Medical Scientist Training Program

Allenstown Elementary School, United States

Medical Scientist Training Program

Allenstown Elementary School, United States
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News Article | April 12, 2017
Site: www.cemag.us

Northwestern Medicine scientists have developed a novel testing platform to assess, in real time, the efficacy of nanomaterials in regulating gene expression. The findings, published in Proceedings of the National Academy of Sciences, could help to facilitate preclinical investigations and optimize nanotherapeutics for cancers before they reach clinical trials. Timothy Sita, a seventh-year MD/PhD student in the Medical Scientist Training Program, was the first author of the study, which looked at the platform in animal models. “This is an important step forward for the field,” said principal investigator Alexander Stegh, PhD, assistant professor of Neurology and of Medicine. “The very thorough optimization that we see in conventional drug development had been missing in the nanotech space, and we felt very strongly about changing this. The system that we developed here really allows us to support those efforts, and evaluate our nanoparticles in the most relevant models, in an in vivo setting.” Chad Mirkin, PhD, the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences and a professor of Medicine in the Division of Hematology/Oncology, was also a corresponding author of the paper. The scientists demonstrated the concept while using nanostructures called spherical nucleic acids (SNAs) to target a resistance factor gene in glioblastoma, an aggressive, incurable type of brain tumor. SNAs, first developed by Mirkin at Northwestern in 1996, consist of dense strands of RNA packed around a nanoparticle core. Because of their unique properties, SNAs are capable of both crossing the blood-brain barrier and entering into tumor cells, where they can directly target gene activity that encourages cancer growth. While these conjugates are a promising tool in the era of precision medicine, scientists previously lacked a quantitative method to assess how SNAs regulated gene activity in living organisms, which would provide new insights into how to optimize the therapies. “We’ve seen that these particles can basically target any cancer gene, but we didn’t know when they worked best or what dosing regimens to use,” Sita says. “As such, preclinical trials weren’t as successful as they could have been.” In the current study, the scientists showed that by using a type of non-invasive imaging on the mice, they could gauge in real time how the nanoparticles affected levels of an intratumoral target protein. “Now we can tweak these particles — play with the shape of the nanoparticle, or how much RNA we load onto the particle, for example — and then assess very quickly whether those changes are more effective or not,” Sita explains. “It’s a platform to help optimize the drugs in mice before they go to human trials, and make something that will translate better to the clinic.” While the method could be generalizable to investigating nanotherapeutics for many types of cancers, the study also has clinical implications unique to glioblastoma. The scientists developed nanoparticles to knock down O6-methylguanine-DNA methyltransferase (MGMT) — a protein which reduces the impact of chemotherapy — in mice with glioblastoma. Through the imaging platform, they discovered that mice had the lowest levels of the protein between 24 to 48 hours after receiving the nanoparticles, suggesting the optimal time to administer chemotherapy. “We showed a very significant reduction in tumor volume when we combined these particles with the chemotherapy,” Sita says. “By silencing this gene that’s causing resistance to the chemotherapy, we can have a much more profound response. That’s the key clinical angle.” Sita, who will be graduating in May, recently matched into a radiation oncology residency at the McGaw Medical Center of Northwestern University, where he intends to continue his research into glioblastoma therapies. Jasmine May, a fifth-year student in the Medical Scientist Training Program, was also a co-author of paper, along with Charles David James, PhD, professor of Neurological Surgery and of Biochemistry and Molecular Genetics, and other Northwestern scientists. Mirkin, Stegh, and James are also members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. This research was supported by the Center for Cancer Nanotechnology Excellence initiative of the National Institutes of Health (NIH) under Award U54 CA151880, National Institute of Arthritis and Musculoskeletal and Skin Diseases Award R01AR060810, Defense Advanced Research Projects Agency Grant HR0011-13-2-0018, the John McNicholas Foundation and the American Cancer Society, National Cancer Institute (NCI)/NIH National Research Service Award Fellowship F30CA174058-01, a Ryan Fellowship, a National Science Foundation graduate research fellowship and a P.E.O. scholar award, the Northwestern University Flow Cytometry Facility, Northwestern University Center for Advanced Microscopy, and Cancer Center Support Grant NCI CA060553.


News Article | April 26, 2017
Site: www.rdmag.com

A new type of microscope, capable of illuminating living cell structures in clear detail, could provide insight into autoimmune diseases and lead to new treatment options. Researchers from the University of Colorado Anschutz Medical Campus believe this new tool— a custom Stimulated Emission Depletion (STED) microscope—could set the stage for future treatment discoveries and visualize antibodies that cause the rare autoimmune disorder neuromyelitis optica, which can result in paralysis and blindness. The researchers used the microscope to actually see the clusters of antibodies atop astrocytes—the brain cell target of the autoimmune response in the disease. “By applying this novel approach we can see firsthand how these antibodies work,” the study's lead author, John Soltys, a current student in the Medical Scientist Training Program at CU Anschutz, said in a statement. “We are looking at the initiation of autoimmune injury in this disease.” Dr. Jeffrey Bennett, Ph.D., the senior author of the study and the associate director of Translational Research at the Center for NeuroScience at CU Anschutz, explained that the microscope allows researchers to view the early stages of various diseases as they form. “We discovered that we could see the natural clustering of antibodies on the surface of target cells,” Bennett said in a statement. “This could potentially correspond with their ability to damage the cells. “We know that once antibody binds to the surface of the astrocyte, we are witnessing the first steps in the disease process,” he added. According to Bennett, the ability to see the antibodies on the brain cells offers researchers an opportunity to develop targeted therapies that do not suppress the body’s immune system like some current treatments for the disease do. The STED microscope—which was built by CU Anschutz physicist Stephanie Meyer, Ph.D.—uses lasers to achieve a higher level of precision and clarity. Lower resolution microscopes are blurry because of the diffraction of light. However, the lasers illuminate a smaller area to acquire a higher resolution image than traditional microscopes. The STED microscope can also highlight entire living cells at extremely high resolution, unlike electron microscopes. “This would have been impossible to see with any kind of normal microscope,” professor Diego Restrepo, Ph.D., director of the Center for NeuroScience and study co-author, said in a statement. “We are inviting other scientists with research projects on campus to use the STED microscope.” The study was published in Biophysical Journal.


News Article | April 26, 2017
Site: www.eurekalert.org

AURORA, Colo. (April 26, 2017) - Using a unique microscope capable of illuminating living cell structures in great detail, researchers at the University of Colorado Anschutz Medical Campus have found clues into how a destructive autoimmune disease works, setting the stage for more discoveries in the future. The scientists were trying to visualize antibodies that cause neuromyelitis optica (NMO), a rare autoimmune disorder that results in paralysis and blindness. Using a custom STED (Stimulated Emission Depletion) microscope built at CU Anschutz, they were able to actually see clusters of antibodies atop astrocytes, the brain cell target of the autoimmune response in NMO. "We discovered that we could see the natural clustering of antibodies on the surface of target cells. This could potentially correspond with their ability to damage the cells," said Professor Jeffrey Bennett, MD, PhD, senior author of the study and associate director of Translational Research at the Center for NeuroScience at CU Anschutz. "We know that once antibody binds to the surface of the astrocyte, we are witnessing the first steps in the disease process." When that domino effect begins, it's hard to stop. But Bennett said the ability to see the antibodies on the brain cells offers a chance to develop targeted therapies that do not suppress the body's immune system like current treatments for the disease do. "By applying this novel approach we can see firsthand how these antibodies work," said the study's lead author, John Soltys, a current student in the Medical Scientist Training Program at CU Anschutz. "We are looking at the initiation of autoimmune injury in this disease." The breakthrough was made possible with the STED microscope, a complex instrument that uses lasers to achieve extreme precision and clarity. It was built by physicist Stephanie Meyer, PhD, at CU Anschutz. This is the first time it has been used in a research project here. "This would have been impossible to see with any kind of normal microscope," said study co-author Professor Diego Restrepo, PhD, director of the Center for NeuroScience. "We are inviting other scientists with research projects on campus to use the STED microscope." According to Meyer, lower resolution microscopes are blurrier than the STED due to diffraction of light. But the STED's lasers illuminate a smaller area to acquire a higher resolution image. Unlike electron microscopes, STED users can see entire living cells at extremely high resolution, as they did in this study. Restrepo said there are only a handful of STEDs in the nation and just one in Colorado. The researchers said the discovery is the result of a unique partnership between clinical neurology, immunology and neuroscience coming together to solve a fundamental question of how antibodies can initiate targeted injury in an autoimmune disease. "These are the building blocks that we can use to carry our research to the next level," Bennett said. The study was published this week in Biophysical Journal.


News Article | May 12, 2017
Site: www.biosciencetechnology.com

When a group of researchers in the Undiagnosed Disease Network at Baylor College of Medicine realized they were spending days combing through databases searching for information regarding gene variants, they decided to do something about it. By creating MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) they are now able to help not only their own lab but also researchers everywhere search databases all at once and in a matter of minutes. This collaborative effort among Baylor, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Harvard Medical School is described in the latest online edition of the American Journal of Human Genetics. "One big problem we have is that tens of thousands of human genome variants and phenotypes are spread throughout a number of databases, each one with their own organization and nomenclature that aren't easily accessible," said Julia Wang, an M.D./Ph.D. candidate in the Medical Scientist Training Program at Baylor and a McNair Student Scholar in the Bellen lab, as well as first author on the publication. "MARRVEL is a way to assess the large volume of data, providing a concise summary of the most relevant information in a rapid user-friendly format." MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER, all separate databases to which researchers across the globe have contributed, sharing tens of thousands of human genome variants and phenotypes. Since there is not a set standard for recording this type of information, each one has a different approach and searching each database can yield results organized in different ways. Similarly, decades of research in various model organisms, from mouse to yeast, are also stored in their own individual databases with different sets of standards. Dr. Zhandong Liu, assistant professor in pediatrics - neurology at Baylor, a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's and co-corresponding author on the publication, explains that MARRVEL acts similar to an internet search engine. "This program helps to collate the information in a common language, drawing parallels and putting it together on one single page. Our program curates model organism specific databases to concurrently display a concise summary of the data," Liu said. A user can first search for a gene or variant, Wang explains. Results may include what is known about this gene overall, whether or not that gene is associated with a disease, whether it is highly occurring in the general population and how it is affected by certain mutations. "MARRVEL helps to facilitate analysis of human genes and variants by cross-disciplinary integration of 18 million records so we can speed up the discovery process through computation," Liu said. "All this information is basically inaccessible unless researchers can access it efficiently and apply it to their own work to find causes, treatments and hopefully identify new diseases." This project started as a necessity for the Model Organism Screening Center for the Undiagnosed Disease Network at Baylor, but as it grew, the group began reaching out to researchers in different disciplines for feedback on how MARRVEL might benefit them. "This program is just the start. I think our tool is going to be a model for us to help clinicians and basic scientists more efficiently use the information already publicly available," Wang said. "It will help us understand and process all of the different mutations that researchers are discovering." "The most exciting part is how this project is bringing so many different researchers together," Liu said. "We are working with labs we might not have normally collaborated with, trying to put together a puzzle of all this data." Both Wang and Liu are thankful to the contributions from the genetics communities allowing them access to the databases as they developed MARRVEL. Others who contributed to the findings include Drs. Rami Al-Ouran, Seon-Young Kim, Ying-Wooi Wan, Michael Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, and Hugo Bellen (Howard Hughes Medical Institute at Baylor) all with Baylor College of Medicine; Yanhui Hu, Aram Comjean, Stephanie E. Mohr, and Norbert Perrimon (Howard Hughes Medical Institute at Harvard Medical School) all with Harvard Medical School. For full funding and acknowledgements please see full publication (available after embargo lifts)


News Article | May 11, 2017
Site: www.eurekalert.org

HOUSTON - (May 11, 2017) - When a group of researchers in the Undiagnosed Disease Network at Baylor College of Medicine realized they were spending days combing through databases searching for information regarding gene variants, they decided to do something about it. By creating MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) they are now able to help not only their own lab but also researchers everywhere search databases all at once and in a matter of minutes. This collaborative effort among Baylor, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Harvard Medical School is described in the latest online edition of the American Journal of Human Genetics. "One big problem we have is that tens of thousands of human genome variants and phenotypes are spread throughout a number of databases, each one with their own organization and nomenclature that aren't easily accessible," said Julia Wang, an M.D./Ph.D. candidate in the Medical Scientist Training Program at Baylor and a McNair Student Scholar in the Bellen lab, as well as first author on the publication. "MARRVEL is a way to assess the large volume of data, providing a concise summary of the most relevant information in a rapid user-friendly format." MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER, all separate databases to which researchers across the globe have contributed, sharing tens of thousands of human genome variants and phenotypes. Since there is not a set standard for recording this type of information, each one has a different approach and searching each database can yield results organized in different ways. Similarly, decades of research in various model organisms, from mouse to yeast, are also stored in their own individual databases with different sets of standards. Dr. Zhandong Liu, assistant professor in pediatrics - neurology at Baylor, a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's and co-corresponding author on the publication, explains that MARRVEL acts similar to an internet search engine. "This program helps to collate the information in a common language, drawing parallels and putting it together on one single page. Our program curates model organism specific databases to concurrently display a concise summary of the data," Liu said. A user can first search for a gene or variant, Wang explains. Results may include what is known about this gene overall, whether or not that gene is associated with a disease, whether it is highly occurring in the general population and how it is affected by certain mutations. "MARRVEL helps to facilitate analysis of human genes and variants by cross-disciplinary integration of 18 million records so we can speed up the discovery process through computation," Liu said. "All this information is basically inaccessible unless researchers can access it efficiently and apply it to their own work to find causes, treatments and hopefully identify new diseases." This project started as a necessity for the Model Organism Screening Center for the Undiagnosed Disease Network at Baylor, but as it grew, the group began reaching out to researchers in different disciplines for feedback on how MARRVEL might benefit them. "This program is just the start. I think our tool is going to be a model for us to help clinicians and basic scientists more efficiently use the information already publicly available," Wang said. "It will help us understand and process all of the different mutations that researchers are discovering." "The most exciting part is how this project is bringing so many different researchers together," Liu said. "We are working with labs we might not have normally collaborated with, trying to put together a puzzle of all this data." Both Wang and Liu are thankful to the contributions from the genetics communities allowing them access to the databases as they developed MARRVEL. Others who contributed to the findings include Drs. Rami Al-Ouran, Seon-Young Kim, Ying-Wooi Wan, Michael Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, and Hugo Bellen (Howard Hughes Medical Institute at Baylor) all with Baylor College of Medicine; Yanhui Hu, Aram Comjean, Stephanie E. Mohr, and Norbert Perrimon (Howard Hughes Medical Institute at Harvard Medical School) all with Harvard Medical School. For full funding and acknowledgements please see full publication (available after embargo lifts) Both Wang and Liu are thankful to the contributions from the genetics communities allowing them access to the databases as they developed MARRVEL. Others who contributed to the findings include Drs. Rami Al-Ouran, Seon-Young Kim, Ying-Wooi Wan, Michael Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, and Hugo Bellen (Howard Hughes Medical Institute at Baylor) all with Baylor College of Medicine; Yanhui Hu, Aram Comjean, Stephanie E. Mohr, and Norbert Perrimon (Howard Hughes Medical Institute at Harvard Medical School) all with Harvard Medical School. For full funding and acknowledgements please see full publication (available after embargo lifts)


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

Brain-computer interface advance allows fast, accurate typing by people with paralysis in Stanford-led study A clinical research publication led by Stanford University investigators has demonstrated that a brain-to-computer hookup can enable people with paralysis to type via direct brain control at the highest speeds and accuracy levels reported to date. The report involved three study participants with severe limb weakness -- two from amyotrophic lateral sclerosis, also called Lou Gehrig's disease, and one from a spinal cord injury. They each had one or two baby-aspirin-sized electrode arrays placed in their brains to record signals from the motor cortex, a region controlling muscle movement. These signals were transmitted to a computer via a cable and translated by algorithms into point-and-click commands guiding a cursor to characters on an onscreen keyboard. Each participant, after minimal training, mastered the technique sufficiently to outperform the results of any previous test of brain-computer interfaces, or BCIs, for enhancing communication by people with similarly impaired movement. Notably, the study participants achieved these typing rates without the use of automatic word-completion assistance common in electronic keyboarding applications nowadays, which likely would have boosted their performance. One participant, Dennis Degray of Menlo Park, California, was able to type 39 correct characters per minute, equivalent to about eight words per minute. This point-and-click approach could be applied to a variety of computing devices, including smartphones and tablets, without substantial modifications, the Stanford researchers said. "Our study's success marks a major milestone on the road to improving quality of life for people with paralysis," said Jaimie Henderson, MD, professor of neurosurgery, who performed two of the three device-implantation procedures. The third took place at Massachusetts General Hospital. Henderson and Krishna Shenoy, PhD, professor of electrical engineering, are co-senior authors of the study, which will be published online Feb. 21 in eLife. The lead authors are former postdoctoral scholar Chethan Pandarinath, PhD, and postdoctoral scholar Paul Nuyujukian, MD, PhD, both of whom spent well over two years working full time on the project at Stanford. "This study reports the highest speed and accuracy, by a factor of three, over what's been shown before," said Shenoy, a Howard Hughes Medical Institute investigator who's been pursuing BCI development for 15 years and working with Henderson since 2009. "We're approaching the speed at which you can type text on your cellphone." "The performance is really exciting," said Pandarinath, who now has a joint appointment at Emory University and the Georgia Institute of Technology as an assistant professor of biomedical engineering. "We're achieving communication rates that many people with arm and hand paralysis would find useful. That's a critical step for making devices that could be suitable for real-world use." Shenoy's lab pioneered the algorithms used to decode the complex volleys of electrical signals fired by nerve cells in the motor cortex, the brain's command center for movement, and convert them in real time into actions ordinarily executed by spinal cord and muscles. "These high-performing BCI algorithms' use in human clinical trials demonstrates the potential for this class of technology to restore communication to people with paralysis," said Nuyujukian. Millions of people with paralysis reside in the United States. Sometimes their paralysis comes gradually, as occurs in ALS. Sometimes it arrives suddenly, as in Degray's case. Now 64, Degray became quadriplegic on Oct. 10, 2007, when he fell and sustained a life-changing spinal-cord injury. "I was taking out the trash in the rain," he said. Holding the garbage in one hand and the recycling in the other, he slipped on the grass and landed on his chin. The impact spared his brain but severely injured his spine, cutting off all communication between his brain and musculature from the head down. "I've got nothing going on below the collarbones," he said. Degray received two device implants at Henderson's hands in August 2016. In several ensuing research sessions, he and the other two study participants, who underwent similar surgeries, were encouraged to attempt or visualize patterns of desired arm, hand and finger movements. Resulting neural signals from the motor cortex were electronically extracted by the embedded recording devices, transmitted to a computer and translated by Shenoy's algorithms into commands directing a cursor on an onscreen keyboard to participant-specified characters. The researchers gauged the speeds at which the patients were able to correctly copy phrases and sentences -- for example, "The quick brown fox jumped over the lazy dog." Average rates were 7.8 words per minute for Degray and 6.3 and 2.7 words per minute, respectively, for the other two participants. The investigational system used in the study, an intracortical brain-computer interface called the BrainGate Neural Interface System*, represents the newest generation of BCIs. Previous generations picked up signals first via electrical leads placed on the scalp, then by being surgically positioned at the brain's surface beneath the skull. An intracortical BCI uses a tiny silicon chip, just over one-sixth of an inch square, from which protrude 100 electrodes that penetrate the brain to about the thickness of a quarter and tap into the electrical activity of individual nerve cells in the motor cortex. Henderson likened the resulting improved resolution of neural sensing, compared with that of older-generation BCIs, to that of handing out applause meters to individual members of a studio audience rather than just stationing them on the ceiling, "so you can tell just how hard and how fast each person in the audience is clapping." Shenoy said the day will come -- closer to five than 10 years from now, he predicted --when a self-calibrating, fully implanted wireless system can be used without caregiver assistance, has no cosmetic impact and can be used around the clock. "I don't see any insurmountable challenges." he said. "We know the steps we have to take to get there." Degray, who continues to participate actively in the research, knew how to type before his accident but was no expert at it. He described his newly revealed prowess in the language of a video game aficionado. "This is like one of the coolest video games I've ever gotten to play with," he said. "And I don't even have to put a quarter in it." The study's results are the culmination of a long-running collaboration between Henderson and Shenoy and a multi-institutional consortium called BrainGate. Leigh Hochberg, MD, PhD, a neurologist and neuroscientist at Massachusetts General Hospital, Brown University and the VA Rehabilitation Research and Development Center for Neurorestoration and Neurotechnology in Providence, Rhode Island, directs the pilot clinical trial of the BrainGate system and is a study co-author. "This incredible collaboration continues to break new ground in developing powerful, intuitive, flexible neural interfaces that we all hope will one day restore communication, mobility and independence for people with neurologic disease or injury," said Hochberg. Stanford research assistant Christine Blabe was also a study co-author, as were BrainGate researchers from Massachusetts General Hospital and Case Western University. The study was funded by the National Institutes of Health (grants R01DC014034, R011NS066311, R01DC009899, N01HD53404 and N01HD10018), the Stanford Office of Postdoctoral Affairs, the Craig H. Neilsen Foundation, the Stanford Medical Scientist Training Program, Stanford BioX-NeuroVentures, the Stanford Institute for Neuro-Innovation and Translational Neuroscience, the Stanford Neuroscience Institute, Larry and Pamela Garlick, Samuel and Betsy Reeves, the Howard Hughes Medical Institute, the U.S. Department of Veterans Affairs, the MGH-Dean Institute for Integrated Research on Atrial Fibrillation and Stroke and Massachusetts General Hospital. Stanford's Office of Technology Licensing holds intellectual property on the intercortical BCI-related engineering advances made in Shenoy's lab. Stanford's departments of Neurosurgery and of Electrical Engineering also supported the work. *CAUTION: Investigational Device. Limited by Federal Law to Investigational Use. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med. .


News Article | February 23, 2017
Site: www.futurity.org

A brain-to-computer hookup recently allowed people with severe limb weakness to type via direct brain control at the highest speeds and accuracy levels reported to date. Two of the participants have amyotrophic lateral sclerosis, also called Lou Gehrig’s disease, and one has a spinal cord injury. They each had one or two baby-aspirin-sized electrode arrays placed in their brains to record signals from the motor cortex, a region controlling muscle movement. The signals were transmitted to a computer via a cable and translated by algorithms into point-and-click commands guiding a cursor to characters on an onscreen keyboard. Each participant, after minimal training, mastered the technique sufficiently to outperform the results of any previous test of brain-computer interfaces, or BCIs, for enhancing communication by people with similarly impaired movement. Notably, they achieved the typing rates without the use of automatic word-completion assistance common in electronic keyboarding applications nowadays, which likely would have boosted their performance. One participant, Dennis Degray of Menlo Park, California, was able to type 39 correct characters per minute, equivalent to about eight words per minute. This point-and-click approach could be applied to a variety of computing devices, including smartphones and tablets, without substantial modifications, the researchers say. Their findings appear in the journal eLife. “Our study’s success marks a major milestone on the road to improving quality of life for people with paralysis,” says Jaimie Henderson, professor of neurosurgery at Stanford University, who performed two of the three device-implantation procedures at Stanford Hospital. The third took place at Massachusetts General Hospital. “This study reports the highest speed and accuracy, by a factor of three, over what’s been shown before,” says co-senior author Krishna Shenoy, professor of electrical engineering. “We’re approaching the speed at which you can type text on your cellphone.” “The performance is really exciting,” says former postdoctoral scholar Chethan Pandarinath, who now has a joint appointment at Emory University and the Georgia Institute of Technology as an assistant professor of biomedical engineering. “We’re achieving communication rates that many people with arm and hand paralysis would find useful. That’s a critical step for making devices that could be suitable for real-world use.” Shenoy’s lab pioneered the algorithms used to decode the complex volleys of electrical signals fired by nerve cells in the motor cortex, the brain’s command center for movement, and convert them in real time into actions ordinarily executed by spinal cord and muscles. “These high-performing BCI algorithms’ use in human clinical trials demonstrates the potential for this class of technology to restore communication to people with paralysis,” says postdoctoral scholar Paul Nuyujukian. Millions of people with paralysis live in the United States. Sometimes their paralysis comes gradually, as occurs in ALS. Sometimes it arrives suddenly, as in Degray’s case. Now 64, Degray became quadriplegic on October 10, 2007, when he fell and sustained a life-changing spinal-cord injury. “I was taking out the trash in the rain,” he said. Holding the garbage in one hand and the recycling in the other, he slipped on the grass and landed on his chin. The impact spared his brain but severely injured his spine, cutting off all communication between his brain and musculature from the head down. “I’ve got nothing going on below the collarbones,” he says. Degray received two device implants at Henderson’s hands in August 2016. In several ensuing research sessions, he and the other two study participants, who underwent similar surgeries, were encouraged to attempt or visualize patterns of desired arm, hand, and finger movements. Resulting neural signals from the motor cortex were electronically extracted by the embedded recording devices, transmitted to a computer and translated by Shenoy’s algorithms into commands directing a cursor on an onscreen keyboard to participant-specified characters. The researchers gauged the speeds at which the patients were able to correctly copy phrases and sentences—for example, “The quick brown fox jumped over the lazy dog.” Average rates were 7.8 words per minute for Degray and 6.3 and 2.7 words per minute, respectively, for the other two participants. The investigational system used in the study, an intracortical brain-computer interface called the BrainGate Neural Interface System, represents the newest generation of BCIs. Previous generations picked up signals first via electrical leads placed on the scalp, then by being surgically positioned at the brain’s surface beneath the skull. An intracortical BCI uses a tiny silicon chip, just over one-sixth of an inch square, from which protrude 100 electrodes that penetrate the brain to about the thickness of a quarter and tap into the electrical activity of individual nerve cells in the motor cortex. Henderson likened the resulting improved resolution of neural sensing, compared with that of older-generation BCIs, to that of handing out applause meters to individual members of a studio audience rather than just stationing them on the ceiling, “so you can tell just how hard and how fast each person in the audience is clapping.” The day will come—closer to five than 10 years from now, Shenoy predicts—when a self-calibrating, fully implanted wireless system can be used without caregiver assistance, has no cosmetic impact. and can be used around the clock. “I don’t see any insurmountable challenges,” he says. “We know the steps we have to take to get there.” Degray, who continues to participate actively in the research, knew how to type before his accident but was no expert at it. He described his newly revealed prowess in the language of a video game aficionado. “This is like one of the coolest video games I’ve ever gotten to play with,” he says. “And I don’t even have to put a quarter in it.” Stanford research assistant Christine Blabe is also a study coauthor, as are BrainGate researchers from Massachusetts General Hospital and Case Western University. Funding came from the National Institutes of Health, the Stanford Office of Postdoctoral Affairs, the Craig H. Neilsen Foundation, the Stanford Medical Scientist Training Program, Stanford BioX-NeuroVentures, the Stanford Institute for Neuro-Innovation and Translational Neuroscience, the Stanford Neuroscience Institute, Larry and Pamela Garlick, Samuel and Betsy Reeves, the Howard Hughes Medical Institute, the US Department of Veterans Affairs, the MGH-Dean Institute for Integrated Research on Atrial Fibrillation and Stroke, and Massachusetts General Hospital. Stanford’s Office of Technology Licensing holds intellectual property on the intercortical BCI-related engineering advances made in Shenoy’s lab.


News Article | February 28, 2017
Site: www.eurekalert.org

CINCINNATI--Researchers at the University of Cincinnati (UC) College of Medicine have discovered a new potential strategy to personalize therapy for brain and blood cancers. These findings are reported in the Feb. 28 edition of Cell Reports. "We found a new combination of therapeutics that could treat cancers that lack a protein called PTEN. PTEN is an important tumor suppressor, which means that it stops cell growth and division according to the needs of the body," says David Plas, PhD, Anna and Harold W. Huffman Endowed Chair for Glioblastoma Experimental Therapeutics. Plas is an associate professor in the Department of Cancer Biology, a member of the University of Cincinnati Cancer Institute and a researcher in the Brain Tumor Center of the UC Gardner Neuroscience Institute. Atsuo Sasaki, PhD, and Hala Elnakat Thomas, PhD, both in the Division of Hematology Oncology at the UC College of Medicine, were collaborators on the study. In early work using experimental therapeutics in human cancer cells and in tumor models, the Plas laboratory showed that stopping the production and function of the protein S6K1 could eliminate PTEN-deficient glioblastoma cells. Glioblastoma, the most aggressive form of brain cancer, is difficult to treat with targeted therapeutics. "We used support from the Huffman Foundation to conduct a sophisticated biochemical analysis of how cells respond to S6K1 targeting," Plas says. "Combining the biochemical results with computational analysis gave us the insight that we needed--there are targets in addition to S6K1 that can be hit to trigger the elimination of PTEN-deficient cancer cells." With the new information, the research team tested pharmaceutical-grade drug combinations for the ability to eliminate PTEN-deficient cancer cells. Results showed that the drugs LY-2779964 and BMS-777607 work together to specifically eliminate PTEN-deficient cells. "This is a completely new combination of targets in oncology," Plas says. "We have great hope that our new data will lead academic and industry researchers to investigate S6K1 as the center of new combination strategies for cancers of the brain, blood and other tissues." Future work in the project will test the safety and efficacy of the new combination using tumor models, with the goal of preparing the combination strategy for clinical trial. Ronald Warnick, MD, medical director of the UC Brain Tumor Center and a professor in the Department of Neurosurgery within the UC College of Medicine, adds that this kind of project is necessary in finding new and beneficial therapies for brain tumors. "There is a desperate need for novel therapeutic agents for patients with glioblastoma," he says. "This combination of drugs has the potential to become a game-changer." This study was funded by the American Cancer Society, the National Institutes of Health (R01 CA133164, R01 CA168815, R21NS100077, R01NS089815), the UC Brain Tumor Center, the Anna and Harold W. Huffman Endowed Chair for Glioblastoma Experimental Therapeutics and the UC Medical Scientist Training Program. Plas cites no conflict of interest.


News Article | December 19, 2016
Site: www.eurekalert.org

CHARLOTTESVILLE, Va., Dec. 19, 2016 - A rare and powerful type of immune cell has been discovered in the meninges around the brain, suggesting the cells may play a critical but previously unappreciated role in battling Alzheimer's, multiple sclerosis, meningitis and other neurological diseases, in addition to supporting our healthy mental functioning. By harnessing the cells' power, doctors may be able to develop new treatments for neurological diseases, traumatic brain injury and spinal cord injuries - even migraines. Further, University of Virginia School of Medicine researchers suspect the cells may be the missing link connecting the brain and the microbiota in our guts, a relationship already shown important in the development of Parkinson's disease. The cells, known as "type 2 innate lymphocytes," previously have been found in the gut, lung and skin - the body's barriers to disease. Their discovery in the meninges, the membranes surrounding the brain, comes as a surprise. They were found as UVA researcher Jonathan Kipnis, PhD, explored the implications of his lab's game-changing discovery last year that the brain and the immune system are directly connected via vessels long thought not to exist "This all comes down to immune system and brain interaction," said Kipnis, chairman of UVA's Department of Neuroscience. "The two were believed to be completely not communicating, but now we're slowly, slowly filling in this puzzle. Not only are these [immune] cells present in the areas near the brain, they are integral to its function. When the brain is injured, when the spinal cord is injured, without them, the recovery is much, much worse." Curiously, the immune cells were found along the vessels discovered by Kipnis' team. "They're right on the lymphatics, which is really weird," noted researcher Sachin Gadani. "You have the lymphatics and they're stacked right on top. They're not inside of them - they're around them." The immune cells play several important roles within the body, including guarding against pathogens and triggering allergic reactions. In exploring their role in protecting the brain, the Kipnis team has determined they are vital in the body's response to spinal cord injuries. But it's their role in the gut that makes Kipnis suspect they may be serving as a vital communicator between the brain's immune response and our microbiomes. That could be of great importance, because our intestinal flora is critical for maintaining our health and wellbeing. "These cells are potentially the mediator between the gut and the brain. They are the main responder to microbiota changes in the gut. They may go from the gut to the brain, or they may just produce something that will impact those cells. But you see them in the gut and now you see them also in the brain," Kipnis said. "We know the brain responds to things happening in the gut. Is it logical that these will be the cells that connect the two? Potentially. We don't know that, but it very well could be." While much more research needs to be done to understand the role of these cells in the meninges, Gadani noted that it's almost certain that the cells are important in a variety of neurological conditions. "It would be inconceivable they're not playing a role in migraines and certain conditions like that," he said. "The long-term goal of this would be developing drugs for targeting these cells. I think it could be highly efficacious in migraine, multiple sclerosis and possibly other conditions." The findings have been published online by the Journal of Experimental Medicine. The article is by Gadani, of UVA's Medical Scientist Training Program; Igor Smirnov; Ashtyn T. Smith; Christopher C. Overall; and Kipnis, who, in addition to being department chairman, is the director of UVA's Center for Brain Immunology and Glia (BIG). The work was supported by the National Institutes of Health, grant NS081026.


News Article | October 31, 2016
Site: www.eurekalert.org

BOSTON (October 31, 2016)--Silencing SIRT2, a member of the sirtuin family of enzymes, reduces the invasiveness of basal-like breast cancer cells in culture and inhibits tumor growth in mice, according to new research led by scientists from Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts in Boston. The absence of SIRT2 appears to accelerate the degradation of Slug, a transcription factor that has previously been implicated in tumor progression and metastasis. The findings, published online in Cell Reports on Oct. 25, reveal underlying molecular mechanisms and potential new approaches to treat one of the deadliest breast cancer subtypes. "Breast cancer is not one disease, and of the several distinct subtypes, basal-like breast cancer represents the most aggressive form. By targeting a master transcription factor regulator in basal-like cells, we were able to reduce malignant behaviors," said senior study author Charlotte Kuperwasser, Ph.D., professor of developmental, molecular and chemical biology at Tufts University School of Medicine and director of the Raymond and Beverly Sackler Laboratory for the Convergence of Biomedical, Physical, and Engineering Sciences at Tufts. "Our findings now provide a molecular rationale for new approaches to help improve the poor clinical outcomes currently associated with these cancers." Estimated to account for up to 20 percent of all breast cancers, basal-like breast cancers are typically triple-negative (lacking HER2 and hormone receptors) and are often resistant to conventional chemo- or radiotherapy. As a result, few effective treatment options currently exist. A number of prior studies, including by Kuperwasser and colleagues, have indicated that the transcription factor Slug plays a central role--basal-like tumor cells commonly have an abnormal overabundance of Slug protein, and depleting Slug in laboratory experiments reduces tumor growth and aggressiveness. However, transcription factors are extremely difficult to target with drugs due to complex interactions with other genes and proteins. In the current study, Kuperwasser and her team worked to identify new targets better suited for therapeutic development by examining the molecular mechanisms that regulate Slug abundance. The researchers found that the sirtuin enzyme SIRT2 had the strongest stabilizing effect. In cultured basal-like tumor cells, silencing SIRT2 through the use of RNA interference molecules led to the rapid degradation of Slug, and caused Slug turnover rates to resemble those seen in normal, non-tumorous cells. This in turn significantly weakened key characteristics of malignant behavior. Without SIRT2, tumor cells had a more than 60 percent reduction in invasive capacity compared to normal basal-like tumor cells. SIRT2-depleted cells also had significantly decreased capacity for growth and self-renewal. This diminished malignancy could be reversed by artificially introducing Slug protein back into cells, demonstrating the direct and necessary relationship between SIRT2, Slug stability and malignant behavior. When the team transplanted SIRT2-depleted basal-like cancer cells into a mouse model of breast cancer, they found that tumor sizes were on average 80 percent smaller than those formed by normal basal-like cells. "The molecular interplay that drives aggressive basal-like breast cancer is quite complex and encompasses processes beyond the genetic level. It was unexpected that SIRT2, a sirtuin family member historically known for playing a role in metabolism and aging, also acts to regulate Slug protein and malignant tumor traits," said study author Wenhui Zhou, a M.D./Ph.D. student at Tufts University School of Medicine and the Cell, Molecular & Developmental Biology program at the Sackler School of Graduate Biomedical Sciences at Tufts. Sirtuin enzymes have previously been implicated in a wide range of cellular processes, such as aging, inflammation and energy expenditure. Their role in cancer is still unclear, but the team found that SIRT2 is highly expressed in basal-like breast cancers compared to other subtypes, based on data from almost 1,000 breast cancer cases from National Cancer Institute's The Cancer Genome Atlas. Due to the widespread presence of sirtuin enzymes, inhibiting SIRT2 directly in humans is likely to affect many other cellular processes, and targeting it requires highly specific inhibitors. Kuperwasser and her team are now exploring candidate inhibitors for efficacy and toxicity in animal tumor models. However, the team's work also revealed the mechanism by which SIRT2 stabilizes Slug--a process known as deacetylation, in which chemical modifications are made to Slug protein after it is created in the cell. Compounds that block specific sites involved in deacetylation on the Slug and SIRT2 proteins could interfere with their interaction, and may represent another effective strategy to target malignancy, according to the authors. "Cancer cells find sophisticated ways to regulate essential proteins they need for their survival and growth. The transcriptional factor Slug is one such protein and is often tightly regulated in both normal and cancer cells. While we have found that SIRT2 plays an important role in prolonging Slug expression, it is too soon to know whether targeting Sirt2 will be sufficient to abolish Slug entirely in cancer cells and therefore lead to tumor regression," said Kuperwasser, who is also a member of the genetics and cell, molecular & developmental biology program faculties at the Sackler School. "A significant amount of work remains to be done before we can verify if targeting SIRT2 can be an Achilles' heel for treating basal-like breast cancers." Additional authors of this study are Thomas K. Ni, Ph.D., American Cancer Society postdoctoral fellow in the Raymond and Beverly Sackler Convergence Laboratory at Tufts University School of Medicine, Ania Wronski, Ph.D., postdoctoral researcher in the Raymond and Beverly Sackler Convergence Laboratory at Tufts University School of Medicine, Benjamin Glass, research laboratory manager at Beth Israel Deaconess Medical Center, Adam Skibinski, M.D., Ph.D., who contributed to the study while a M.D./Ph.D. student at Tufts University School of Medicine and the Sackler School and who is now a diagnostic radiology resident at the University of Washington, and Andrew Beck, Ph.D., associate professor at Harvard Medical School in the department of pathology at Beth Israel Deaconess Medical Center. This study was supported by awards from the Raymond and Beverly Sackler Laboratory for the Convergence of Biomedical, Physical, and Engineering Sciences at Tufts, Art beCAUSE Breast Cancer Foundation, the American Cancer Society (PF-14-046-01-DMC), the Breast Cancer Research Foundation, and the National Institute of Child Health and Human Development (HD073035) and the National Cancer Institute of the National Institutes of Health (CA170851). Zhou and Skibinski were also supported by the Medical Scientist Training Program funded by the National Institute of General Medical Sciences (GM008448) of the National Institutes of Health, a program that trains M.D./Ph.D. students to become the physician-scientists. Zhou, Wenhui et al. "The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer." Cell Reports, Volume 17, Issue 5, 1302 - 1317. DOI: 10.1016/j.celrep.2016.10.006 About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences are international leaders in medical and population health education and advanced research. Tufts University School of Medicine emphasizes rigorous fundamentals in a dynamic learning environment to educate physicians, scientists, and public health professionals to become leaders in their fields. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, the biomedical sciences, and public health, as well as for research at the cellular, molecular, and population health level. The School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical and prevention science.

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