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News Article | May 5, 2017
Site: www.scientificcomputing.com

A collaboration between stroke neurologists at the Medical University of South Carolina (MUSC) and bioengineers at the University of Massachusetts has led to the creation of a realistic, 3D-printed phantom of a stenotic intracranial artery that is being used to standardize protocols for high-resolution MRI, also known as vessel-wall MRI, at a network of U.S. and Chinese institutions, according to an article published online March 9, 2017 by the Journal of NeuroInterventional Surgery. High-resolution or vessel-wall MRI has been used to study the plaque components in vessels in the brain for more than ten years and has the potential to elucidate the underlying pathology of intracranial atherosclerotic disease (ICAD), the leading cause of stroke worldwide, as well as to gauge patient risk and inform clinical trials of new therapies. However, progress has been stymied by the lack of standardization in high-resolution MRI protocols, which poses an obstacle to multicenter trials. "There is a lot of exciting research that is possible with high-resolution MRI techniques, but it has much less opportunity to affect patient care if it can't be systematically distributed to multiple sites and multiple populations," says Tanya N. Turan, M.D., director of the MUSC Stroke Division and senior author of the article. To overcome this obstacle, Turan worked with bioengineers at the University of Massachusetts to produce a phantom of a stenotic intracranial vessel using imaging sequences obtained from a single patient with ICAD at MUSC. The 3-D printed ICAD phantom mimics both the stenotic vessel and its plaque components, including the fibrous cap and the lipid core. The phantom is being shared with collaborating institutions so that it can be used to standardize high-resolution MRI protocols. The imaging data presented in the Journal of NeuroInterventional Surgery article demonstrate the feasibility of using the phantom for standardization and were obtained from six U.S. and two Chinese sites. Producing the phantom was a major step in the right direction for standardizing high-resolution MRI ICAD protocols. However, several more years may be necessary to complete the process. The next major challenge for these investigators will be establishing parameters for MRI machines from a variety of manufacturers. So far, MRI parameters have been established for Siemens and GE systems but work is still under way on Philips systems. The phantom is also being shared with sites in China, where the burden of intracranial stenosis is especially high. Turan is collaborating with Weihai Xu, M.D., of Peking Union Medical College, the lead Chinese site, to collect additional data to assess interrater reliability among the participating institutions. Once high-resolution MRI protocols have been standardized and good interrater reliability demonstrated, the international team plans to conduct a prospective observational trial to examine risk prediction at participating centers, which would more quickly meet the required patient enrollment than would a trial conducted in the U.S. alone. "We're only going to be able to advance the field more quickly if we work together," says Turan. "The phantom gives us the tool to be able to work together."


News Article | May 5, 2017
Site: www.scientificcomputing.com

A collaboration between stroke neurologists at the Medical University of South Carolina (MUSC) and bioengineers at the University of Massachusetts has led to the creation of a realistic, 3D-printed phantom of a stenotic intracranial artery that is being used to standardize protocols for high-resolution MRI, also known as vessel-wall MRI, at a network of U.S. and Chinese institutions, according to an article published online March 9, 2017 by the Journal of NeuroInterventional Surgery. High-resolution or vessel-wall MRI has been used to study the plaque components in vessels in the brain for more than ten years and has the potential to elucidate the underlying pathology of intracranial atherosclerotic disease (ICAD), the leading cause of stroke worldwide, as well as to gauge patient risk and inform clinical trials of new therapies. However, progress has been stymied by the lack of standardization in high-resolution MRI protocols, which poses an obstacle to multicenter trials. "There is a lot of exciting research that is possible with high-resolution MRI techniques, but it has much less opportunity to affect patient care if it can't be systematically distributed to multiple sites and multiple populations," says Tanya N. Turan, M.D., director of the MUSC Stroke Division and senior author of the article. To overcome this obstacle, Turan worked with bioengineers at the University of Massachusetts to produce a phantom of a stenotic intracranial vessel using imaging sequences obtained from a single patient with ICAD at MUSC. The 3-D printed ICAD phantom mimics both the stenotic vessel and its plaque components, including the fibrous cap and the lipid core. The phantom is being shared with collaborating institutions so that it can be used to standardize high-resolution MRI protocols. The imaging data presented in the Journal of NeuroInterventional Surgery article demonstrate the feasibility of using the phantom for standardization and were obtained from six U.S. and two Chinese sites. Producing the phantom was a major step in the right direction for standardizing high-resolution MRI ICAD protocols. However, several more years may be necessary to complete the process. The next major challenge for these investigators will be establishing parameters for MRI machines from a variety of manufacturers. So far, MRI parameters have been established for Siemens and GE systems but work is still under way on Philips systems. The phantom is also being shared with sites in China, where the burden of intracranial stenosis is especially high. Turan is collaborating with Weihai Xu, M.D., of Peking Union Medical College, the lead Chinese site, to collect additional data to assess interrater reliability among the participating institutions. Once high-resolution MRI protocols have been standardized and good interrater reliability demonstrated, the international team plans to conduct a prospective observational trial to examine risk prediction at participating centers, which would more quickly meet the required patient enrollment than would a trial conducted in the U.S. alone. "We're only going to be able to advance the field more quickly if we work together," says Turan. "The phantom gives us the tool to be able to work together."


TEL-AVIV, Israel, April 20, 2017 (GLOBE NEWSWIRE) -- RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, today announced the publication of an article describing the positive results from the Phase I clinical study with YELIVA® (ABC294640)1 in advanced solid tumors. The article2, entitled “A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors”, was authored by scientists from the Medical University of South Carolina (MUSC) Hollings Cancer Center and Apogee Biotechnology and was published in Clinical Cancer Research. The article is available online on the journal’s website3. YELIVA® is a Phase II-stage, proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA® blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. The open-label, dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) first-in-human Phase I study with YELIVA® treated 21 patients with advanced solid tumors, most of whom were gastrointestinal cancer patients, including pancreatic, colorectal and cholangiocarcinoma cancers. The Phase I study was conducted at the MUSC Hollings Cancer Center and led by Principal Investigators Melanie Thomas, MD, and Carolyn Britten, MD. The primary objectives of the study were to identify the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) and to evaluate the safety of YELIVA®. The secondary objectives of the study were to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of YELIVA® and to assess its antitumor activity. Final results from the Phase I study with YELIVA® in patients with advanced solid tumors confirmed that the study successfully met its primary and secondary endpoints, demonstrating that the drug is well-tolerated and can be safely administered to cancer patients. There was one partial response in a patient with cholangiocarcinoma and six patients had stable disease as their best response. The study included the first-ever longitudinal analyses of plasma S1P levels as a potential PD biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA® resulted in a rapid and pronounced decrease in S1P levels over the first 12 hours, with return to baseline at 24 hours, which is consistent with clearance of the drug. A Phase II study with YELIVA® for the treatment of advanced hepatocellular carcinoma (HCC) is ongoing at MUSC Hollings Cancer Center. The study is supported by a grant from the NCI, awarded to MUSC, which is intended to fund a broad range of studies on the feasibility of targeting sphingolipid metabolism for the treatment of a variety of solid tumor cancers, with additional support from RedHill. A Phase Ib/II study with YELIVA® for the treatment of refractory or relapsed multiple myeloma is ongoing at Duke University Medical Center. The study is supported by a $2 million grant from the NCI Small Business Innovation Research Program (SBIR) awarded to Apogee, in conjunction with Duke University, with additional support from RedHill. A Phase I/II clinical study evaluating YELIVA® in patients with refractory/relapsed diffuse large B-cell lymphoma and Kaposi sarcoma patients is ongoing at the Louisiana State University Health Sciences Center. The study is supported by a grant from the NCI awarded to Apogee, with additional support from RedHill. A Phase Ib study to evaluate YELIVA® as a radioprotectant for prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the third quarter of 2017. YELIVA® recently received FDA Orphan Drug designation for the treatment of cholangiocarcinoma. RedHill plans to initiate a Phase IIa clinical study with YELIVA® in patients with advanced, unresectable, intrahepatic and extrahepatic cholangiocarcinoma in the third quarter of 2017. A Phase II study to evaluate the efficacy of YELIVA® in patients with moderate to severe ulcerative colitis is planned to be initiated in the second half of 2017. About YELIVA® (ABC294640): YELIVA® (ABC294640) is a Phase II-stage, proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities. RedHill is pursuing with YELIVA® multiple clinical programs in oncology, inflammatory and gastrointestinal indications. By inhibiting SK2, YELIVA® blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid-signaling molecule that promotes cancer growth and pathological inflammation. SK2 is an innovative molecular target for anticancer therapy because of its critical role in catalyzing the formation of S1P, which is known to regulate cell proliferation and activation of inflammatory pathways. YELIVA® was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI and radioprotection models, as well as the ABC-101 Phase I clinical study in cancer patients with advanced solid tumors. The Phase I study included the first-ever longitudinal analysis of plasma S1P levels as a potential pharmacodynamic (PD) biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA® resulted in a rapid and pronounced decrease in S1P levels, with several patients having prolonged stabilization of disease. YELIVA® received Orphan Drug designation from the U.S. FDA for the treatment of cholangiocarcinoma. The development of YELIVA® was funded to date primarily by grants and contracts from U.S. federal and state government agencies awarded to Apogee Biotechnology Corp., including the U.S. National Cancer Institute, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Defense and the FDA Office of Orphan Products Development. About RedHill Biopharma Ltd.: RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) is a specialty biopharmaceutical company headquartered in Israel, primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for the treatment of gastrointestinal and inflammatory diseases and cancer. RedHill has a U.S. co-promotion agreement with Concordia for Donnatal®, a prescription oral adjunctive drug used in the treatment of IBS and acute enterocolitis, as well as an exclusive license agreement with Entera Health for EnteraGam®, a medical food intended for the dietary management, under medical supervision, of chronic diarrhea and loose stools. RedHill’s clinical-stage pipeline includes: (i) RHB-105 - an oral combination therapy for the treatment of Helicobacter pylori infection with successful results from a first Phase III study; (ii) RHB-104 - an oral combination therapy for the treatment of Crohn's disease with an ongoing first Phase III study, a completed proof-of-concept Phase IIa study for multiple sclerosis and QIDP status for nontuberculous mycobacteria (NTM) infections; (iii) BEKINDA® (RHB-102) - a once-daily oral pill formulation of ondansetron with an ongoing Phase III study for acute gastroenteritis and gastritis and an ongoing Phase II study for IBS-D; (iv) RHB-106 - an encapsulated bowel preparation licensed to Salix Pharmaceuticals, Ltd.; (v) YELIVA® (ABC294640) - a Phase II-stage, orally-administered, first-in-class SK2 selective inhibitor targeting multiple oncology, inflammatory and gastrointestinal indications; (vi) MESUPRON - a Phase II-stage first-in-class, orally-administered protease inhibitor, targeting pancreatic cancer and other solid tumors and (vii) RIZAPORT® (RHB-103) - an oral thin film formulation of rizatriptan for acute migraines, with a U.S. NDA currently under discussion with the FDA and marketing authorization received in two EU member states under the European Decentralized Procedure (DCP). More information about the Company is available at: www.redhillbio.com. 1 YELIVA® is an investigational new drug, not available for commercial distribution. 2 The article was authored by Carolyn D. Britten, Melanie B. Thomas, Elizabeth Garrett-Mayer, Steven H. Chin, Keisuke Shirai, Besim Ogretmen, Tricia A. Bentz, Alan Brisendine, Kate Anderton, Susan L. Cusack, Lynn W. Maines, Yan Zhuang and Charles D. Smith. This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control, and cannot be predicted or quantified and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, preclinical studies, clinical trials, and other therapeutic candidate development efforts; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials; (iii) the extent and number of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates; (v) the Company’s ability to successfully market Donnatal® and EnteraGam®, (vi) the Company’s ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and of the results obtained with its therapeutic candidates in research, preclinical studies or clinical trials; (ix) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; and (xii) estimates of the Company’s expenses, future revenues capital requirements and the Company’s needs for additional financing; (xiii) competitive companies and technologies within the Company’s industry. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on February 23, 2017. All forward-looking statements included in this Press Release are made only as of the date of this Press Release. We assume no obligation to update any written or oral forward-looking statement unless required by law.


Language disturbances (aphasia) are common after stroke and can manifest as difficulty identifying the correct word to use (semantic problems) and/or difficulty pronouncing words (phonemic problems). Speech therapy has long been a standard of post-stroke care and can improve aphasia. However, the neurological basis of therapy-mediated recovery is poorly understood, and researchers do not know why some patients improve with therapy while others show little response. The ability of the residual language network to rebuild itself (a characteristic called structural plasticity) is directly related to how much benefit a patient receives from speech therapy, report investigators at the Medical University of South Carolina (MUSC) in an article published online June 19, 2017 by Annals of Neurology. Their study also supports the dual-stream language model, which holds that ventral brain networks are associated with semantic skills and dorsal networks with phonemic skills. "Producing speech is a two-step process - first selecting the correct word using semantic associations and, then, pronouncing it phonetically," explains lead author Emilie T. McKinnon, an M.D., PhD candidate in MUSC's Department of Neurology. "The current theory is that different parts of the brain house these two processes. If that's the case, these areas have to communicate with each other to produce language. So, the question is, when one of those regions is damaged, how is that connection restored? We looked at the microstructure of one of those connections to try to see what happens when language processing improves." The team tested eight aphasia patients, all of whom had had a single stroke at least one year prior that affected the ILF region. Participants were tested for confrontational naming ability one week before and one week after receiving a three-week course of intensive speech therapy. In addition, participants underwent four magnetic resonance imaging (MRI) sessions - two before speech therapy and two after. A novel aspect of the study was how the MRIs were conducted and assessed. The investigators leveraged recent advancements in diffusion-weighted imaging and image analysis, providing greater sensitivity to microstructural white matter changes and revealing previously hidden differences. "Diffusion-weighted imaging has been around a long time and it's useful for mapping and studying brain networks, but the commonly used analysis techniques can be improved upon," explains McKinnon. "We used diffusion kurtosis imaging and kurtosis-based tractography to calculate how water diffuses in the brain and identify areas of high resistance. Where water diffuses unimpeded, kurtosis is near zero. The more barriers it meets, the higher the kurtosis. So, it's a measure of how complex the environment is. We used this strategy because we could get so much more information and it only required adjusting the MRI settings and adding about five minutes of scanner time." The team focused in each patient on the ILF area with the lowest mean kurtosis (MK), indicating that this segment, the 'bottleneck', had the most damage. They found a significant correlation between pre- to post-therapy MK increases at the bottleneck (i.e., kurtosis values changing toward normal ranges in the most damaged area) and therapy-related semantic language improvements (r=-0.90, p Furthermore, when the research team applied more conventional measurement strategies, the results were not statistically significant -- suggesting that traditional methods may be less sensitive to the microstructural changes associated with recovery. "Emilie [McKinnon] comes from an engineering background, and so she was able to translate a sophisticated mathematical model into something that's clinically useful to help us better understand how the brain works," says Leonardo Bonilha, M.D., PhD, an associate professor of neurology at MUSC and senior author on the article. " She used improvements in MRI acquisition techniques and applied a complex mathematical calculation to the numbers that came out of the scanner to understand how the brain's structure had changed based on the diffusion of water in that area." The finding that kurtosis improvements are related to structural improvements is an important clue to how aphasia recovery occurs. "We saw that people got better because their brain network got structurally stronger," says Bonilha. "The residual connections got stronger in an area where semantic knowledge is integrated. Phonemics weren't related to these changes." McKinnon hopes that the findings will ultimately contribute to therapeutic decision-making. "The goal is to be able to look at an MRI and see where the patient's residual strength is," she says. "If we see that the ventral area is really weak, but the phonemics network is damaged beyond repair, we could recommend semantically oriented therapies." Additionally, this strategy may be useful in other conditions. For example, other brain functions such as motor control are also damaged by stroke. "The same microstructural changes would have to happen to recover use of a hand," says McKinnon. "So, you could look for the same results with post-stroke motor rehabilitation and, maybe, beyond stroke, in cases of neurodegeneration or brain damage, such as traumatic brain injury. If we can find a relationship between the network structure and function, then we could use this technique to assess recovery potential and progress." Conflict of interest: Coauthors Joseph A. Helpern, Ph.D., and Jen H. Jensen, Ph.D. are co-inventors on patents related to diffusional kurtosis imaging. Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


News Article | June 13, 2017
Site: www.eurekalert.org

A molecule that enables immune cells in the gut to distinguish between pathogens and normal microbes is essential to prevent colitis, report researchers at the Medical University of South Carolina in Scientific Reports A healthy gut requires a molecule called gp96 to train the immune system to tolerate food and normal microbes, report researchers at the Medical University of South Carolina (MUSC) in the May 19, 2017 issue of Scientific Reports. The study emphasizes the importance of gp96 in maintaining a balanced immune system in the gut. A healthy gut depends on a balance of inflammatory and tolerant T cells, which make up part of the adaptive immune system. In patients with colitis, inflammatory T cells in the lower intestines mistake the molecular structures of food or healthy gut bacteria for dangerous pathogens that must be destroyed. To determine how this happens, Bei Liu, M.D., associate professor in the MUSC Department of Microbiology and Immunology, considered the idea that these patients' adaptive immune systems might be poorly trained. T cells are trained by professional antigen-presenting cells (pAPCs) in the gut. pAPCs express toll-like receptors on their surfaces that recognize and trap molecular patterns called antigens on bacteria, food and our own cells. A pAPC that has trapped a specific antigen will travel to a lymph node and display that antigen to a naive, untrained T cell. The T cell then differentiates to a mature state and travels throughout the body to locate its antigen. Tolerogenic pAPCs train tolerant T cells to accept harmless antigens, while inflammatory pAPCs train inflammatory T cells to attack harmful antigens on microbes or molecules that may enter the gut. Liu and her team found that without gp96-a molecule inside most cells that helps Toll-like receptors and integrins fold and function properly-pAPCs in the gut were more inflammatory. First, the group generated a new genetic knockout mouse that did not carry gp96 in its pAPCs. Without gp96, pAPCs were less able to travel to lymph nodes, for which they need integrins, and less able to respond to bacterial antigens, for which they need functioning toll-like receptors. In fact, inflammatory pAPCs greatly outnumbered tolerant ones in the lymph nodes and the colon. Because pAPCs train T cells according to their kind, the shift in their cell type also caused a shift in the types of T cells that left the lymphatic system and traveled back to the gut. More inflammatory-type T cells and less tolerant-type T cells were found in the colon of mice without gp96 as compared to wild-type mice. This was good proof that gp96 is needed to maintain the proper balance of T cell populations, but Liu and her group wanted to connect that finding to a biological function relevant to humans. They examined oral tolerance, a state in which the immune system is trained to remain neutral to food and harmless bacteria. The loss of oral tolerance may be an early change in people who develop food allergies and inflammatory bowel disease. They fed chicken ovalbumin to wild-type and gp96 knockout mice. Through adoptive transfer, these mice then received donor T cells that had not been exposed to ovalbumin and therefore did not recognize it as a tolerable antigen. The idea was to see if those naive donor T cells would receive antigen-specific training from their pAPCs and then become tolerant to ovalbumin. Donor T cells adopted a tolerant state in wild-type mice, but not in gp96 knockout mice. Their pAPCs were unable to properly train their immune T cells to tolerate ovalbumin. Given this finding, it was likely that mice without gp96 would develop signs of inflammatory bowel disease as they grew, unable to adapt to a normal diet. As expected, gp96 knockout mice grew normally at first. At about 24 weeks, however, seventy percent of them developed spontaneous colitis, while none of the wild-type mice did. Mice without gp96 also had higher levels of gut immunoglobulin A, which is associated with chronic inflammation. This is the first study to describe the roles of the molecular chaperone gp96 in maintaining gut homeostasis. Although this study offered proof that gp96 is required to prevent colitis, further study is needed to connect the loss of gp96 to the development of colitis in human patients. Yet this ubiquitous molecule may have a fundamental responsibility to maintain proper immune balance in the gut. In fact, gp96 is tasked with folding a number of proteins that immune cells need to function. Next, Liu is building on these findings to determine if there are certain microbes in the gut that activate inflammatory disease or colon cancer in humans. "This study shines a light on the pathogenesis of inflammatory bowel disease and offers a positive impact on its future clinical management," says Liu. Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


Communicating via spoken language is a fundamental human capability that enables us to form connections with other people by sharing knowledge and emotions, working together and assessing our experiences. Thus, losing the ability to comprehend speech due to a stroke, traumatic brain injury or neurological disorder such as dementia, is particularly devastating. Auditory word comprehension is a complex cognitive process that requires the participation of multiple brain areas to transform initial auditory signals into meaningful abstract concepts. The first, and most basic, aspect of understanding spoken language is the auditory processing of speech sounds. However, many subsequent steps involving multi-layered, hierarchical brain networks are necessary to derive phonemes, syllables, words, syntax, meaning and context. Currently, our understanding of exactly which brain areas handle the various aspects of spoken language comprehension is incomplete. The prevailing theory is that neocortical regions adjacent to the auditory cortex are primarily responsible for word comprehension. However, recent studies in patients with primary progressive aphasia have challenged this concept and suggest that the left temporal pole may play a central role. To unravel these conflicting findings, a team of researchers, led by Leonardo Bonilha, M.D., Ph.D., associate professor in MUSC's Department of Neurology, in close collaboration with Julius Fridriksson, Ph.D., Professor of Communication Sciences and Disorders at the University of South Carolina's (USC) Arnold School of Public Health and the USC Aphasia Lab, developed a novel study methodology to identify the specific neural structures that, when damaged by stroke, are associated with impaired auditory word comprehension. "We need to better define what takes place in the brain when someone understands speech so we're better able to help those with aphasia who cannot do that anymore," explains Bonilha."Evidence indicates that areas associated with speech comprehension are in the posterior lateral temporal lobe and close to those responsible for hearing. What we need to define is how they are linked to other brain areas that process all the secondary associations that enable you to understand and connect meaning to the sounds you hear." Capitalizing on their recent work to optimize connectome mapping in individuals with post-stroke brain lesions, the team designed a study combining traditional voxel-based lesion symptom mapping (VLSM) with connectome-lesion symptom mapping (CLSM). CLSM, a new brain mapping method based on the concept of the human brain connectome, provides a three-dimensional map of all medium- and long-range white matter connections outside of the area damaged by the stroke. "Before CLSM, we primarily looked at the stroke lesion, the damaged area," explains Bonilha. "We focused on understanding what brain areas were gone and matched those to what function was gone. But, of course, brain functions don't depend exclusively on one area. Using the connectome, we can see the impact of the stroke beyond the lesion and begin to identify networks that the damage has disconnected beyond the stroke lesion. These areas might appear to be OK on MRI after the stroke, but, in fact, they are disconnected and do not receive the signals they need to function." The team reasoned that assessing white matter networks beyond the area of cortical necrosis may provide a more comprehensive assessment of brain damage, residual brain integrity and its impact on language processing. They recruited 67 people with chronic aphasia who had suffered a one-time ischemic stroke at least 6 months prior to the study. Each participant was assessed for word comprehension, aphasia and aphasia severity, as well as semantic processing. Magnetic resonance imaging (MRI) was conducted to facilitate VSLM and CSLM. The computational steps to measure the connectome from MRI were developed in collaboration with Chris Rorden, Ph.D., professor of neuroimaging and endowed chair in USC's Department of Psychology. VLSM and CLSM are complementary. "Both tools provide valuable information," says Bonilha. "The connectome tells us about areas outside the lesion that were highly connected to that region and where reduced connections post-stroke are affecting a particular function. But the connectome is not good for looking at areas inside the lesion to determine what functions happen there. That's where voxel-based methods are more useful." Study results supported the prevailing view that posterior lateral and inferior aspects of the temporal cortex are most critical for word comprehension. In addition, these areas may serve as a 'hub' that integrates the auditory and conceptual information necessary to recognize words. CLSM results also explained why other studies suggest that the temporal pole plays a role in word comprehension by revealing that the temporal pole is functionally and structurally connected to the middle temporal gyrus. The authors propose that, when the pole is disproportionally affected, an indirect knock-on effect may lead to a statistical association with poor word comprehension. This study provides a more comprehensive description of crucial neuronal networks involved in speech comprehension that may contribute to improved targeting of therapy for individuals with impaired auditory speech comprehension. Its findings demonstrate that temporal poles (in the anterior temporal lobe) are part of a broader network associated with semantic interpretation. However, when the effect of object recognition is factored out, only the core of that network (i.e., the middle and inferior temporal areas) is necessary for word comprehension. While the left temporal pole has an indirect role in word comprehension, the anterior temporal regions most likely play a central role in additional and deeper levels of semantic processing. The study's findings also indicate that the temporal pole is likely to be essential for recognizing objects -- an important early process for matching spoken words to pictures or objects. Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


News Article | May 8, 2017
Site: www.eurekalert.org

"Juicing" Th17 cells with FDA-approved small molecule β-catenin and p110δ inhibitors during in vitro expansion for adoptive T cell therapy (ACT) profoundly improves their therapeutic properties, report investigators at the Medical University of South Carolina (MUSC) in an article published online ahead of print on April 20, 2017 by JCI Insight. ACT involves harvesting T cells, rapidly amplifying and/or modifying them in the laboratory to boost their cancer-fighting ability, and then reinfusing them back to the patient to boost anticancer immunity. One challenge for ACT has been that the rapid expansion of T cells in the laboratory can cause them to age and wear out, decreasing their longevity after reinfusion. "Juicing" Th17 cells with the FDA-approved small molecules enhanced their potency, function and stem-like (less differentiated) quality, suggesting that they would persist better after reinfusion into patients, and also reduced regulatory T cells in the tumor microenvironment, which can blunt the immune response. These findings highlight novel investigative avenues for next-generation immunotherapies, including vaccines, checkpoint modulators, and ACT. "This is exciting because we might be able to overcome some of the delays and disadvantages of rapid expansion in the laboratory," explains senior author Chrystal M. Paulos, Ph.D., associate professor of immunology and Endowed Peng Chair of Dermatology at MUSC and a member of the MUSC Hollings Cancer Center. "We might be able to use fewer cells (for ACT) because we can pharmaceutically 'juice' these T cells to make them more fit in the oppressive tumor microenvironment." Building upon their previous findings that ICOS costimulation is critical for generating human TH17 cells and for enhancing their antitumor activity, an MUSC research team led by Paulos and including postdoctoral fellow Kinga Majchrzak report for the first time that repurposing FDA-approved small molecule drugs that inhibit two ICOS-induced pathways greatly enhances the antitumor potency of T cells. Several biologic properties of the Wnt/ β-catenin and P13Kδ pathways led the team to suspect that they supported the antitumor activities of Th17 cells. For example, these pathways are active in both regulating T cell cytokine production during the immune response and in promoting self-renewal of hematopoietic stem cells (HSCs) and sustaining HSCs in an undifferentiated state. So, they designed a series of experiments to determine whether these two pathways were also active in enhancing Th17 antitumor memory and effectiveness. To test this idea, they pharmaceutically inhibited PI3Kδ and β-catenin in Th17 cells (using idelalisib [CAL-101] to block the PI3Kδ pathway and indomethacin [Indo] to inhibit β-catenin)-anticipating that this would weaken Th17 cells' antitumor activity. To their surprise, the exact opposite occurred. ICOS-stimulated Th17 cells that were treated in vitro with CAL-101 plus Indo elicited a more potent antitumor response against melanoma in mice. "My post-doc student came to me and said, 'I think I made a mistake because the data are going in the opposite direction to what we originally predicted!" says Paulos. "So, she repeated the experiment several times but we kept getting the same result. The data showed that using drugs to inhibit these pathways actually made the Th17 cells even better at killing tumors." The team found that Th17 cells treated with CAL-101 express less FoxP3, suggesting that the drug suppresses Treg conversion while sustaining central memory-like Th17 cells. This finding is highly important because the phenotypic plasticity of Th17 cells in vivo allows their conversion to Tregs or Th1 cells with weak antitumor properties. These data suggest that treatment with CAL-101 can halt the development of these poorly therapeutic phenotypes and, thus, enhance the T cells' antitumor activity. While the findings were initially counterintuitive and perplexing from a mechanistic perspective, in retrospect Paulos sees that they make sense. "Essentially, the T cells are younger," explains Paulos. "We know that T cells used for ACT age and wear out over time. Somehow these drugs sustain their youth and function. They're able to keep all the properties of their youth-they expand better and they're more functional and handle the oppressive tumor microenvironment better." The discovery that existing FDA-approved drugs that block p110δ and β-catenin can make T cells more efficient tumor killers in vivo is an exciting prospect for Paulos' team. "From a clinical standpoint, this finding indicates that the therapeutic effectiveness of ACT could be improved by simple treatments with readily available drugs. It opens a lot of new investigative avenues for next-generation immunotherapy trials," she says. "This research offers tremendous promise for the treatment of patients with serious forms of skin cancer," says Dirk M. Elston, M.D., chair of the Department of Dermatology and Dermatologic Surgery at MUSC. Paulos has a patent on ICOS signaling in adoptive T cell transfer therapy (US 9133436), and Paulos, Majchrzak, and J.S. Bowers have a patent on pharmaceutical drug combinations or genetic strategies that instill durable antitumor T cell memory and activity (patent application P1685). Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org. The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 120 faculty cancer scientists with an annual research funding portfolio of $44 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.


News Article | May 8, 2017
Site: www.eurekalert.org

No words can describe how happy Quanita Estell is to hear her six-year-old son come home with hilarious stories to tell. First, she enjoys his sense of humor, but mostly she's thrilled to see Joseph, who was diagnosed with autism spectrum disorder at 2, is becoming better able to communicate. It's been a long journey involving extensive treatment. But it's paid off. Now she gets to hear all about his adventures learning to surf in a program that helps children who have autism. Water and music seem to work wonders for him, but she knows they still have a tough road ahead. It's one reason she plans to enroll in a new nationwide genetic study to track down clues to the causes of autism with the goal of potentially developing new treatments. The study opens April 1 at the Medical University of South Carolina. "We try to get involved with anything that can help them," she says of a disorder that affects an estimated one out of 68 children. The prevalence of autism has increased significantly over the past two decades, and while some think that it may be leveling off, MUSC autism researcher Laura Carpenter, Ph.D., says the verdict's still out. What she does know is a lot has been spent researching a disorder where few treatments have been developed. Carpenter says she sees that potentially changing thanks to such studies as SC SPARK or Simons Foundation Powering Autism Research for Knowledge, which has launched a nationwide genetic study with the ambitious goal of enrolling 50,000 families to allow scientists to better understand the genetic changes that contribute to autism. MUSC is the South Carolina clinical partner for SPARK and will be serving the entire state. Anyone of any age on the autism spectrum, including Asperger's syndrome and PDD-NOS or pervasive developmental disorder/not otherwise specified, is eligible to join. Researchers also want parents and siblings to be a part of the study, which involves providing medical history and saliva samples. Individuals who enroll with parents' participation will receive compensation. There are more than 20 clinical sites nationwide participating. Participants who enroll get access to the SPARK resources online, which include webinars featuring national experts. "It's a real honor to be chosen," Carpenter says. "Many of the other clinical sites also selected are some of the leaders in autism research. This will open a lot of opportunities for MUSC to partner with other leaders in autism research." It's those partnerships that can lead to change. The majority of the money for research in autism has gone towards trying to figure out the genetic factors that lead to autism, and what researchers have found is that there are likely hundreds of genes that play a role, and to complicate matters, there are also likely environmental factors contributing to the development of the condition. "Now some experts are starting to talk about the 'autisms,' instead of autism -- meaning there are multiple pathways to developing autism. We think epigenetics plays a really big role, meaning that the environment probably influences which genes are active and which genes are ultimately implicated in autism. And we think it's probably a complex combination of genes and environment that lead to autism. What we know is that there are multiple genetic disorders that are associated with higher incidence of autism, but there is no one genetic change that results in autism. It's much more complicated than we had originally thought." What also has become clear is that researchers need a much larger sample size than anyone ever dreamed about. That's what SPARK is all about, she says. To put it in perspective, she considers a typical large, local study one that enrolls about 300 participants. The state's goal as part of the 50,000 being sought for recruitment is enrolling 1,000 participants, she says. "So, it's just a scale that has never been done before, and I think this is what is needed in order to move the field forward." The more representative the sample of participants, the better the research. That's why Carpenter wants to get the word out statewide. People can enroll at various community events, by coming to MUSC, and even asking for a home visit. Participants also can enroll online in the comfort and privacy of their own homes. "The state brings something really unique to the network in that we have a really diverse population. I think we have the potential to partner with people who don't necessarily participate in research very often. In order to get answers about a disorder that's so diverse, you really need to have everybody participate so that you have a representative sample," she says. "We will be holding their hand throughout the participation process. In order for the data to be most useful to the doctors and scientists, we really need people with autism, both their biological parents, and any siblings who are willing to participate." MUSC is committed to advancing treatments and care to improve the quality of life for those on the spectrum, she says. This initiative adds to many ongoing projects at MUSC, including: Carpenter is lead researcher on the CATS study and preliminary findings are showing that too many young adults on the autism spectrum are failing to thrive. "One of the things we know about autism is that if you intervene early, intensively with behavioral interventions, we can change the trajectory so that some kids will have really outstanding outcomes. So autism is treatable. But we also know that about 50 percent of kids will continue to have significant impairments, even if they get the best early intensive intervention - even the Cadillac of care, the best quality, the highest intensity - at least 50 percent of them will still need a lot of services after that. That tells us that we still need to develop other treatments." There's another advantage to SC SPARK that shows just how innovative a research project it is. It's a stepping stone to personalized medicine, she says. Should a treatment be developed for a certain genetic sample, for example, those participants who match the profile can be notified in case they want to take advantage of any treatment that has been shown to be potentially effective. The genetic analysis identifies people who carry known genes with autism links. According to SPARK, an estimated 5 to 10 percent of families are expected to receive genetic results in the first analysis. The genetic information gets re-analyzed every year, and as new autism genes are identified, additional genetic results will be returned. A genetic diagnosis is important because it can help in diagnosis and eliminate the need for additional testing, enable families to better understand the recurrence risk, identify opportunities to network with similar participants and be a pipeline to learn about clinical trials and/or treatments specific to their diagnoses. It also takes research to a new level and will enable autism studies of all types to get off the ground more quickly, something that's really needed, says Carpenter. MUSC is rolling this out in April, which is Autism Awareness month. April 2 marks an international celebration of Light it Up Blue, a day dedicated to raising awareness about the disorder. It's a good time to launch enrollment, she says. "This study is amazing and totally groundbreaking. Not only are we going to get this huge cohort of people and genetic information for this effort, but now these groups of SPARK participants are going to be notified when new ideas come on board. They'll be ready to go. One of the ideas is that autism may eventually be something that is treated with a more precision approach and, if that is the case and you have this really big sample of people, you might be able to pick out the ones you think will respond better for one treatment versus others."


Primary colorectal tumors secrete VEGF-A, inducing CXCL1 and CXCR2-positive myeloid-derived suppressor cell (MDSC) recruitment at distant sites and establishing niches for future metastases, report Medical University of South Carolina (MUSC) investigators in an article published online ahead of print on April 28, 2017 by Cancer Research. Liver-infiltrating MDSCs help bypass immune responses and facilitate tumor cell survival in the new location. This research illuminates mechanisms by which primary tumors contribute to premetastatic niche formation and suggests CXCR2 antagonists may reduce metastasis. Recent cancer research shows that premetastatic 'niches' form at sites far from the original tumor before new tumors occur. In colorectal cancer (CRC), these supportive microenvironments form in preferred secondary organs, such as the liver and lung, and facilitate the colonization, survival, and growth of metastasizing tumor cells. However, the mechanisms responsible for the formation of these premetastatic 'niches,' including what role(s) the primary tumor may play, are not well understood. It is critical to better understand the mechanics of CRC metastasis, as it is the second leading cause of cancer deaths in the US and patients with advanced cases often die because current treatments for widely metastasized disease are not effective. MUSC investigators led by Raymond N. DuBois, M.D., Ph.D., dean of the MUSC College of Medicine and professor of Biochemistry and Molecular Biology, have now illuminated how primary CRC tumors contribute to premetastatic 'niche' formation. "The idea that some sort of 'priming' needs to take place for metastasis to occur in distant organs - that there is some sort of activity in the future tumor location - is not new. But most research has focused on growth factors, chemokines and pro-inflammatory cytokines. There hasn't been much work looking at immune cell activity in distant organs prior to metastasis," explains DuBois. "We knew that the type and density of immune cells in the primary tumor plays a role in progression. For example, when more immature myeloid cells are present in the tumor, it becomes resistant to immune attack. But we didn't know what to expect in a metastatic model." To explore this area, the team first evaluated whether the presence of a primary tumor affected immune cell profiles in premetastatic liver and lung tissues of mice. They found that the presence of a primary cecal tumor caused MDSCs to begin infiltrating the liver before metastasis began. Working backward from this finding, they used a series of experiments to reveal the chain of events that led up to MDSC infiltration. Because CXCR2 is essential for drawing MDSCs out of the bloodstream and toward CRC tumors and colonic mucosa, the team began looking for CXCR2 and its ligands (CXCL1, CXCL2, and CXCL5) in mouse liver tissue. The team not only found that the ligand, CXCL1, attracted MDSCs from the bloodstream into premetastatic liver tissue, but also that administering a CXCR2 antagonist inhibited CXCL1 chemotaxis. This demonstrated that CXCR2 is required for CXCL1 to induce MDSC liver infiltration. In other words, the CXCL1-CXCR2 axis is required to recruit MDSCs to the liver. Importantly, they also found that liver- infiltrating MDSCs secrete factors that promote cancer cell survival and metastatic tumor formation without invoking the innate and adaptive immune responses. Next, because VEGF is known to induce CXCL1 expression in lung cancer, the research team examined whether VEGF secreted by CRC tumors also regulated CXCL1 expression. Their results demonstrated that VEGF-A secretion by primary CRC tumor cells stimulates macrophages to produce CXCL1. Interestingly, although VEGF-A knockdown inhibited liver metastasis, it did not affect the growth of the primary tumor. "We did not expect to find that a primary tumor could affect a distant organ before any of the cancer cells arrived on site," says DuBois. "We were surprised to see these changes before a single metastatic cell took up residence." Together, these studies reveal that VEGF-A secreted by the primary CRC tumor stimulates macrophages to produce CXCR1, which recruits CXCR2-expressing MDSCs from the bloodstream into healthy liver tissue. The MDSCs then create a premetastatic 'niche' or micro-environment where cancer cells can grow to form new tumors. These results demonstrate for the first time that cells in the primary tumor contribute to forming distant pre-metastatic 'niches' which facilitate the spread of disease. "Now that we know the primary tumor puts things in motion remotely prior to metastasis, we should be able to inhibit this process and have a positive impact on survival," explains DuBois. "We now know which molecules and immune cells are involved and that if we disrupt the CXCL1-CXCR2 axis we can possibly reduce the spread of disease. Both antibodies and small molecules can inhibit this pathway, but they have not yet been optimized. I hope these findings will speed up the development of inhibitors of the CXCR2 pathway." Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


News Article | September 27, 2017
Site: www.eurekalert.org

Why do some drug users continue to seek out drugs despite the prospect of losing family, friends, health or livelihood? There are notable features -- cues -- of the early drug-using environment that often develop into persistent and powerful triggers for relapse. Epigenetic factors -- enzymes in the brain that alter the packaging and accessibility of genes without changing the genes themselves -- influence this process, according to research at the Medical University of South Carolina (MUSC) appearing online on September 27, 2017 in Neuron. A major challenge in addiction science is to understand how transient experiences lead to long-lasting risk for relapse in users who try to quit, according to MUSC professor Christopher W. Cowan, Ph.D., William E. Murray SmartState® Endowed Chair in Neuroscience, and senior researcher on the project. "Our goal was to discover the brain mechanisms responsible for the rewarding effects of the drug and the motivation to seek it even after long periods of abstinence," says Cowan. The brains of drug users who have progressed to addiction differ markedly from those of early or casual users. Long-lasting associations form between the early use of a drug and different aspects of the early drug-using environment, such as the location in which a drug was first taken or the emotions a user was experiencing at the time. This can cause addicted users who have quit to experience cravings when in a similar setting. Understanding these connections could lead to better treatments for addiction. Cowan's challenge was to determine which genes were activated in the early drug-using environment. Cowan and his fellow researchers had previously found that the epigenetic enzyme histone deacetylase 5 (HDAC5) slows the rodent brain from forming associations between cocaine and simple cues in the environment, such as light and sound. HDAC5 is found in high amounts in neurons in the nucleus accumbens, part of the reward center of the brain that reacts strongly to cocaine, opioids and alcohol -- both in rodents and humans. When HDACs are in the nucleus of neurons, they change the way genomic DNA is packaged in the cell nucleus and often block the ability of certain genes to be turned on. In the new study, rodents were trained to press a lever to receive a dose of cocaine. Each time they received a dose, a lamp went on above the lever and a brief sound was generated. These served as simple environmental cues for drug use. Next, some rodents were given a form of HDAC5 that traveled straight to the nuclei of neurons. Those rodents still pressed the lever just as many times to receive drug, meaning that HDAC5, on its own, was likely not blocking genes that promoted early drug-seeking behavior. Yet the next experiment proved that HDAC5 reduced drug-seeking behavior during abstinence. To simulate withdrawal and abstinence, rodents were given rest without cocaine for one week, followed by a period during which they had access to the lever again. To simulate relapse, the rodents were shown the environmental cues again, this time without having pressed the lever. The presentation of the cues triggered robust lever pressing, indicating drug seeking, in control animals, proving that the associations between drug and environment persisted in their brains. In contrast, animals who had the nuclear form of HDAC5 did not press the lever nearly as often, even after the experimenters gave the animals a small priming dose of cocaine, which often produces strong drug-seeking behaviors. HDAC5, the gene suppressor, did not prevent addiction-like behaviors from forming, but it did prevent later drug seeking and relapse during abstinence -- at least in rodents. The researchers next used a cutting-edge technique that encourages epigenetic enzymes to bind to DNA, allowing them to identify all the genes inhibited by HDAC5. The gene for NPAS4 was a top hit, and significant for an important reason: it is an early-onset gene, meaning that its effects could be exerted on the brain rapidly unless HDAC5 was there to inhibit it -- just the molecular event Cowan and his team were seeking. In similar experiments, animals with less NPAS4 in the nucleus accumbens took more time to form those early connections between environmental cues and cocaine, but they still sought the drug just as often during later simulated relapse. Apparently, NPAS4 accounts for some addiction-related learning and memory processes in the brain, but not all of them, meaning that HDAC5 must be regulating additional genes that reduce relapse events. Cowan thinks uncovering additional downstream genes could help researchers untangle the details of how the brain transitions from early drug use to addiction, and how new treatments might be developed to reduce relapse in individuals suffering from substance use disorders. Animals in the research setting may not mimic the full complexity of human addiction. However, abstinent patients report cravings when given reminders of their drug-associated environment or cues, and animals and humans share similar enzyme pathways and brain structures. Perhaps most exciting for addiction research is that these processes may be similar in the transition to cocaine, alcohol and opioid addictions. "We might have tapped into a mechanism with relevance to multiple substance use disorders," says Cowan. Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents in six colleges (Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing, and Pharmacy), and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion, with an annual economic impact of more than $3.8 billion and annual research funding in excess of $250 million. MUSC operates a 700-bed medical center, which includes a nationally recognized children's hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute-designated center), Level I trauma center, Institute of Psychiatry, and the state's only transplant center. In 2016, U.S. News & World Report named MUSC Health the number one hospital in South Carolina. For more information on academic programs or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.

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