News Article | April 24, 2017
(UT Southwestern Medical Center) Researchers from UT Southwestern Medical Center have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types.
News Article | April 24, 2017
Researchers from UT Southwestern Medical Center have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types.
News Article | April 24, 2017
Researchers from UT Southwestern Medical Center have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types.
News Article | March 22, 2017
Fat cells were found to help the liver during fasting and for being responsible for the regulation of glucose and uridine during the fasting stage. Uridine is a metabolite used by the body in a series of bioprocesses such as building RNA molecules. The findings of this study could change the way we treat a number of diseases, among which are diabetes, cancer and neurological disorders. The research was carried out by researchers at the UT Southwestern Medical Center, and its findings were published in the journal Science. The results of this study were replicated in rat, mouse and human studies. Metabolites are important substances which result from a metabolic activity of the body. For instance, the glucose (quantity of sugar in the blood) produced while metabolizing starches or complex sugars is a metabolite. Similar to glucose, every cell in the human body has to use uridine to function properly. The liver produces uridine for the circulatory system, as many textbooks indicate. However, this study found that the liver doesn't just produce uridine, but it's the primary producer of this metabolite, only in the fed state. At the same time, the production of uridine is passed on to the fat cells during the fasted state. According to the study, this new way of understanding the production of uridine in the body is similar to the process of labor division. During fasting, it's the liver that produces glucose, and fat cells help it with the production of uridine for the bloodstream. While uridine is known to have multiple roles inside the human body, the current research was the first to report fat cells producing plasma uridine while the body is going through the fasting stage. Additionally, the finding is that the energy balance of the body is regulated by a fat cell-liver-uridine axis. "It turns out that having uridine in your gut helps you absorb glucose; therefore uridine helps in glucose regulation," noted Dr. Philipp Scherer, senior author of the study and Director of UT Southwestern's Touchstone Center for Diabetes Research. Dr. Yingfeng Deng, the lead author of the research, observed that the levels of uridine in the blood increase during fasting, and drop during feeding. In the feeding process, the liver is responsible for a drop in the levels of uridine, as it secretes it into bile. The uridine is then transported to the gallbladder, and then to the gut, where it plays an important role in absorbing nutrients. "We clarify the mechanism underlying the rapid reduction of plasma uridine upon refeeding, which involves both reduction of uridine synthesis in adipocytes and enhancement of its clearance through the bile," noted the research. Further research starting from these findings will investigate the effects of reducing feeding-induced uridine levels in organs that use mainly uridine from plasma. Additionally, whether or not bariatric surgery affects udirine levels as well is another possible research direction. The results of this question could impact the way we treat the severely obese, as this study also underlined that there is a direct connection between temperature regulation and metabolism. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.
News Article | April 25, 2017
Anna Gunby can't run around as smoothly as most 4-year-olds because her wobbly legs are affected by a rare brain disease that also hinders her intellect. She can't identify colors. She can't count objects. Her attention span is short. "But there's definitely hope," said Anna's mother, Courtney Gunby. "Maybe one day she'll be able to live on her own, operate a vehicle or go swimming by herself. There's hope that she could have some sense of normalcy to her life." A study led by investigators in UT Southwestern's Peter O'Donnell Jr. Brain Institute offers novel insight into how a newly designed diet can help children like Anna cope with Glut1 deficiency -- a rare disease that severely inhibits learning and muscle control by starving the brain of glucose, its main energy source. And scientists are already beginning to expand on the findings published in JAMA Neurology by testing an edible oil that smaller studies indicate can improve cognitive abilities in patients. Combining the new diet with the supplemental oil derived from castor beans could provide a life-changing treatment that trail blazes a brighter future for thousands of children in the U.S. who otherwise face a lifetime of stunted brain function. Patients with Glut1 deficiency usually can't learn beyond an elementary school level and often can't live independently as adults. "We're talking about helping people be independent from their parents. The question every parent asks is, 'Will my child be able to have an independent life when we're gone?' Right now it's very questionable whether they'll be able to achieve independence," said Dr. Juan Pascual, Associate Professor of Neurology and Neurotherapeutics, Pediatrics, and Physiology at UT Southwestern Medical Center. Dr. Pascual led the JAMA study that relied on data from a worldwide registry he created in 2013 for Glut1 deficiency patients. The research tracked 181 patients for three years, finding that a modified Atkins diet that includes less fat and slightly more carbohydrates than the standard ketogenic diet helped reduce seizures and improved the patients' long-term health. The study also found earlier diagnosis and treatment of the disease improved their prognosis. In addition, Dr. Pascual is overseeing national clinical trials that are testing whether triheptanoin (C7) oil improves the intellect of patients by providing their brains an alternative fuel to glucose. The trials will last five years and are funded with more than $3 million from the National Institutes of Health.
News Article | April 26, 2017
Researchers at the Texas Biomedical Device Center (TxBDC) at The University of Texas at Dallas have been awarded a contract worth up to $5.8 million from the Defense Advanced Research Projects Agency (DARPA) to investigate a novel approach to accelerate the learning of foreign languages. The contract is part of DARPA's Targeted Neuroplasticity Training (TNT) program, which seeks to advance the pace and effectiveness of a specific kind of learning -- cognitive skills training -- through precise activation of peripheral nerves, which in turn can strengthen neural connections in the brain. "Military personnel are required to utilize a wide variety of complex perceptual, motor and cognitive skills under challenging conditions," said Dr. Robert Rennaker, Texas Instruments Distinguished Chair in Bioengineering, director of the TxBDC and chairman of the Department of Bioengineering. "Mastery of these difficult skills, including fluency in foreign language, typically requires thousands of hours of practice," said Rennaker, who served in the U.S. Marine Corps. DARPA's TNT program aims to develop an optimized strategy to accelerate acquisition of complex skills, which would significantly reduce the time needed to train foreign language specialists, intelligence analysts, cryptographers and others. Rennaker and his colleagues at the TxBDC will focus on developing an approach that uses vagus nerve stimulation (VNS) during training to specifically reinforce neural networks that are involved in learning a particular task. VNS is an FDA-approved method for treating various illnesses, such as depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve in the neck. When stimulated, the vagus nerve affects the brain, where it boosts the release of chemicals called neuromodulators. These chemicals facilitate synaptic plasticity, a process in which the connections between brain cells change and strengthen during learning. "Imagine you're struggling to learn something new, like multiplication tables or how to hit a golf ball. When you get it right, when that light bulb comes on, this system is being activated," Rennaker said. "By stimulating the vagus nerve during the learning process, we're artificially releasing these chemicals to enhance those connections active during learning." In the DARPA project, the aim is to accelerate learning of foreign languages by stimulating the vagus nerve during specific tasks. "DARPA is approaching the study of synaptic plasticity from multiple angles to determine whether there are safe and responsible ways to enhance learning and accelerate training for skills relevant to national security missions," said Doug Weber, TNT program manager at DARPA. Over the past several years, researchers at the TxBDC have developed techniques to pair VNS with traditional rehabilitation to enhance recovery from an injury, an innovation they call Targeted Plasticity Therapy (TPT). In preliminary clinical studies, their technique has been shown to restore movements, reduce pain, increase feeling, improve memory and possibly speed up learning. "This new project is focused on understanding if TPT can be used to accelerate learning in non-injured individuals," Rennaker said. "If successful, this approach could benefit not only those that need to rapidly learn a new language but also those with learning impediments or conditions such as autism or brain injuries." Dr. Michael Kilgard, Margaret Fonde Jonsson Professor in the School of Behavioral and Brain Sciences and associate director of the TxBDC, is the principal investigator. "We believe that we will be able to substantially increase the rate of language learning. With VNS, we may be able to improve on the brain's natural ability to learn," Kilgard said. "We're trying to march forward and make new technologies that aren't currently available. I think it's exciting." In addition to Rennaker and Kilgard, other co-principal investigators on the project are Dr. Seth Hayes, assistant professor in the Department of Bioengineering; Dr. Sven Vanneste, associate professor in the School of Behavioral and Brain Sciences; and Dr. Diana Easton, clinical professor in the Erik Jonsson School of Engineering and Computer Science. Also participating are Dr. Jane Wigginton from UT Southwestern Medical Center and Dr. Beverly Wright from Northwestern University.
News Article | April 26, 2017
Researchers from UT Southwestern Medical Center have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types. The nanovaccine consists of tumor antigens – tumor proteins that can be recognized by the immune system – inside a synthetic polymer nanoparticle. Nanoparticle vaccines deliver minuscule particulates that stimulate the immune system to mount an immune response. The goal is to help people’s own bodies fight cancer. “What is unique about our design is the simplicity of the single-polymer composition that can precisely deliver tumor antigens to immune cells while stimulating innate immunity. These actions result in safe and robust production of tumor-specific T cells that kill cancer cells,” said Dr. Jinming Gao, a Professor of Pharmacology and Otolaryngology in UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. A study outlining this research, published online in Nature Nanotechnology, reported that the nanovaccine had anti-tumor efficacy in multiple tumor types in mice. The research was a collaboration between the laboratories of study senior authors Dr. Gao and Dr. Zhijian “James” Chen, Professor of Molecular Biology and Director of the Center for Inflammation Research. The Center was established in 2015 to study how the body senses infection and to develop approaches to exploit this knowledge to create new treatments for infection, immune disorders, and autoimmunity. Typical vaccines require immune cells to pick up tumor antigens in a “depot system” and then travel to the lymphoid organs for T cell activation, Dr. Gao said. Instead, nanoparticle vaccines can travel directly to the body’s lymph nodes to activate tumor-specific immune responses. “For nanoparticle vaccines to work, they must deliver antigens to proper cellular compartments within specialized immune cells called antigen-presenting cells and stimulate innate immunity,” said Dr. Chen, also a Howard Hughes Medical Institute Investigator and holder of the George L. MacGregor Distinguished Chair in Biomedical Science. “Our nanovaccine did all of those things.” In this case, the experimental UTSW nanovaccine works by activating an adaptor protein called STING, which in turn stimulates the body’s immune defense system to ward off cancer. The scientists examined a variety of tumor models in mice: melanoma, colorectal cancer, and HPV-related cancers of the cervix, head, neck, and anogenital regions. In most cases, the nanovaccine slowed tumor growth and extended the animals’ lives. Other vaccine technologies have been used in cancer immunotherapy. However, they are usually complex – consisting of live bacteria or multiplex biological stimulants, Dr. Gao said. This complexity can make production costly and, in some cases, lead to immune-related toxicities in patients. With the emergence of new nanotechnology tools and increased understanding of polymeric drug delivery, Dr. Gao said, the field of nanoparticle vaccines has grown and attracted intense interest from academia and industry in the past decade. “Recent advances in understanding innate and adaptive immunity have also led to more collaborations between immunologists and nanotechnologists,” said Dr. Chen. “These partnerships are critical in propelling the rapid development of new generations of nanovaccines.” The investigative team is now working with physicians at UT Southwestern to explore clinical testing of the STING-activating nanovaccines for a variety of cancer indications. Combining nanovaccines with radiation or other immunotherapy strategies such as “checkpoint inhibition” can further augment their anti-tumor effectiveness. Study lead authors from UT Southwestern were Dr. Min Luo, research scientist; Dr. Hua Wang, Instructor of Molecular Biology; and Dr. Zhaohui Wang, postdoctoral fellow. Other UTSW researchers involved included graduate students Yang Li, Chensu Wang, Haocheng Cai, and Mingjian Du; Dr. Gang Huang, Instructor of Pharmacology and in the Simmons Comprehensive Cancer Center; Dr. Xiang Chen, research specialist; Dr. Zhigang Lu, Instructor of Physiology; Dr. Matthew Porembka, Assistant Professor of Surgery and a Dedman Family Scholar in Clinical Care; Dr. Jayanthi Lea, Associate Professor of Obstetrics and Gynecology and holder of the Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology; Dr. Arthur Frankel, Professor of Internal Medicine and in the Simmons Comprehensive Cancer Center; and Dr. Yang-Xin Fu, Professor of Pathology and Immunology, and holder of the Mary Nell and Ralph B. Rogers Professorship in Immunology. Their work was supported by the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, a UTSW Small Animal Imaging Resource grant and a Simmons Comprehensive Cancer Center support grant.
News Article | April 27, 2017
With the advance of nanotechnology, nanoparticle vaccines have gained increased interest as a way to fight diseases. Now, researchers from UT Southwestern Medical Center have developed a first-of-its-kind nanoparticle immunotherapy that has a single-polymer composition. The vaccine contains tumor proteins that can be recognized by the immune system, known as tumor antigens, encased inside a synthetic polymer nanoparticle. When delivered to the body, the nanoparticles help fuel the immune system to fight off cancer. In mouse studies, the nanovaccine stunted tumor growth and prolonged the animals’ lives. Multiple types of cancer models were investigated including melanoma, colorectal cancer, and HPV-related cancers of the cervix, head, and neck. “What is unique about our design is the simplicity of the single-polymer composition that can precisely deliver tumor antigens to immune cells while stimulating innate immunity,” Dr. Jinming Gao, professor of pharmacology and otolaryngology in UT Southwestern’s Harold c. Simmons comprehensive Cancer Center, said in a prepared statement. “These actions result in safe and robust production of tumor-specific T cells that kill cancer cells.” Unlike typical vaccines, the nanoparticle vaccines can be delivered directly into the lymph nodes to prompt a tumor-specific immune response, Gao said. The new nanovaccine activates an adaptor protein known as STING which prompts an immune response to defend against cancer. “For nanoparticle vaccines to work, they must deliver antigens to proper cellular compartments within specialized immune cells called antigen-presenting cells and stimulate innate immunity,” Dr. Zhijian “James” Chen, professor of molecular biology and director of the Center for Inflammation Research, said in a statement. “Our nanovaccine did all of those things.” Other vaccines used in cancer immunotherapy are usually more complex, making them more expensive to produce and sometimes resulting in immune-related toxicities, according to Gao. The team is now gearing up to move into clinical investigations of the STING-activating nanoparticle vaccines for multiple types of cancers. The researchers think that using nanovaccines in combination with radiation or other immunotherapies, such as checkpoint inhibitors, could increase the anti-tumor effectiveness. The findings were published April 24 in Nature Nanotechnology.
News Article | June 13, 2017
Dennis Kothmann jots several numbers on a clipboard then pauses, his pen frozen on the last figure. His eyebrows furrow and he quietly mouths a calculation. His doctor sits across from him, gauging how well the retired math teacher and calculus whiz can count down from 100 by sevens -- an exercise aimed at measuring his recently diminished memory and concentration. "It's a difficult calculation to keep in my head," admits Mr. Kothmann, whose clipboard is soon filled with a series of mistakes. The 71-year-old patient at UT Southwestern Medical Center has endured several life changes since being diagnosed last fall with glioblastoma, the deadliest and most common form of primary brain cancer. Doctors surgically removed a tumor from Mr. Kothmann's brain and performed radiation, extending his life by at least several months but also permanently weakening his cognition. Now he's looking to scientific ingenuity to save his life. Mr. Kothmann is among a pool of glioblastoma patients across the globe who are opting against the standard treatment of chemotherapy in favor of playing a crucial role in perhaps ushering in a new era of fighting brain cancer. He is participating in an international clinical trial involving immunotherapy, while other patients are testing everything from cap-like devices that produce electric fields to medications that disable cancer-associated proteins. "Chemo hasn't worked very well for other people with this disease," the Fort Worth native explained as a nurse prepared to deliver his latest infusion through his arm. "Why not try something different, give yourself a chance?" Glioblastoma kills most patients within months without the standard care of tumor-removing surgery, radiation, and chemotherapy. With those treatments, about half will still die in about 14-15 months. The standardized care was established little more than a decade ago, and since then scientists have kept working to find more effective approaches to fighting the tumors. A large part of that effort is focused on immunotherapy -- using the body's immune system to protect against and destroy cancer cells. Because glioblastoma has an ability to turn down the body's immune response and go undetected, doctors have developed several experimental approaches aimed at helping the body recognize and attack the tumors. One involves mixing white blood cells with cells from an extracted tumor and injecting them back into the patient as a vaccine. Another medication -- being tested by Mr. Kothmann -- is designed to disable the tumor's ability to go undetected and allow the immune system to do its job. Dr. Edward Pan, who oversees the neuro-oncology clinical trials at UT Southwestern, said results from multiple immunotherapy studies around the world will give scientists an idea within the next year of whether the approach holds promise. But even if the immunotherapies benefit only a portion of patients, the data could help scientists identify a series of individualized treatments that could be selectively chosen based on the patient. "It may be that the ultimate cure lies in personalized medicine, where people with the same kind of tumor respond to very different treatments," said Dr. Pan, Medical Director of UT Southwestern's Annette G. Strauss Center for Neuro-Oncology. UT Southwestern is implementing other cutting-edge strategies to treat brain cancer, including a tool that measures the chemicals within a tumor to more quickly determine whether a treatment is working. Doctors are also working to organize a clinical trial that would test a combination of treatments intended to kill tumors by disabling proteins that help the cancer cells survive. The effort stems from a new study that found the medications -- traditionally used separately to treat lung cancer and arthritis -- eliminated the brain tumors in mice when used together. In addition, Dr. Pan is part of a team measuring the efficacy of a special cap designed to kill cancer cells by creating low intensity electric fields that disable cell division. Patients cover their scalp with electrodes linked to a portable generator and are asked to use the device for at least 18 hours a day. A study published this year showed 13 percent of patients who used the device plus chemotherapy were alive after five years compared to 5 percent who underwent only chemotherapy. Dr. Pan is unsure how effective these strategies will be in the long term but is thankful to have patients like Mr. Kothmann willing to help find answers. "If patients want doom and gloom, there's no reason for them to enroll in these trials. The reason they come here is because they want to know if there's something else for them beyond the standard treatment regimen," said Dr. Pan, Associate Professor of Neurology & Neurotherapeutics and Neurological Surgery. Mr. Kothmann explains his bout with brain cancer with an inspiring air of positivity, his jovial smile belying the grim prospects for beating such a disease. Then his eyes suddenly well with tears as he describes how his wife Candace -- sitting next to him -- has helped him cope. Moments later the tears are gone, replaced by another broad smile. "There's no sense in getting down," Mr. Kothmann said, his wife nodding in agreement. "That's not going to make me better." Mr. Kothmann was diagnosed with glioblastoma in November, the discovery stemming from unexplained symptoms that prompted a visit to the doctor. Severe headaches. Bouts of confusion. Vision problems. He was even occasionally colliding with the sides of doorways. "He wasn't as mentally sharp," Mrs. Kothmann said. "He's a very smart man, so I figured something could be wrong." Brain imaging later showed a tumor had affected his optical nerve, permanently limiting his vision in the right side of both eyes. But the family didn't know the serious nature until doctors surgically removed the tumor and diagnosed him with glioblastoma. "I remember seeing him crying sometime after the surgery and I asked him why," Mrs. Kothmann said. "He told me, 'I'm just so happy. Life is wonderful.'" The Kothmanns have been married 26 years and have three adult children, including a daughter whose expertise as a nurse helped guide her father toward UT Southwestern where Dr. Pan signed him up for a clinical trial.He resumed his work as a math tutor at Tarrant County College, determined to continue life as normal. But he soon had to retire, the surgery and radiation treatments taking their toll on his concentration and short-term memory. Mr. Kothmann shows up every two weeks for immunotherapy infusions, hoping not only to beat the disease but eventually return to the job he loves. In the meantime, he offers a simple piece of advice to other newly diagnosed brain cancer patients: "Don't think about it," he said. "Think about getting well. You just go with what you've got and do the best you can."
Mayo M.J.,UT Southwestern
Clinics in Liver Disease | Year: 2013
Primary biliary cirrhosis and primary sclerosing cholangitis share some clinical features with autoimmune hepatitis, but when features of autoimmune hepatitis are present, prognosis can be affected and immunosuppressive treatment warranted. The presence of severe interface hepatitis in primary biliary cirrhosis portends a worse prognosis and should prompt evaluation for possible autoimmune hepatitis overlap and treatment with immunosuppression. Specific models to identify which subjects benefit most from the addition of immunosuppression need to be developed. Drug-induced liver injury and IgG4 disease may masquerade as autoimmune hepatitis or primary sclerosing cholangitis and are important to consider in the differential diagnosis of the overlap or variant syndromes. © 2013 Elsevier Inc.