tail allowed the scientists to see what happened when LINE-1 RNA could get to the protein-making spot, but without its usual appendage. Here's where it gets interesting. Without the poly(A) tail, almost no jumping happened - because the tailless LINE-1 RNA couldn't interact well with a protein called ORF2p. ORF2p is actually one of the two proteins that the LINE-1 RNA tells the cell to make. Once ORF2p binds to the RNA's tail, it sets in motion the steps needed for a jump to occur. Moran compares it to a Lego set - where one kind of tail could get unplugged and another slotted in to serve some, but not all, of the same functions. In other words, the LINE-1 parasite is especially crafty. LINE-1 also has a competitor parasite, called Alu. And when LINE-1 RNA lacked the tail and couldn't jump, Alu RNA did much better at jumping. Alu RNA also sports a poly(A) sequence at its end, which has already been shown to be vital to its ability to jump. But the Alu RNA doesn't contain the instructions for making a protein. This suggests, says Moran, that the two parasites compete to have access to ORF2p proteins. That is, Alu is a parasite of a parasite. Moran and his team continue to build on their new finding that poly(A) sequences are crucial for retrotransposition. They're studying how Alu interacts with ORF2p, and how the use of a replacement for the poly(A) tail may be helpful in other research. They're also interested in how the cell, or host, fights off jumping genes and protects DNA from damage. "Our DNA is a sea of junk copies of LINE-1 that can't jump, and a small minority of LINE-1s that can," says Moran, who is the Gilbert S. Omenn Collegiate Professor of Human Genetics in the U-M Department of Human Genetics. "We need to understand at the RNA level how these LINE-1 RNAs are chosen for jumping, and how we can stop them." Explore further: Two human proteins found to affect how 'jumping gene' gets around


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Site: http://phys.org/biology-news/

Understanding the structure of this enzyme, separase, could lead to better treatments for cancer, which occurs when cells divide out of control, said Dr. Hongtao Yu, Professor of Pharmacology and a Howard Hughes Medical Institute (HHMI) Investigator at UT Southwestern. "Chromosomes contain the genetic blueprint for life, and must be precisely duplicated and equally partitioned during each cell division. The cohesin complex forms a molecular ring to encircle the duplicated chromosomes and tether them together until the moment of chromosome separation," said Dr. Yu, senior author of the study published online in Nature. "In organisms from fungi to humans, separase - an enzyme that breaks down proteins - cleaves and opens the cohesin ring to allow chromosome separation and subsequent partition into the two new daughter cells." Despite its central role in cell biology, the atomic structure of separase has eluded scientists since its discovery nearly two decades ago. This situation left a void in the understanding of the enzyme's mechanism and regulation, the researchers said. "We determined the atomic structure of separase from a fungus that can grow at high temperatures. The structure reveals how separase recognizes and cleaves the cohesin ring, allowing the chromosomes to separate," said Dr. Yu, a Michael L. Rosenberg Scholar in Medical Research and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "This particular protein is very unstable in species that grow at normal temperature, such as human body temperature, but was more stable in the high-temperature fungus that we studied." Because of the enzyme's role in cell division, chemical inhibitors of separase are expected to block cell proliferation and therefore may have therapeutic value in treating cancer. "The fungal separase that we studied is very similar to human separase. For that reason, we believe our structure will aid in the design of such inhibitors," he said, "because once you have the shape of the structure, you can computationally look for molecules that will bind to it." Study co-authors included Dr. Zhonghui Lin, a research specialist at the HHMI and in the Department of Pharmacology, and Dr. Xuelian "Sue" Luo, Associate Professor of Pharmacology and Biophysics. Explore further: New key mechanism in cell division discovered More information: Structural basis of cohesin cleavage by separase, Nature, DOI: 10.1038/nature17402

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