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The Promising Outlook of Mesenchymal Stem Cell Therapy as a Novel Treatment for Traumatic Brain InjuriesBy: Haley ZangaDate: December 9th, 2017Biology Capstone ThesisAbstractTraumatic brain injury (TBI) is a major cause of death and disability in the United States. To date, there are no pharmacologic agents or effective treatments to improve neural structural repair and functional recovery after a TBI. The current treatment for acute and chronic TBI consists of management of damaged tissues and rehabilitation. Thus, there is a need to develop further treatments for traumatic brain injuries (TBIs). Stem cell therapy, specifically using mesenchymal stem cells (MSCs), have become a promising area for future therapeutic use for TBIs due to their ability to differentiate into neural lineages, selectively migrate to damaged areas, cross the blood-brain barrier, reduce inflammation in the injured tissue, and their ability to secrete chemokines and growth factors. Recently, numerous pre-clinical studies have investigated the effects of intravenously administering MSCs into animal models with induced TBIs. The results showed reduced motor deficits, neural and astrocyte markers which are indicative of signs of differentiation towards neuron and astrocyte-like cells and migration towards the injury site. Overall, investigations including pre-clinical studies, have yielded promising results that suggest that MSCs may be a novel treatment for TBI. Although the benefits of stem cell therapy have been clearly shown in pre-clinical studies, questions remain regarding the biological mechanisms, dose, route and timing of stem cell delivery. Further research is needed to aid in the design of clinical studies. I. Introduction A traumatic brain injury (TBI) is characterized as an alteration in brain function or other evidence of brain injury that results from an external mechanical force (11). It can possibly lead to permanent or temporary impairments, usually associated with diminished or an altered state of consciousness (18). Traumatic brain injuries (TBIs) are becoming more prevalent affecting an estimated 1.5 million Americans annually (5) and contributing to 50% of all trauma-related deaths. Falls account for 35% of the moderate to severe TBIs in the U.S, followed by motor-vehicle or traffic-related accidents which account for 17% (9). TBIs affect the patient as they cause deficits in social, cognitive, motor as well as behavioral functioning; they also impact the family and friends around as they are the ones who normally provide care for their loved one. Of the TBIs that result each year about 50,000 deaths occur, and nearly 100,000 injuries lead to life-long impairments (5). Injury severity, type and location, the individuals age and more are all factors to consider when looking at TBI, meaning no two TBIs are the samea reason this type of injury is so complex. Current acute treatment of TBI has been limited to preventing further swelling and pressure in the brain and optimizing cerebral perfusion, to prevent further cerebral edema, inflammation and cellular death (5). Chronic treatment however focuses on cognitive, motor, and behavioral rehabilitation. The primary focus on treating TBI patients is aimed at reducing the extent of the injury rather than repairing the damage. As of right now, little treatment options are available for patients with TBI. Early recognition, acute care, and rehabilitation strategies have led to an improved survival rate; however, it has also lead to survivors with significant impairments in motor, cognition and social aspect of their lives. Although the injured brain has shown some limited capacity to recover, no current therapeutic treatment is available to alter the underlying pathological process via support, repair, or replacement of the damaged tissue and cells. Due to the serious morbidity and mortality associated with TBI, new therapies are needed.The use of stem cells for regeneration and repair is now becoming an emerging treatment option for TBIs. Recent research has shown success in stem cell therapy in neurodegenerative diseases such as Parkinson disease (10). Studies have shown that the use of exogenous stem cell transplantation increases cellular proliferation and promote neural differentiation in the injured region of the brain (1). This has encouraged TBI researchers to investigate stem cell therapy as a new treatment option for treating patients with traumatic brain injuries. Based on pre-clinical studies that have shown clear evidence that stem cells have the potential in helping the brain repair/recover and help with functional recovery after brain damage, makes the use of stem cell-based therapy a potential new innovative treatment for TBI patients (5). Understanding the regenerative capacities of stem cells, as well as the impact of stem cells on proliferation and differentiation will help us further improve the functional recovery and repair after brain injury. In this review, I will start with a brief introduction explaining what TBIs are and discussing their pathophysiology. Next, I will look at the biology of MSCs followed by their potential mechanism of action, and the applications of MSCs in pre-clinical studies. Lastly, I will discuss some of the limitations and further research that is needed in this field. The goal of my paper is to discuss the use of MSCs as a novel treatment for TBIs. II. Pathophysiology of TBI4253084328000TBIs can result from many things such as direct impact or from extreme acceleration, deceleration, rotating forces or outside forces that impact the head that causes the brain to “rattle” back and forth (2). By better understanding the pathophysiology of TBIs it may give us some insight on how stem cells can be used for therapeutic treatment of TBI patients.TBI induces a complex pathophysiological cascade of cellular events. TBI pathophysiology consists of blood-brain barrier (BBB) breakdown, widespread neuroinflammation, diffuse axonal injury, and neurodegeneration (10). Although there are many models that exist for TBI, there is a general consensus that TBI can be classified into two groups: primary injury and secondary injury (4).The primary injury is generally considered “external” and occurs immediately after damage to the central nervous system (14). FIGURE 1: The Pathophysiology of TBI (3) Externally, the skulls job is to provide protection for the brain but with a TBI there could be simple scalp hematomas, hemorrhagic contusions, and herniation. More serious complications can result such as neuronal death and damage and more complex and diffuse lesions (4). The physical damage happens to the axons of the neurons, which are either stretched or torn, glial cells, nerve fibers, and the BBB and meninges may be damaged. This axonal injury is characterized by swelling and even complete severing of axons, which is a major and common result of TBI (4).?The primary injury leads to the secondary injury.Secondary injury is an?indirect?result of the injury and occurs gradually involving an array of cellular processes. It is a result from the processes initiated by the initial trauma caused in the primary injury. It occurs hours and days following the primary injury and plays a vast role in the damage done to the brain and death that results from TBI (9). Following the initial injury caused by the trauma, an intense localization of inflammation occurs, worsening the damage already done and expanding the site of injury to include neighboring neurons.?The primary injury leads to ischemia, where it reduces the oxygen and glucose supply to the cells. This forces the cells to convert to anaerobic respiration and causes a buildup of lactic acid. After the depletion of ATP in the cells, the ion pumps in the cell membrane lose functionality leading to a leakage of calcium ions into the cells and mitochondria. This in turn leads to the formation of free radicals that results in apoptosis and necrosis of the neurons (4). The inflammatory response consists of the recruitment and migration of leukocytes and microglia to the site of injury and the release of cytokines, some of the which promote an inflammatory response where others produce an anti-inflammatory response in addition to nitric oxide, hypoxia, the release of endogenous excitatory amino acids, and other cytotoxic effects which exacerbates the neural cell death (4). These complex cascades of events are key characteristic to the secondary injury of TBI. As stated above, the initial forces from the TBI can disrupt the BBB. Consequently, the disruption of the BBB and vascular neuronal network following TBI often leads to uncontrolled inflammation, intracranial pressure, and cerebral ischemia. The BBB plays an important role in homeostasis as it maintains ion concentrations, regulates the flow of elements into the brain, and protects the brain from foreign elements circulating in the bloodstream. When a TBI occurs, the BBB’s tight-lock is compromised which then allows the passage of immune cells to get into the central nervous system. Astrocytes that are part of the BBB are also key players in the brains defense response to TBI. After an injury occurs, the astrocytes will invade the damaged area creating what is called a glial scar to protect the rest of the brain by isolating the site of injury and protecting the neurons that are still intact. The glial scar encloses an area containing inhibitory molecules that prevents the regrowth of neurons and inhibits the repair of the BBB. The astrocytes in the glial scar, however, encourage the survival of surrounding neurons by secreting various metabolites such as glucose, growth factors, and nutrients (4). The neuronal loss after TBI is both local and diffuse because of the primary and secondary phases of the injury (2). The pathophysiology of TBI is complex, and still not fully understood. With the understanding we have now and using mice and rats as animal models of this pathophysiology to study, it may help us better understand the pathophysiology in humans who have TBIs. III. Background: Stem Cell Sources With the lack of current treatment options for TBIs, researchers have started to consider using stem cells as a therapeutic treatment option. Given their capacity to regenerate cells lost through disease or injury, stem cells offer a promising possibility to use as a treatment for TBIs. Stem cells are considered multi- or pluripotent because they have this remarkable ability to develop into many different cell types in the body. When a stem cell divides, each new cell can remain a stem cell or become a cell with a specialized function such as a muscle cell, blood cell, or even a neural cell (17). Due to the limited capability of the brain to repair and replace the missing tissue after injury, stem cell transplantation has now become a prospective treatment for TBI patients since transplanted cells have shown the potential to differentiate into region-specific cells and integrate into the host tissue to replace the lost and damaged tissue (23). Transplanted cells also could provide a type of “nourishment” support to the host tissue and help facilitate regeneration (23). With the understanding of how stem cells work, researchers have started using stem cells in pre-clinical studies to see if the use of stem cells could be the new “cure” for TBI patients. Stem cell therapy has now become a hot topic for treating traumatic brain injuries since recent research has shown that stem cell therapy has positive therapeutic effects in patients with neurodegenerative diseases such as Parkinson’s and was shown to be clinically safe when administered in patients with injuries such as myocardial infarction, stroke, and acute kidney injury (2). Using stem cells for traumatic brain injury treatment could potentially mean overcoming the damage done to the neurons in the brain. The stem cells would work to repair (or partially heal) the connections between the nerves and cells within the brain. In the end, the goal is that this will help restore motor, cognitive, and behavioral functions that are often lost because of a TBI. Over the past two decades, researchers have explored a wide array of cell sources for neural transplantation. These cells include adult neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs) isolated from fetal or embryonic tissue, and mesenchymal stromal cells (MSCs) such as bone marrow stromal cells and umbilical cord cells. NSCs can be used and isolated from many parts of the fetal or adult brain. They are multipotent and possess the ability to differentiate into cells of neural origin that include neurons, oligodendrocytes, and astroglia. A serious challenge with NSC transplantation is the ability to deliver cells to the area of interest (10). Although these cells are more difficult to isolate and culture, they do hold a significant potential for use in stem cell therapy in TBI patients. ESCs are pluripotent self-renewable cells that are derived from early blastocyst embryos (24). With their pluripotent ability, these cells can generate neural cells like NSCs, including neurons, glial cells and oligodendrocytes (under appropriate culture conditions) (10). Since these cells can proliferate without limit and can become almost any cell type they are being looked at for use as a treatment for TBI patients. However, due to the ethical problems that surround using ESCs it has created some limitations to using ESCs for stem cell therapy. It was discovered by Jiang and his colleagues (19) that MSCs isolated from bone marrow had the ability to differentiate down all three germ cell lines. These progenitor cells differentiated to phenotypic endothelial, hepatic, and neural cells (5). Some of these bone marrow-derived cells have shown the ability to develop phenotypic characteristics of neural cell lineage after transplantation in animals, providing evidence that they may be useful in treating TBI. MSCs also have shown the ability to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro. These adult stem cells have shown to develop neural phenotypes under specific conditions both in vitro and in vivo (5). However, throughout the scientific community, there is much controversy around whether MSCs and bone marrow-derived MSCs can turn into neural lineages. If it can occur, scientists agree that it is not likely to play a significant role in the CNS repair and protection. It has been hypothesized that their most beneficial mechanism if microenvironment alternation though cell-cell interaction, inflammatory alteration, and growth factor production instead of tissue replacement (5). A significant amount of preclinical research done using MSCs to treat TBI have come from the laboratory of Chopp and his colleagues (8). They were one of the first scientists to use bone marrow-derived MSCs as a therapy for TBI, back in 2001 where they transplanted whole bone marrow adjacent to the site of injury. They had seen that cells survived one month, migrated toward the site of injury, developed characteristic like neurons and astrocytes, and even improved the overall motor function. Around the same time, they also reported on the intravenous and intra-arterial administration of MSCs in induced TBI in rats. They found that the cells also survived, migrated to the area of injury and expressed neural cell markers. Animals that were treated intravenously were also found to have reduced motor and NSS deficits. Chopp and his colleagues were the first true pioneers of using MSCs in TBI animals. VI. Biology of Mesenchymal Stem Cells (MSC) Due to the obstacles of using adult NSCs, and the ethical problems that surround ESCs, MSCs have now become a popular choice to use for stem cell therapy. MSCs have become of interest to scientists since these mesoderm-derived cells are found in many tissues such as adult bone marrow, adipose tissue, skin, umbilical cord blood, peripheral blood, and amniotic fluid and can give rise to many tissue-specific cell types such as bone, cartilage, muscle, fat cells and connective tissue (25). MSCs Differential Potential to NSCsAs stated earlier, MSCs can differentiate into neural cells. The ability of MSCs to differentiate into neural cells was first recognized by Sanchez-Ramos and his colleagues (2000). They showed that both mice and human MSCs had the ability to differentiate into neurons and glia-like cells under certain culture conditions. Further evidence of neural differentiation potential of MSCs was shown by Azizi et al (1998). They showed that it was possible to inject MSCs into the brain where they displayed migratory abilities similar to those of NSCs. Furthermore, when stained with antibodies before implantation, this staining disappeared throughout the experiment showing MSCs had differentiated into another lineage where MSCs acquired the phenotype of their host tissue (4). Secretion of Chemokines and Growth FactorsIt was also found that these MSCs are capable of secreting cytokines, chemokines and growth factors. These factors secreted by MSCs, such as neurotrophic factors have important roles in creating favorable microenvironments for the proliferation of neural cells at the injury site (26). With these findings, recent research has highlighted the possibility of genetically modifying MSCs for the purpose of producing soluble growth factors, cytokines, and chemokines (1). These soluble factors are capable of enhancing the survival of stem and neuronal cells. These neurotrophic factors secreted by MSCs have been found to promote angiogenesis and neurogenesis in the injured brain, thus enhancing the multiplication of neuronal cells at the damaged site (4). Homing of MSCs at the Site of InjuryMSCs have also shown the ability to migrate to sites of TBI injury. Many mechanisms have been postulated, yet no one knows how this is works exactly. One idea shown by López Ponte (22) and colleagues was that MSCs migration is influenced by several chemokines and growth factors. Another mechanism postulated is the adhesion of MSCs to the endothelium of injured tissue due to the expression of vascular cell adhesion molecule (VCAM-1) (4). Immunosuppressive PropertiesIn addition to their ability to differentiate into different cell lineages, and their tendency to migrate towards the injury site, there has also been research suggesting that MSCs provide immunosuppressive properties. The evidence has suggested that cytockines, chemokines, microglial activation and recruitment of circulating leukocytes mediates secondary injury and repair after TBI (6). Two studies done to explore this idea, mixed MSCs in vitro with a lymphocyte reaction, and showed that there was a suppression of the proliferative response of the lymphocytes (20, 21). This effect also showed an increase number of MSCs. Also, the suppressed lymphocytes were found to recover their properties when stimulated in the absence of MSCs (4). This effect of MSCs could help in reducing the effects of the secondary injury of TBIs.Facilitated Regenerative ProcessMSCs have also been found to facilitate the injured tissues own regenerative process. MSCs implanted into mouse hippocampus were found to heighten the proliferation, migration, and differentiation of native NSCs. This mechanism is thought to be related to chemokines released by MSCs or indirectly via activation of the astrocytes. This was shown when looking at lung tissue treated with MCSs, researchers found a decreased expression of inflammation-associated cytokines which facilitated the repair of the injured lung tissue (4). Crossing the BBBThe ability to cross the BBB is important for neurotherapeutic drugs. Researchers have been looking into strategies to enable access through the BBB and recent research has shown that MSCs might already possess the ability to cross the BBB. The mechanism of which this occurs has been published by Steingen et al (2008). After the MSCs come into contact with the endothelium, they exit the bloodstream and integrate into the endothelium though the use of adhesion molecules (i.e. VCAM-1/VLA-4 and β1 integrin). After crossing the endothelial barrier, the MSCs then invade the host tissue. It was also reported that MSCs could cross the BBB through paracellular pathways even though the presence of tight junctions would normally inhibit this activity. This showed the researchers that MSCs seem to influence tight junction barriers leading to their temporary elimination. The MSCs ability to cross the BBB is a unique and promising feature supporting the usefulness of MSCs as a TBI treatment method (4). The use of MSCs have been brought to many scientist’s attention in studies in regenerative medicine due to their important abilities and properties they possess, showing scientists how beneficial using MSCs may be for treating TBIs. V. Pre-Clinical StudiesMany pre-clinical studies have been done using animal models such as mice and rats to determine the effects on neurological outcomes after transplantation of stem cells. The aim of these studies is to investigate the roles that MSCs play after experimental TBIs in rats are induced, to help our understanding of using MSCs for stem cell therapy in humans. With the known advantages of MSCs and the previous findings Chopp (27) had published, more and more researchers have started looking into using MSCs in TBI induced animals. A variety of studies have shown that stem cell therapy in mice and rats with a TBI has had significant improvements in cognitive and motor functions. One study, in particular, done by Lu, Dunyue et al, (7) measured the effect of bone marrow stromal cells (MSCs) administered intravenously in rats with TBI. Rats were injected with MSCs labeled with BrdU into the tail vein 24h after TBI and examined throughout a two-week period to evaluate neurological functions using NSS scores and the Rotarod test. As seen below in Figure 2 there was a significant reduction in neurological deficits at day 7 and 14 compared to the controls. Figure 3, showed similar results where there was a significant improvement in motor function at day 14 after treatment compared to the control. These results suggest that i.v administration of MSCs may be useful in treating patients with TBI. Figure 2 (right) NSS scores at different times after TBI. *Mean NSS score in TBI +MSC group at 7 and 14 days after MSC administration is notably lower than the control group. Figure 3 (left) Percentage of the preinjury time on Rotarod at different times after injury. Scores of Rotarod at day 14 after MSC administration in TBI MSC group are notably higher than those in the control group (7). This is just one study showing that the use of MSC in TBI can improve motor and cognitive functions. Another study by Khalili et al (26) also looked at the transplantation of MSCs into a Wistar rat model with an induced TBI. Their studied showed that some of the BrdU labeled MSCs migrated into the parietal lobes of the injured brain, whereas the immunofluorescence microscopy of coronal sections showed no localization of BrdU positive cells in the traumatic brain injury group (Figure 4). This migration to the injured brain tissue was seen at 14 days after traumatic brain injury in rats. This type of TBI model with the administration of MSCs has been rarely reported. Figure 4 BrdU-labeled mesenchymal stem cells migrated to injured cerebral tissue following intravenous transplanation. (A) BrdU-labeled MSC (arrow) migrated into injured brain in the cell transplanation group via intravenous transplation. (B) No BrdU-positive cells were observed in the traumatic brain injury group (26). Figure 5 Expression of neuronal nuclei (NeuN) in injured brain tissue after MSC transplanation. (A) Some BrdU-positive MSCs express NeuN. (FITC)-conjugated anti-mouse IgG-labeled MSCs were in green color. (B) BrdU-labeled MSCs with rhodamine-conjugated anti-rat IgG antibody as secondary antibody were in red color. (C) (DAPI)-labeled MSCs. DAPI indicated nuclei in blue color. (D) NeuN-BrdU-DAPI (26). Figure 6 Expression of astrocyte marker glial brillary acidic protein (GFAP) in injured brain tissue after mesenchymal stem cell (MSC) transplantation.?(A) Some BrdU-positive MSCs express GFAP. Labeled MSCs were indicated in red color. (B) BrdU labeled MSCs with (FITC)-labeled anti-mouse IgG antibody as secondary antibody were in green color. (C) (DAPI)-labeled MSCs. DAPI indicated nuclei in blue color. (D) GFAP-BrdU-DAPI (26). In addition, double staining showed that some implanted (intravenously) MSC expressed a neuronal marker (NeuN) and a astrocyte marker (GFAP) in the cell transplantation group (Figures 5, 6) and promoted functional recovery that was seen at the end of the second week. Not only did they see migration and neural associated markers, but they also saw rat deficits that were improved significantly in the cell transplantation group compared with the traumatic brain injury group (control) at 14 days post-injury. The control group, on the contrary, showed no improvement in animal behavior after induced TBI. These findings showed that at 24 hours after TBI, intravenously injected MSCs improved neurological function, which is similar to other investigations such as Li and Chopp (27) and to the study I discussed above (7).VI. Potential Mechanism of ActionThe physiology of stem cell therapy and the interaction of the transplanted cells within the tissues they are being transplanted into is still poorly understood. Significant investigation into potential mechanisms of action that may lead to functional recovery is yielding valuable insight. Throughout the scientific community, there is still debate on the mechanism of action of stem cell therapy. However, many ideas have been hypothesized. Understanding the mechanism of action can ultimately help the development and further understanding of using stem cells as a treatment for TBI patients. There have been several suggested mechanisms of action leading to recovery of function after adult stem cell therapy. Possibilities that have been expressed are: 1) That stem cells differentiate into local/regional cell types and support cell replacement. Yet, many scientists have agreed that it is very unlikely since bone morrow MSCs cannot become functional neural cells in vivo (5). 2) Stem cells may act as supportive cells, determining the fate of the damaged cells, by improving cell survival or increasing cell proliferation through direct contact, or even altering the local milieu through growth factors or chemokine section, which is most likely since a variety of studies have noted increases in growth factor production with MSC therapy (5). 3) Stem cells may be acting to reduce inflammation since it has been shown that stem cells migrate towards sites of inflammation and may act through the microenvironment in reducing inflammation, and modulating inflammatory mediators (5). 4) MSC’s could enhance angiogenesis (4). These four mechanisms are possibilities potentially leading to the recovery of brain function after adult stem cell therapy. Although, the mechanism of action is still unknown there are several aspects of the biology of MSCs that support the idea that the mechanism of action is their ability to secrete various growth factors and chemokines that can stabilize the endothelium preventing excessive permeability, and promote a microenvironment for regeneration of the damaged cerebral tissues (2). This idea is very much different than the primary mechanism of action that was proposed, that MSCs could differentiate into neural cells, however, there is little evidence that suggests these cells can become functional neurons. One study by Galindo et al (2011), even investigated the cytokines secreted by MSCs in a model of traumatic brain injury and showed that these factors induced the expression of glial brillary acidic protein (astrocyte marker) and modulated the in vivo inflammation in experimental traumatic brain injury. These results suggested that is very likely MSCs are acting through these neurotrophic affects (26). VII. Conclusions and PerspectivesTraumatic brain injuries can be life-changing not only to the patient but to the patient’s family as well. The current treatment options out there for these patients are limited. As technology keeps growing we as scientists are trying to find a better way to provide treatment to these patients. Through the advantages and properties that mesenchymal stem cells possess, they therefore may have the capability of helping neural tissue damage that resulted from the TBI. MSCs have shown us their prospective role in healing the damaged tissue by aiding in decreasing the inflammation in the host tissue, encouraging the regeneration of damaged nerves, and their tendency of homing near the injury site. MSCs ability to migrate across the BBB would also overcome a major problem faced in treating TBI which is selective and targeted delivery to the injured brain tissue. Over the last few decades, our understanding of MSCs as a treatment for TBI has grown.The use of MSCs in traumatic brain injuries has been able to decrease neurological deficits and provide therapeutic benefits in an animal model. Through many studies and experiments done in animal models researchers have seen the potential of using these cells for acute and diffuse traumatic brain injuries. However, even though a significant amount of research has been looked at about the complexity of the pathophysiology and utilization of stem cell therapy as a treatment of TBI, a lot still remains unclear and further research is needed to better understand and to determine the best method to promote recovery of the damaged brain tissue.Furthermore, better understanding the mechanisms of MSCs in TBI is also important to help us apply them successfully in clinical applications. Our well characterized pre-clinical studies with animal models for TBIs should help guide further clinical trials. However, many studies on the application of MSCs in TBIs done in rats and mice have been done over the course of days and months. Longer-term studies are needed to explore the safety and efficacy of these cells during long-term therapy. Our limited understanding of potential complications, routes of administration, and use of combination therapy are three other topics that need to be explored further. Stem cell therapy has shown a promising outlook in the management of TBI, a condition that has been “resistant” to previous interventions. Progress in the laboratory will help in the translation of knowledge to the clinic side where we can continue to build a foundation of evidence that will clarify the role of stem cell therapy in treating TBI. References (MLA):Drago, Denise et al. “The Stem Cell Secretome and Its Role in Brain Repair.”?Biochimie?95.12 (2013): 2271–2285.? Gennai, S. et al. “Cell-Based Therapy for Traumatic Brain Injury.” Ed. J. G. Hardman.?BJA: British Journal of Anaesthesia?115.2 (2015): 203–212.? Guha, A. Management of traumatic brain injury: some current evidence and applications. 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