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News Article | April 21, 2017
Site: www.eurekalert.org

Memphis, Tenn. - Which causes fewer eye infections - contact lens wear or LASIK surgery? While traditionally contacts were thought to be safer than a surgical procedure, an analysis by ophthalmologists from the Hamilton Eye Institute at the University of Tennessee Health Science Center indicates otherwise. A meta-data analysis comparing the incidence of microbial keratitis, an infection of the cornea caused by bacteria or a virus, for contact lens wearers versus post-LASIK (laser-assisted in situ keratomileusis) patients indicates that over time the infection rate for the contact lens wearers was higher than for those who had LASIK to correct their vision. An article on the findings was published in the Journal of Cataract & Refractive Surgery, a high-impact, peer-reviewed scientific journal. "Microbial keratitis is a relatively rare complication associated with contact lens use and LASIK postoperatively," the article said. The authors were Jordan Masters, MD; Mehmet Kocak, PhD; and Aaron Waite, MD. "The risk for microbial keratitis was similar between patients using contact lenses at one year, compared with LASIK. Over time, the risk for microbial keratitis was higher for contact lens use than for LASIK, specifically with extended-wear lenses." Literature in the PubMed database between December 2014 and July 2015 was analyzed. The results showed that after one year of daily soft-contact lens wear, there were fewer microbial keratitis cases than after LASIK, approximately two fewer cases per 10,000. If the surgery is assumed to have essentially a one-time risk for infection, after five years of extrapolation, contact lens wearers would show 11 more cases per 10,000 than those with surgery. "Most contact lens wearers use them for decades, which means they have a much higher risk of corneal infection compared to the risk with LASIK," said Dr. Waite, director of the Cornea, Cataract, and Refractive Surgery Program at the Hamilton Eye Institute and associate professor in the Department of Ophthalmology at UT Health Science Center. Microbial keratitis can be devastating, since it can lead to vision loss. It can also be expensive. Contact lens wear has been associated as a risk factor in the development of the condition. Factors, including hygiene, lens type, and history of use, contribute to the risk. According to the analysis, the approximately 38 million contact lens wearers in the United States accounted for an estimated 1 million clinical visits related to microbial keratitis at a cost of about $174.9 million in 2010. "We did this analysis to directly compare the rate for corneal infections between contact lens use and LASIK," Dr. Waite said. "Contact lenses carry a real risk of infection. In our experience with contact lens infections, some patients have lost vision and have needed a corneal transplant, or even lost the eye. There are cases where LASIK could have prevented this vision loss. LASIK does carry a rare risk of infection, however, it is a one-time risk compared to a continuous risk for infection in contact lens users. We wanted to compare the rates to get hard numbers." This is believed to be the first meta-analysis comparing the rates of microbial keratitis in contact lens wearers to those who have had LASIK surgery. "It is difficult to compare complications from contact lens use to LASIK, because the complication rate of both is so rare, but our analysis definitely shows that the infection rate is higher with contact lens use compared to LASIK," Dr. Waite said. More studies are needed to focus on other complications, such as vision loss and dry eye, to further explore the safety and risk of complications. As Tennessee's only public, statewide, academic health system, the mission of the University of Tennessee Health Science Center (UTHSC) is to bring the benefits of the health sciences to the achievement and maintenance of human health, with a focus on the citizens of Tennessee and the region, by pursuing an integrated program of education, research, clinical care, and public service. Offering a broad range of postgraduate and selected baccalaureate training opportunities, the main UTHSC campus is located in Memphis and includes six colleges: Dentistry, Graduate Health Sciences, Health Professions, Medicine, Nursing and Pharmacy. UTHSC also educates and trains cohorts of medicine, pharmacy and/or health professions students -- in addition to medical residents and fellows -- at its major sites in Knoxville, Chattanooga and Nashville. Founded in 1911, during its more than 100 years, UT Health Science Center has educated and trained more than 57,000 health care professionals in academic settings and health care facilities across the state. For more information, visit http://www. . Follow us on Facebook: facebook.com/uthsc, on Twitter: twitter.com/uthsc and on Instagram: instagram.com/uthsc.


Immunotherapy fights cancer by supercharging the immune system's natural defenses or contributing additional immune elements that can help the body kill cancer cells. In recent decades, immunotherapy has become an important tool in treating a wide range of cancers, including breast cancer, melanoma and leukemia. But alongside its successes, scientists have discovered that immunotherapy sometimes has powerful—even fatal—side-effects. Much still needs to be learned about how the immune system fights cancer, and in this area, supercomputers play an important role. Not every immune therapy works the same on every patient. Differences in an individual's immune system may mean one treatment is more appropriate than another. Furthermore, tweaking one's system might heighten the efficacy of certain treatments. Researchers from Wake Forest School of Medicine and Zhejiang University in China developed a novel mathematical model to explore the interactions between prostate tumors and common immunotherapy approaches, individually and in combination. In a study published in February 2016 in Nature Scientific Reports, they used their model to predict how prostate cancer would react to four common immunotherapies: - Androgen deprivation therapy—used to control prostate cancer cell growth by suppressing or blocking the production and action the hormone androgen in men; - Vaccines—which train the immune system to recognize and destroy harmful substances; - Treg depletion—where the subpopulation of T cells, which modulate the immune system, are reduced to increase the efficacy of immunotherapy treatments; and - IL-2 neutralization—which disables interleukin, a type of signaling molecule in the immune system. To study the systematic effects of these four treatments, the researchers incorporated data from animal studies into their complex mathematical models and simulated tumor responses to the treatments using the Stampede supercomputer at the Texas Advanced Computing Center (TACC). "We do a lot of modeling which relies on millions of simulations," said Jing Su, a researcher at the Center for Bioinformatics and Systems Biology at Wake Forest School of Medicine and assistant professor in the Department of Diagnostic Radiology. "To get a reliable result, we have to repeat each computation at least 100 times. We want to explore the combinations and effects and different conditions and their results." The researchers found that the depletion of T Cells and the neutralization of Interleukin 2 can have a stronger effect when combined with androgen deprivation therapy and vaccines. The study highlights a potential therapeutic strategy that may manage prostate tumor growth more effectively. It also provides a framework for studying tumor-related immune mechanisms and the selection of therapeutic regimens in other types of cancer. In separate work published in Nature Scientific Reports in April 2017, Zhou and collaborators from Wake Forest School of Medicine used TACC's high performance computing resources to predict how ribonucleic acids (RNA) and proteins interact with greater accuracy than previous methods. RNA-protein interactions are import to the function of RNAs, especially in the case of long noncoding RNAs (lncRNAs), which play essential roles in a variety of biological processes, including cancer development. In their study, they first performed an analysis of 1,342 RNA-protein interacting complexes from the Nucleic Acid Database and identified diverse interface properties between them, including both binding and non-binding sites. They then used a three-step method to predict the interacting regions between them using both the sequences and structures of the proteins and RNAs. Compared with existing methods, which use only sequences, the model was found to be more accurate and outperformed the leading current method by 20 percent. The computationally-intensive work represents the first approach that uses local conformations to analyze and predict the binding sites of protein, RNA and RNA-protein interacting pairs. "TACC provides an important assistance for discovering clinically meaningful and actionable knowledge across highly heterogeneous biomedical big data sets," Zhou said. [The research was supported by the National Institutes of Health (U01HL111560 and R01LM010185).] Biological agents used in immunotherapy—including those that target a specific tumor pathway, aim for DNA repair, or stimulate the immune system to attack a tumor—function differently from radiation and chemotherapy. Whereas toxicity and efficacy typically increase with the dose level for cell-destroying chemicals or x-rays, this relationship may not be true for biological agents. Specifically, toxicity may increase at low dose levels and then plateau at higher dose levels when the biological agent has reached a saturation level in the body. Efficacy may even decrease at higher dose levels. Because traditional dose-finding designs, which focus on identifying the maximum tolerated dose, are not suitable for trials of biological agents, novel designs that consider both the toxicity and efficacy of these agents are imperative. Chunyan Cai, assistant professor of biostatistics at UT Health Science Center (UTHSC)'s McGovern Medical School, uses TACC systems to design new kinds of dose-finding trials for combinations of immunotherapies. Writing in the Journal of the Royal Statistics Society Series C (Applied Statistics), Cai and her collaborators, Ying Yuan, and Yuan Ji, described efforts to identify biologically optimal dose combinations (BODC) for agents that target the PI3K/AKT/mTOR signaling pathway, which has been associated with several genetic aberrations related to the promotion of cancer. "Our research is motivated by a drug combination trial at the MD Anderson Cancer Center for patients diagnosed with relapsed lymphoma," Cai said. "The trial combined two novel biological agents that target two different components in the PI3K/AKT/mTOR signaling pathway." Both agents individually demonstrated the ability to partially inhibit the signaling pathway and provide therapeutic value. By combining these two agents, the investigators expected to obtain a more complete inhibition of the PI3K/AKT/mTOR pathway, and thereby achieve better treatment responses. The trial investigated the combinations of four dose levels of agent A with four dose levels of agent B, resulting in 16 dose combinations. The goal was to find the biologically optimal dose combination among those possibilities. Cai and her colleagues introduced a dose-finding trial design that explicitly accounted for the unique properties of biological agents. "Our design is conducted in two stages," she said. "In stage one, we escalate doses along the diagonal of the dose combination matrix as a fast exploration of the dosing space. In stage two, on the basis of the observed toxicity and efficacy data from stages one, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination." They investigated six different dose-toxicity and dose-efficacy scenarios and carried out 2,000 simulated trials for each of the designs using the Lonestar supercomputer at TACC. The simulations compared the percentage of the biologically optimal dose combination (BODC), the percentage of patients allocated to the BODC, the average efficacy rate, the number of patients assigned to over-toxic doses, and the total numbers of patients assigned in stage I and stage II of the trial. The optimal dose-finding design, they discovered, gives higher priority to trying new doses in the early stage of the trial, and toward the end of the trial assigns patients to the most effective dose that is safe. "Extensive simulation studies show that the design proposed has desirable operating characteristics in identifying the biologically optimal dose combination under various patterns of dose-toxicity and dose-efficacy relationships," she concluded. [The research was supported by the National Cancer Institute (Award Number R01 CA154591) and the National Institutes of Health's Clinical and Translational Science Award grant (UL1 TR000371).] Data-driven research and clinical dosing studies are essential for understanding how the immune system responds to treatments and determining the proper doses of biological agents. Also, critical, however, are mechanisms that bring together the research of a whole community—to share, compare and integrate disparate research findings. The VDJServer, which launched last year, serves as such a resource. The server enables researchers to analyze high-throughput immune repertoire sequencing data over the web using the high-performance computing resources available at TACC. Repertoire sequencing investigates the collection of trans-membrane antigen-receptor proteins located on the surface of T and B cells—white blood cells that play a key role in the human immune response. A form of next-generation genetic analysis, repertoire sequencing has transformed the field of immunotherapy, enabling quantitative analyses that help scientists understand the function of immunity in health and disease. VDJServer was developed by bioinformaticians and immunologists from UT Southwestern Medical Center, J. Craig Venter Institute and Yale University in partnership with computational experts at TACC. "VDJServer provides access to sophisticated analysis software and TACC's high-performance computing resources through an intuitive interface designed for users who are primarily biologists and clinicians," said project leader Lindsay Cowell, an associate professor of Clinical Sciences at UT Southwestern Medical Center, whose group developed the software at the core of VDJServer. "In addition, we provide platforms for sharing data, analysis results, and analysis pipelines," she said. "Access to these analyses and resource-sharing accelerates research and enables insights that wouldn't be possible without the opportunity for data integration." Researchers can upload B- and T-cell-receptor data and tap into TACC's computing power through the site to perform data-driven studies. Immune repertoire analysis is relevant in many contexts, including cancer immunology. One example of this type of research is a collaboration between the Cowell group and Marco Davila, a cancer researcher at the Moffitt Cancer Center. Together they are developing chimeric antigen receptors - genetically engineered receptors enabling T-cells to express receptors with the antigen specificity of an antibody. These receptors would allow the T-cells to recognize and kill cancer cells. "The team is using VDJServer to perform bioinformatics analyses to identify appropriate antibodies that may target specific cancer types," explained Cowell. "That's followed up with experimental validation to determine that the antibodies are appropriate." VDJServer speeds up scientists' understanding of the immune system and help cultivate reproducible findings, according to Matt Vaughn, TACC's Director of Life Science Computing. "Immunotherapy is a relatively young field and the computational tools are emerging alongside with knowledge of the domain," Vaughn said. "Community-oriented efforts like VDJServer are important because they provide a centralized workbench where best of breed algorithms and workflows can be used much more quickly than if they were released just as source code and at the end of a long publication cycle. They're also available democratically: anyone can use software at VDJServer regardless of how computationally experienced they are." Whether in support of population-level immune response studies, clinical dosing trials or community-wide efforts like VDJServer, TACC's advanced computing resources are helping scientists put the immune system to work to better fight cancer. Explore further: Immunotherapy for glioblastoma well tolerated; survival gains observed More information: Jiesi Luo et al, RPI-Bind: a structure-based method for accurate identification of RNA-protein binding sites, Scientific Reports (2017). DOI: 10.1038/s41598-017-00795-4 Huaidong Chen et al. Relational Network for Knowledge Discovery through Heterogeneous Biomedical and Clinical Features, Scientific Reports (2016). DOI: 10.1038/srep29915


News Article | May 17, 2017
Site: www.sciencedaily.com

The body has a natural way of fighting cancer -- it's called the immune system, and it is tuned to defend our cells against outside infections and internal disorder. But occasionally, it needs a helping hand. Immunotherapy fights cancer by supercharging the immune system's natural defenses or contributing additional immune elements that can help the body kill cancer cells. In recent decades, immunotherapy has become an important tool in treating a wide range of cancers, including breast cancer, melanoma and leukemia. But alongside its successes, scientists have discovered that immunotherapy sometimes has powerful -- even fatal -- side-effects. Much still needs to be learned about how the immune system fights cancer, and in this area, supercomputers play an important role. Not every immune therapy works the same on every patient. Differences in an individual's immune system may mean one treatment is more appropriate than another. Furthermore, tweaking one's system might heighten the efficacy of certain treatments. Researchers from Wake Forest School of Medicine and Zhejiang University in China developed a novel mathematical model to explore the interactions between prostate tumors and common immunotherapy approaches, individually and in combination. In a study published in February 2016 in Nature Scientific Reports, they used their model to predict how prostate cancer would react to four common immunotherapies: To study the systematic effects of these four treatments, the researchers incorporated data from animal studies into their complex mathematical models and simulated tumor responses to the treatments using the Stampede supercomputer at the Texas Advanced Computing Center (TACC). "We do a lot of modeling which relies on millions of simulations," said Jing Su, a researcher at the Center for Bioinformatics and Systems Biology at Wake Forest School of Medicine and assistant professor in the Department of Diagnostic Radiology. "To get a reliable result, we have to repeat each computation at least 100 times. We want to explore the combinations and effects and different conditions and their results." The researchers found that the depletion of T Cells and the neutralization of Interleukin 2 can have a stronger effect when combined with androgen deprivation therapy and vaccines. The study highlights a potential therapeutic strategy that may manage prostate tumor growth more effectively. It also provides a framework for studying tumor-related immune mechanisms and the selection of therapeutic regimens in other types of cancer. In separate work published in Nature Scientific Reports in April 2017, Zhou and collaborators from Wake Forest School of Medicine used TACC's high performance computing resources to predict how ribonucleic acids (RNA) and proteins interact with greater accuracy than previous methods. RNA-protein interactions are import to the function of RNAs, especially in the case of long noncoding RNAs (lncRNAs), which play essential roles in a variety of biological processes, including cancer development. In their study, they first performed an analysis of 1,342 RNA-protein interacting complexes from the Nucleic Acid Database and identified diverse interface properties between them, including both binding and non-binding sites. They then used a three-step method to predict the interacting regions between them using both the sequences and structures of the proteins and RNAs. Compared with existing methods, which use only sequences, the model was found to be more accurate and outperformed the leading current method by 20 percent. The computationally-intensive work represents the first approach that uses local conformations to analyze and predict the binding sites of protein, RNA and RNA-protein interacting pairs. "TACC provides an important assistance for discovering clinically meaningful and actionable knowledge across highly heterogeneous biomedical big data sets," Zhou said. [The research was supported by the National Institutes of Health (U01HL111560 and R01LM010185).] Biological agents used in immunotherapy -- including those that target a specific tumor pathway, aim for DNA repair, or stimulate the immune system to attack a tumor -- function differently from radiation and chemotherapy. Whereas toxicity and efficacy typically increase with the dose level for cell-destroying chemicals or x-rays, this relationship may not be true for biological agents. Specifically, toxicity may increase at low dose levels and then plateau at higher dose levels when the biological agent has reached a saturation level in the body. Efficacy may even decrease at higher dose levels. Because traditional dose-finding designs, which focus on identifying the maximum tolerated dose, are not suitable for trials of biological agents, novel designs that consider both the toxicity and efficacy of these agents are imperative. Chunyan Cai, assistant professor of biostatistics at UT Health Science Center (UTHSC)'s McGovern Medical School, uses TACC systems to design new kinds of dose-finding trials for combinations of immunotherapies. Writing in the Journal of the Royal Statistics Society Series C (Applied Statistics), Cai and her collaborators, Ying Yuan, and Yuan Ji, described efforts to identify biologically optimal dose combinations (BODC) for agents that target the PI3K/AKT/mTOR signaling pathway, which has been associated with several genetic aberrations related to the promotion of cancer. "Our research is motivated by a drug combination trial at the MD Anderson Cancer Center for patients diagnosed with relapsed lymphoma," Cai said. "The trial combined two novel biological agents that target two different components in the PI3K/AKT/mTOR signaling pathway." Both agents individually demonstrated the ability to partially inhibit the signaling pathway and provide therapeutic value. By combining these two agents, the investigators expected to obtain a more complete inhibition of the PI3K/AKT/mTOR pathway, and thereby achieve better treatment responses. The trial investigated the combinations of four dose levels of agent A with four dose levels of agent B, resulting in 16 dose combinations. The goal was to find the biologically optimal dose combination among those possibilities. Cai and her colleagues introduced a dose-finding trial design that explicitly accounted for the unique properties of biological agents. "Our design is conducted in two stages," she said. "In stage one, we escalate doses along the diagonal of the dose combination matrix as a fast exploration of the dosing space. In stage two, on the basis of the observed toxicity and efficacy data from stages one, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination." They investigated six different dose-toxicity and dose-efficacy scenarios and carried out 2,000 simulated trials for each of the designs using the Lonestar supercomputer at TACC. The simulations compared the percentage of the biologically optimal dose combination (BODC), the percentage of patients allocated to the BODC, the average efficacy rate, the number of patients assigned to over-toxic doses, and the total numbers of patients assigned in stage I and stage II of the trial. The optimal dose-finding design, they discovered, gives higher priority to trying new doses in the early stage of the trial, and toward the end of the trial assigns patients to the most effective dose that is safe. "Extensive simulation studies show that the design proposed has desirable operating characteristics in identifying the biologically optimal dose combination under various patterns of dose-toxicity and dose-efficacy relationships," she concluded. [The research was supported by the National Cancer Institute (Award Number R01 CA154591) and the National Institutes of Health's Clinical and Translational Science Award grant (UL1 TR000371).] Data-driven research and clinical dosing studies are essential for understanding how the immune system responds to treatments and determining the proper doses of biological agents. Also, critical, however, are mechanisms that bring together the research of a whole community -- to share, compare and integrate disparate research findings. The VDJServer, which launched last year, serves as such a resource. The server enables researchers to analyze high-throughput immune repertoire sequencing data over the web using the high-performance computing resources available at TACC. Repertoire sequencing investigates the collection of trans-membrane antigen-receptor proteins located on the surface of T and B cells -- white blood cells that play a key role in the human immune response. A form of next-generation genetic analysis, repertoire sequencing has transformed the field of immunotherapy, enabling quantitative analyses that help scientists understand the function of immunity in health and disease. VDJServer was developed by bioinformaticians and immunologists from UT Southwestern Medical Center, J. Craig Venter Institute and Yale University in partnership with computational experts at TACC. "VDJServer provides access to sophisticated analysis software and TACC's high-performance computing resources through an intuitive interface designed for users who are primarily biologists and clinicians," said project leader Lindsay Cowell, an associate professor of Clinical Sciences at UT Southwestern Medical Center, whose group developed the software at the core of VDJServer. "In addition, we provide platforms for sharing data, analysis results, and analysis pipelines," she said. "Access to these analyses and resource-sharing accelerates research and enables insights that wouldn't be possible without the opportunity for data integration." Researchers can upload B- and T-cell-receptor data and tap into TACC's computing power through the site to perform data-driven studies. Immune repertoire analysis is relevant in many contexts, including cancer immunology. One example of this type of research is a collaboration between the Cowell group and Marco Davila, a cancer researcher at the Moffitt Cancer Center. Together they are developing chimeric antigen receptors -- genetically engineered receptors enabling T-cells to express receptors with the antigen specificity of an antibody. These receptors would allow the T-cells to recognize and kill cancer cells. "The team is using VDJServer to perform bioinformatics analyses to identify appropriate antibodies that may target specific cancer types," explained Cowell. "That's followed up with experimental validation to determine that the antibodies are appropriate." VDJServer speeds up scientists' understanding of the immune system and help cultivate reproducible findings, according to Matt Vaughn, TACC's Director of Life Science Computing. "Immunotherapy is a relatively young field and the computational tools are emerging alongside with knowledge of the domain," Vaughn said. "Community-oriented efforts like VDJServer are important because they provide a centralized workbench where best of breed algorithms and workflows can be used much more quickly than if they were released just as source code and at the end of a long publication cycle. They're also available democratically: anyone can use software at VDJServer regardless of how computationally experienced they are." Whether in support of population-level immune response studies, clinical dosing trials or community-wide efforts like VDJServer, TACC's advanced computing resources are helping scientists put the immune system to work to better fight cancer. [VDJServer is supported by a National Institute of Allergy and Infectious Diseases research grant (#1R01A1097403)]


News Article | May 17, 2017
Site: www.eurekalert.org

The body has a natural way of fighting cancer - it's called the immune system, and it is tuned to defend our cells against outside infections and internal disorder. But occasionally, it needs a helping hand. Immunotherapy fights cancer by supercharging the immune system's natural defenses or contributing additional immune elements that can help the body kill cancer cells. In recent decades, immunotherapy has become an important tool in treating a wide range of cancers, including breast cancer, melanoma and leukemia. But alongside its successes, scientists have discovered that immunotherapy sometimes has powerful -- even fatal -- side-effects. Much still needs to be learned about how the immune system fights cancer, and in this area, supercomputers play an important role. Not every immune therapy works the same on every patient. Differences in an individual's immune system may mean one treatment is more appropriate than another. Furthermore, tweaking one's system might heighten the efficacy of certain treatments. Researchers from Wake Forest School of Medicine and Zhejiang University in China developed a novel mathematical model to explore the interactions between prostate tumors and common immunotherapy approaches, individually and in combination. In a study published in February 2016 in Nature Scientific Reports, they used their model to predict how prostate cancer would react to four common immunotherapies: To study the systematic effects of these four treatments, the researchers incorporated data from animal studies into their complex mathematical models and simulated tumor responses to the treatments using the Stampede supercomputer at the Texas Advanced Computing Center (TACC). "We do a lot of modeling which relies on millions of simulations," said Jing Su, a researcher at the Center for Bioinformatics and Systems Biology at Wake Forest School of Medicine and assistant professor in the Department of Diagnostic Radiology. "To get a reliable result, we have to repeat each computation at least 100 times. We want to explore the combinations and effects and different conditions and their results." The researchers found that the depletion of T Cells and the neutralization of Interleukin 2 can have a stronger effect when combined with androgen deprivation therapy and vaccines. The study highlights a potential therapeutic strategy that may manage prostate tumor growth more effectively. It also provides a framework for studying tumor-related immune mechanisms and the selection of therapeutic regimens in other types of cancer. In separate work published in Nature Scientific Reports in April 2017, Zhou and collaborators from Wake Forest School of Medicine used TACC's high performance computing resources to predict how ribonucleic acids (RNA) and proteins interact with greater accuracy than previous methods. RNA-protein interactions are import to the function of RNAs, especially in the case of long noncoding RNAs (lncRNAs), which play essential roles in a variety of biological processes, including cancer development. In their study, they first performed an analysis of 1,342 RNA-protein interacting complexes from the Nucleic Acid Database and identified diverse interface properties between them, including both binding and non-binding sites. They then used a three-step method to predict the interacting regions between them using both the sequences and structures of the proteins and RNAs. Compared with existing methods, which use only sequences, the model was found to be more accurate and outperformed the leading current method by 20 percent. The computationally-intensive work represents the first approach that uses local conformations to analyze and predict the binding sites of protein, RNA and RNA-protein interacting pairs. "TACC provides an important assistance for discovering clinically meaningful and actionable knowledge across highly heterogeneous biomedical big data sets," Zhou said. [The research was supported by the National Institutes of Health (U01HL111560 and R01LM010185).] Biological agents used in immunotherapy -- including those that target a specific tumor pathway, aim for DNA repair, or stimulate the immune system to attack a tumor -- function differently from radiation and chemotherapy. Whereas toxicity and efficacy typically increase with the dose level for cell-destroying chemicals or x-rays, this relationship may not be true for biological agents. Specifically, toxicity may increase at low dose levels and then plateau at higher dose levels when the biological agent has reached a saturation level in the body. Efficacy may even decrease at higher dose levels. Because traditional dose-finding designs, which focus on identifying the maximum tolerated dose, are not suitable for trials of biological agents, novel designs that consider both the toxicity and efficacy of these agents are imperative. Chunyan Cai, assistant professor of biostatistics at UT Health Science Center (UTHSC)'s McGovern Medical School, uses TACC systems to design new kinds of dose-finding trials for combinations of immunotherapies. Writing in the Journal of the Royal Statistics Society Series C (Applied Statistics), Cai and her collaborators, Ying Yuan, and Yuan Ji, described efforts to identify biologically optimal dose combinations (BODC) for agents that target the PI3K/AKT/mTOR signaling pathway, which has been associated with several genetic aberrations related to the promotion of cancer. "Our research is motivated by a drug combination trial at the MD Anderson Cancer Center for patients diagnosed with relapsed lymphoma," Cai said. "The trial combined two novel biological agents that target two different components in the PI3K/AKT/mTOR signaling pathway." Both agents individually demonstrated the ability to partially inhibit the signaling pathway and provide therapeutic value. By combining these two agents, the investigators expected to obtain a more complete inhibition of the PI3K/AKT/mTOR pathway, and thereby achieve better treatment responses. The trial investigated the combinations of four dose levels of agent A with four dose levels of agent B, resulting in 16 dose combinations. The goal was to find the biologically optimal dose combination among those possibilities. Cai and her colleagues introduced a dose-finding trial design that explicitly accounted for the unique properties of biological agents. "Our design is conducted in two stages," she said. "In stage one, we escalate doses along the diagonal of the dose combination matrix as a fast exploration of the dosing space. In stage two, on the basis of the observed toxicity and efficacy data from stages one, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination." They investigated six different dose-toxicity and dose-efficacy scenarios and carried out 2,000 simulated trials for each of the designs using the Lonestar supercomputer at TACC. The simulations compared the percentage of the biologically optimal dose combination (BODC), the percentage of patients allocated to the BODC, the average efficacy rate, the number of patients assigned to over-toxic doses, and the total numbers of patients assigned in stage I and stage II of the trial. The optimal dose-finding design, they discovered, gives higher priority to trying new doses in the early stage of the trial, and toward the end of the trial assigns patients to the most effective dose that is safe. "Extensive simulation studies show that the design proposed has desirable operating characteristics in identifying the biologically optimal dose combination under various patterns of dose-toxicity and dose-efficacy relationships," she concluded. [The research was supported by the National Cancer Institute (Award Number R01 CA154591) and the National Institutes of Health's Clinical and Translational Science Award grant (UL1 TR000371).] Data-driven research and clinical dosing studies are essential for understanding how the immune system responds to treatments and determining the proper doses of biological agents. Also, critical, however, are mechanisms that bring together the research of a whole community -- to share, compare and integrate disparate research findings. The VDJServer, which launched last year, serves as such a resource. The server enables researchers to analyze high-throughput immune repertoire sequencing data over the web using the high-performance computing resources available at TACC. Repertoire sequencing investigates the collection of trans-membrane antigen-receptor proteins located on the surface of T and B cells -- white blood cells that play a key role in the human immune response. A form of next-generation genetic analysis, repertoire sequencing has transformed the field of immunotherapy, enabling quantitative analyses that help scientists understand the function of immunity in health and disease. VDJServer was developed by bioinformaticians and immunologists from UT Southwestern Medical Center, J. Craig Venter Institute and Yale University in partnership with computational experts at TACC. "VDJServer provides access to sophisticated analysis software and TACC's high-performance computing resources through an intuitive interface designed for users who are primarily biologists and clinicians," said project leader Lindsay Cowell, an associate professor of Clinical Sciences at UT Southwestern Medical Center, whose group developed the software at the core of VDJServer. "In addition, we provide platforms for sharing data, analysis results, and analysis pipelines," she said. "Access to these analyses and resource-sharing accelerates research and enables insights that wouldn't be possible without the opportunity for data integration." Researchers can upload B- and T-cell-receptor data and tap into TACC's computing power through the site to perform data-driven studies. Immune repertoire analysis is relevant in many contexts, including cancer immunology. One example of this type of research is a collaboration between the Cowell group and Marco Davila, a cancer researcher at the Moffitt Cancer Center. Together they are developing chimeric antigen receptors - genetically engineered receptors enabling T-cells to express receptors with the antigen specificity of an antibody. These receptors would allow the T-cells to recognize and kill cancer cells. "The team is using VDJServer to perform bioinformatics analyses to identify appropriate antibodies that may target specific cancer types," explained Cowell. "That's followed up with experimental validation to determine that the antibodies are appropriate." VDJServer speeds up scientists' understanding of the immune system and help cultivate reproducible findings, according to Matt Vaughn, TACC's Director of Life Science Computing. "Immunotherapy is a relatively young field and the computational tools are emerging alongside with knowledge of the domain," Vaughn said. "Community-oriented efforts like VDJServer are important because they provide a centralized workbench where best of breed algorithms and workflows can be used much more quickly than if they were released just as source code and at the end of a long publication cycle. They're also available democratically: anyone can use software at VDJServer regardless of how computationally experienced they are." Whether in support of population-level immune response studies, clinical dosing trials or community-wide efforts like VDJServer, TACC's advanced computing resources are helping scientists put the immune system to work to better fight cancer. [VDJServer is supported by a National Institute of Allergy and Infectious Diseases research grant (#1R01A1097403)]


Cadre of experts led by Dr. Martin C. Robson, previously simultaneous President of the American Burn Association and Chairman of the American Board of Plastic Surgery SALT LAKE CITY, UT--(Marketwired - Jun 30, 2017) - PolarityTE™, Inc. ( : COOL) today announced the appointment of some of the world's most-highly-regarded experts in burn and wound care to its Clinical Board of Advisors, as it drives toward the introduction of the Company's flagship product, SkinTE™. This cadre of plastic and reconstructive surgeons includes Drs. Martin C. Robson, William L. Hickerson, Jeffrey W. Shupp, Mark S. Granick, David J. Smith, Jr. and Gerhard S. Mundinger. "As we prepare for clinical and market launch of SkinTE™ in the near future, we are excited to bring on a tremendous block of experience and knowledge in burn and wound care surgery with the addition of this group of thought leaders to our esteemed Clinical Board of Advisors," said Denver Lough, MD, PhD, Chairman, Chief Executive Officer, and Chief Scientific Officer of PolarityTE™. "Our goal is to deliver our revolutionary skin regeneration technology in the easiest and most pragmatic manner, which requires the perspective of burn and wound care surgeons who have spent significant time in the trenches treating patients." Emeritus Professor at the University of South Florida, Dr. Robson previously served as President of the American Burn Association, where he received its Distinguished Service Award, and as President of the Wound Healing Society. Dr. Robson also has been Chairman of the American Board of Plastic Surgery, Chairman of the Residency Review Committee for Plastic Surgery, Chairman of the Plastic Surgery Research Council and President of the Association of Academic Chairmen of Plastic Surgery. Dr. Robson received his Doctorate of Medicine from the Johns Hopkins University and completed his general surgery residency at the Brooke Army Medical Center, and his plastic surgery residency at Yale. He has served as Chief of Plastic Surgery at the University of Chicago, Wayne State University, and the University of Texas Medical Branch. He is a Fellow of the American College of Surgeons and holds Honorary Fellowships from the Royal College of Surgeons of England and the Royal Australasian College of Surgeons. He is a recipient of the Lifetime Scientific Achievement Awards from the Wound Healing Society, the Association of Advanced Wound Care and the World Union of Wound Healing Societies. He has authored over 650 publications mostly devoted to wound healing, wound infection, burns and proliferative scarring. Dr. Robson has made numerous contributions to the growth of importance for wound and skin injuries, and he "hopes to inspire today's generation to revolutionize the treatment, care and methods behind skin-related injuries through the scientific pioneers that exist today." Dr. William L. Hickerson is currently the Chief of Burn Surgery and the Professor of Plastic Surgery at the University of Tennessee-Health Science Center College (UTHSC). He is also the Medical Director of the Firefighters' Burn Center in Memphis, TN, which is the region's only comprehensive burn care unit. At UTHSC, Dr. Hickerson earned his Doctorate of Medicine, served as chief resident of general surgery and completed his plastic surgery residency. Dr. Hickerson is certified by the American Boards of General Surgery and Plastic Surgery. Dr. Hickerson has authored and co-authored over 40 medical articles about trauma, plastic surgery, skincare and wound cares. He is a well-respected expert in the field of burn surgery and has professional memberships with the American Burn Association, the American Association of Plastic Surgeons and the Association of Academic Chairmen of Plastic Surgery. At MedStar Washington Hospital Center, Dr. Jeffrey W. Shupp is the lead investigator of the Firefighters' Burn and Surgical Research Laboratory as well as the Director of the Burn Center. Dr. Shupp also directs the department of Burn Research at MedStar Health Research Institute. Outside of his leadership roles, Dr. Shupp is an Associate Professor of Surgery at the Uniformed Services University of the Health Sciences in Washington, D.C. and an Associate Professor of Biomedical Engineering at The Catholic University of America, also in Washington, D.C. After earning his Doctorate of Medicine from the Virginia Commonwealth University School of Medicine, Dr. Shupp joined MedStar Washington Hospital Center to complete his residency in general surgery and his three-year fellowship in burn surgery. Dr. Shupp has done extensive research in a wide range of topics such as: burn surgery, thermal injury, burn injury and molecular pathology. His research has resulted in over 65 peer-reviewed publications. Dr. Shupp is highly recognized for his help in developing and designing MedStar Washington Hospital Center's Burn and Surgical research program, a nationally renowned institution that encompasses all aspects of burn research: multi-center clinical trials, pre-clinical, translational, and basic science research. Dr. Mark Granick is currently the Professor and the Chief of Plastic Surgery at Rutgers New Jersey Medical School. Dr. Granick is affiliated with St. Barnabas Medical Center, Newark Beth Israel Medical Center and University Newark Hospital, all of which are in New Jersey. Dr. Granick has over 40 years of experience in plastic surgery, and he specializes in complex reconstructive surgery and surgical wound care. Dr. Granick received his B.A. from Cornell University and his Doctorate of Medicine from Harvard Medical School. He completed his residency and fellowship at Harvard Medical School and the University of Pittsburgh, respectively. Dr. Granick is certified by the American Boards of Plastic Surgery and of Otolaryngology, Head and Neck Surgery. Dr. Granick has edited nine textbooks, written 50 book chapters and authored 150 peer-reviewed scholarly publications. As demonstrated by his lifetime appointment to Strathmore's Who's Who and Castle Connelly's mention of Dr. Granick in Top Doctors in the New York Metropolitan Area for the last nine consecutive years, Dr. Granick is internationally and nationally recognized as a top plastic surgeon. Dr. David J. Smith, Jr. is currently the Richard G. Connar Professor and Chairman of the Department of Surgery at the University of South Florida, and serves as the Chief Medical Officer for the Center for Advanced Medical Learning and Simulation. Dr. Smith previously enjoyed a long career at the University of Michigan where, among other roles, he was a Professor of Surgery and Section Head for Plastic and Reconstructive Surgery, and Associate Chairman for the Department of Surgery. Dr. Smith received his B.A. from Wesleyan University, and his Doctorate of Medicine from the Indiana University School of Medicine. He completed his residency in plastic surgery at the University of Indiana Medical Center, and completed a fellowship in hand surgery at the Christine M. Kleinert Institute for Hand and Microsurgery in Louisville, KY. Among his many appointments and memberships, Dr. Smith is the past President of the American Association for Hand Surgery, the past Chairman of the American Board of Plastic Surgery, and past President of the Association of Academic Chairmen of Plastic Surgery. He has authored more than 140 peer-reviewed publications in prominent medical journals, in addition to more than 40 book chapters. He has served on numerous editorial boards for peer-reviewed medical journals, including Surgery, Plastic and Reconstructive Surgery, Annals of Plastic Surgery, and the Journal of Surgical Research. Dr. Gerhard S. Mundinger is the Director of Plastic Surgery at the Children's Hospital of New Orleans, and an Assistant Professor of Clinical Surgery and Assistant Professor of Cell Biology and Anatomy at Louisiana State University Health Sciences Center in New Orleans. From 2014 to 2015, he served as Administrative Chief of Service for the Johns Hopkins Department of Plastic Surgery. Dr. Mundinger received his B.A. from the University of Michigan, Ann Arbor and his Doctorate of Medicine from Johns Hopkins University School of Medicine in Baltimore, Maryland, where he also completed his residency in plastic and reconstructive surgery. Dr. Mundinger then completed a fellowship in pediatric and adult craniofacial surgery at Seattle Children's Hospital. He has received numerous awards, including the Johns Hopkins Frank L. Coulson Award for Clinical Excellence. Dr. Mundinger has authored over 60 peer-reviewed original publications in prominent medical journals, including the New England Journal of Medicine. He is a nationally and internationally respected expert in his field, as evidenced by invitations he has received to speak at worldwide conferences on reconstructive microsurgery, surgical education, craniofacial surgery, aesthetic surgery, and vascularized composite tissue (face and hand) transplantation. About the PolarityTE™ Clinical Board of Advisors The PolarityTE™ Clinical Board of Advisors is comprised of leading experts from various fields of study aligned to potential clinical application of the Company's revolutionary platform technology. The PolarityTE™ platform has been shown to regenerate skin in a preclinical model, and has the potential to regenerate bone, muscle, cartilage, fat, blood vessels and nerves. In addition to the five new appointees, the Clinical Board of Advisors includes: About SkinTE™ and the PolarityTE™ Platform SkinTE™ is the Company's lead product in development for skin regeneration. Its investigational platform and the Company's namesake, PolarityTE, is being developed to simplify regeneration and allow tissue and cellular elements to function naturally. Using our revolutionary platform, we seek to utilize cell and tissue polarity in order to create a spectrum of uniquely functional tissues in a way that mirrors the natural development of the human body. Our goal is to apply the platform across all cells, tissues and composite structures, transforming regenerative medicine into what has been envisioned since its inception. PolarityTE™, Inc. is a regenerative medicine company positioned to be the first to successfully regenerate human skin. The Company's novel regenerative medicine and tissue engineering platform was developed and patented by chairman and chief executive officer, Denver Lough M.D., Ph.D. This radical and proprietary technology employs a patient's own cells for the healing of full-thickness, functionally-polarized tissues. If clinically successful, the PolarityTE™ platform will provide medical professionals with a truly new paradigm in wound healing and reconstructive surgery by utilizing a patient's own tissue substrates for the regeneration of skin, bone, muscle, cartilage, fat, blood vessels and nerves. The PolarityTE™ platform leverages natural and biologically-sound principles which are readily adaptable to a wide spectrum of organ and tissue systems. This revolutionary technology, paired with the Company's world-renowned clinical advisory board, position PolarityTE™ to drastically change the field and future of translational regenerative medicine. More information can be found online at www.PolarityTE.com. Certain statements contained in this release are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Forward looking statements contained in this release relate to, among other things, the Company's ongoing compliance with the requirements of The NASDAQ Stock Market and the Company's ability to maintain the closing bid price requirements of The NASDAQ Stock Market on a post reverse split basis. They are generally identified by words such as "believes," "may," "expects," "anticipates," "should'" and similar expressions. Readers should not place undue reliance on such forward-looking statements, which are based upon the Company's beliefs and assumptions as of the date of this release. The Company's actual results could differ materially due to risk factors and other items described in more detail in the "Risk Factors" section of the Company's Annual Reports and other filings with the SEC (copies of which may be obtained at www.sec.gov). Subsequent events and developments may cause these forward-looking statements to change. The Company specifically disclaims any obligation or intention to update or revise these forward-looking statements as a result of changed events or circumstances that occur after the date of this release, except as required by applicable law.


News Article | May 30, 2017
Site: www.prnewswire.com

Kevin Donly, D.D.S., Vice President: Professor and Chair, Department of Developmental Dentistry, UTHSC-SA; Professor, Department of Pediatrics, UTHSC-SA. Jessica Y. Lee, D.D.S., M.P.H., Ph.D., Secretary-Treasurer: Professor and Chair, Department of Pediatric Dentistry, University of North Carolina; Professor, Department of Health Policy and Management, Gillings School of Global Public Health, University of North Carolina at Chapel Hill. Jade Miller, D.D.S., Immediate Past President: Associate faculty member, University of the Pacific School of Dentistry, University of Washington School of Dentistry and University of Nevada School of Medicine; private practitioner, Reno, Nev. Tegwyn H. Brickhouse, D.D.S, Ph.D., At-Large Trustee: Chair, Department of Pediatric Dentistry, Virginia Commonwealth University School of Dentistry, Richmond, Va.; Director, Oral Health Services Research Core, Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry. About the American Academy of Pediatric Dentistry The American Academy of Pediatric Dentistry is the recognized authority on children's oral health. As advocates for children's oral health, the AAPD promotes evidence-based policies and clinical guidelines; educates and informs policymakers, parents and guardians, and other health care professionals; fosters research; and provides continuing professional education for pediatric dentists and general dentists who treat children. Founded in 1947, the AAPD is a not-for-profit professional membership association representing the specialty of pediatric dentistry. Its 10,000 members provide primary care and comprehensive dental specialty treatments for infants, children, adolescents and individuals with special health care needs. For further information, visit the AAPD website at http://www.aapd.org or the AAPD's consumer website at http://www.mychildrensteeth.org. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/aapd-names-new-board-officers-and-trustees-300459609.html


News Article | September 20, 2017
Site: www.prnewswire.com

BIRMINGHAM, Ala., Sept. 20, 2017 /PRNewswire-USNewswire/ -- Southern Research and the University of Tennessee Health Science Center (UTHSC) have formed a partnership to advance promising research that could lead to new drugs that address unmet medical needs. The collaborative program links the drug discovery and development expertise of Birmingham-based Southern Research with UTHSC's four-campus research network, which was involved in sponsored programs valued at $240.5 million in fiscal year 2016. "We believe there are a lot of synergies between the two organizations," said Mark Suto, Ph.D., vice president of Drug Discovery for Southern Research. "UTHSC brings novel scientific insights into diseases with poor treatment options, and we have proven capabilities in drug discovery and development." "This collaboration with talented UTHSC researchers has great potential to lead to significant discoveries," Suto added. The new UTHSC/SR Collaborative Research Network (CORNET) Award in Drug Discovery and Development represents an extension of a program launched by Steven R. Goodman, Ph.D., vice chancellor for research at UTHSC in 2016. The CORNET Awards are designed to provide seed money to support new collaborative research teams and their projects. To-date, the program has provided over $1.1 million in funding to promising university research teams. Glen E. Palmer, Ph.D., an associate professor in the College of Pharmacy at UTHSC, has been selected to receive the first jointly funded UTHSC/SR CORNET Award. Palmer is targeting the development of an entirely new class of antifungal medications to combat a range of invasive fungal infections, which are blamed in an estimated 1.5 million deaths a year. "I want to congratulate Dr. Glen Palmer on being our first UTHSC/SR CORNET Award recipient and a second-time CORNET awardee," Goodman said. "The UTHSC/SR CORNET Award is focused on drug discovery and development for any human disease. We are hopeful that Dr. Palmer's exciting work and our partnership with Southern Research will lead to a new class of medications against invasive fungal infections." TEAMWORK APPROACH Under the new program, UTHSC scientists can apply for funding to advance their research. The partnership is awarding Palmer $50,000 per year for up to two years, with funding for year two dependent upon progress made in year one. Research projects receiving funding from the UTHSC/SR CORNET Award can take advantage of the shared resources of Southern Research and UTHSC to facilitate drug discovery and development efforts aimed at any disease. Southern Research's established drug discovery infrastructure will play a key role in the partnership. The organization's High-Throughput Screening (HTS) Center has a library of more than 1 million compounds and state-of-the-art robotic equipment for a wide variety of screens. The Birmingham-based non-profit also has deep expertise in medicinal chemistry and pre-clinical drug development, along with bio-containment laboratories and other resources. Southern Research scientists have discovered seven FDA-approved drugs used in cancer treatment and have evaluated a significant percentage of all medicines on the market. Southern Research and UTHSC will jointly own intellectual property resulting from projects receiving support from the program. Outside partners will be sought for clinical development and commercialization when projects reach an advanced stage. INITIAL PROJECT Palmer's research project, titled "Targeting the Aromatic Amino Acid Synthesis Pathway to Develop a New Class of Broad Spectrum Antimicrobial Agents," aims to develop first-in-class broad-spectrum antimicrobial agents for the treatment of what are often fatal invasive fungal infections. These infections are a serious and growing global health problem, with mortality rates often exceeding 50 percent for many fungal pathogens. Disturbingly, some of these pathogens are developing resistance to the antifungal drugs now in use. "Mortality rates associated with invasive fungal infections have remained alarmingly high, as many of the antifungal drugs currently available are ineffective in treating these infections, or in some cases themselves are toxic to the patients," Palmer said. "Over the last few years, my lab has devised some novel approaches to discover new antimicrobial compounds. The collaborative effort between the University of Tennessee Health Science Center and Southern Research will provide a framework with the resources needed to apply these methods on a scale at which they can have a real impact," he added. "Additionally, it will bring the know-how and experience needed to progress the experimental therapeutics we discover towards new and improved drugs to ultimately improve the prognoses of patients with life-threatening invasive fungal infections." Southern Research's HTS Center will assist Palmer in screening around 200,000 compounds for active chemical leads as part of the project. Southern Research's Chemistry Department will play an integral role in the work after the initial active compounds are identified.


Graves D.T.,University of Pennsylvania | Oates T.,UTHSC
Journal of Oral Microbiology | Year: 2011

Both lesions of endodontic origin and periodontal diseases involve the host response to bacteria and the formation of osteolytic lesions. Important for both is the upregulation of inflammatory cytokines that initiate and sustain the inflammatory response. Also important are chemokines that induce recruitment of leukocyte subsets and bone-resorptive factors that are largely produced by recruited inflammatory cells. However, there are differences also. Lesions of endodontic origin pose a particular challenge since that bacteria persist in a protected reservoir that is not readily accessible to the immune defenses. Thus, experiments in which the host response is inhibited in endodontic lesions tend to aggravate the formation of osteolytic lesions. In contrast, bacteria that invade the periodontium appear to be less problematic so that blocking arms of the host response tend to reduce the disease process. Interestingly, both lesions of endodontic origin and periodontitis exhibit inflammation that appears to inhibit bone formation. In periodontitis, the spatial location of the inflammation is likely to be important so that a host response that is restricted to a subepithelial space is associated with gingivitis, while a host response closer to bone is linked to bone resorption and periodontitis. However, the persistence of inflammation is also thought to be important in periodontitis since inflammation present during coupled bone formation may limit the capacity to repair the resorbed bone. © 2011 Dana T. Graves et al.

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