Science Translational Medicine

  • [Editorial] APOE {varepsilon}4 Status and Traumatic Brain Injury on the Gridiron or the Battlefield
    Gandy, S., DeKosky, S. T.
  • [Perspectives] Drug-Based Optical Agents: Infiltrating Clinics at Lower Risk
    Fluorescent agents with specificity to cellular and subcellular moieties present promise for enhancing diagnostics and theranostics, yet challenges associated with regulatory approvals of experimental agents stifle the clinical translation. As a result, targeted fluorescent agents have remained predominantly as preclinical imaging tools. We discuss the potential of using optically labeled drugs to accelerate the clinical acceptance of optical and optoacoustic agents, in analogy to nuclear medicine approaches. This strategy, corroborated with microdosing studies, outlines a promising approach for overcoming bottlenecks and advancing photonic clinical imaging.
    Scheuer, W., van Dam, G. M., Dobosz, M., Schwaiger, M., Ntziachristos, V.
  • [Research Articles] Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model
    Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.
    Goldstein, L. E., Fisher, A. M., Tagge, C. A., Zhang, X.-L., Velisek, L., Sullivan, J. A., Upreti, C., Kracht, J. M., Ericsson, M., Wojnarowicz, M. W., Goletiani, C. J., Maglakelidze, G. M., Casey, N., Moncaster, J. A., Minaeva, O., Moir, R. D., Nowinski, C. J., Stern, R. A., Cantu, R. C., Geiling, J., Blusztajn, J. K., Wolozin, B. L., Ikezu, T., Stein, T. D., Budson, A. E., Kowall, N. W., Chargin, D., Sharon, A., Saman, S., Hall, G. F., Moss, W. C., Cleveland, R. O., Tanzi, R. E., Stanton, P. K., McKee, A. C.
  • [Research Articles] Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency
    Aromatic l-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector–mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[18F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.
    Hwu, W.-L., Muramatsu, S.-i., Tseng, S.-H., Tzen, K.-Y., Lee, N.-C., Chien, Y.-H., Snyder, R. O., Byrne, B. J., Tai, C.-H., Wu, R.-M.
  • [Research Articles] CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients
    Regulatory T cells (Tregs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25+ FoxP3+ Tregs in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration–approved CD25-blocking monoclonal antibody daclizumab with regard to human Treg survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25high CD45RAneg Tregs. Moreover, daclizumab-treated CD45RAneg Tregs lost suppressive function and regained the ability to produce interferon-, consistent with reprogramming. To understand the impact of daclizumab on Tregs in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in Tregs in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms Tregs in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated Tregs while avoiding autoimmunity.
    Rech, A. J., Mick, R., Martin, S., Recio, A., Aqui, N. A., Powell, D. J., Colligon, T. A., Trosko, J. A., Leinbach, L. I., Pletcher, C. H., Tweed, C. K., DeMichele, A., Fox, K. R., Domchek, S. M., Riley, J. L., Vonderheide, R. H.
  • [Research Articles] High-Throughput Sequencing Detects Minimal Residual Disease in Acute T Lymphoblastic Leukemia
    High-throughput sequencing (HTS) of lymphoid receptor genes is an emerging technology that can comprehensively assess the diversity of the immune system. Here, we applied HTS to the diagnosis of T-lineage acute lymphoblastic leukemia/lymphoma. Using 43 paired patient samples, we then assessed minimal residual disease (MRD) at day 29 after treatment. The variable regions of TCRB and TCRG were sequenced using an Illumina HiSeq platform after performance of multiplexed polymerase chain reaction, which targeted all potential V-J rearrangement combinations. Pretreatment samples were used to define clonal T cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, and paired posttreatment samples were evaluated for MRD. Abnormal T lymphoblast identification by multiparametric flow cytometry was concurrently performed for comparison. We found that TCRB and TCRG HTS not only identified clonality at diagnosis in most cases (31 of 43 for TCRB and 27 of 43 for TCRG) but also detected subsequent MRD. As expected, HTS of TCRB and TCRG identified MRD that was not detected by flow cytometry in a subset of cases (25 of 35 HTS compared with 13 of 35, respectively), which highlights the potential of this technology to define lower detection thresholds for MRD that could affect clinical treatment decisions. Thus, next-generation sequencing of lymphoid receptor gene repertoire may improve clinical diagnosis and subsequent MRD monitoring of lymphoproliferative disorders.
    Wu, D., Sherwood, A., Fromm, J. R., Winter, S. S., Dunsmore, K. P., Loh, M. L., Greisman, H. A., Sabath, D. E., Wood, B. L., Robins, H.
  • [Editors' Choice] A Tinier Target for B Cell Therapy in Multiple Sclerosis
    Obhrai, J. S.
  • [Editors' Choice] Coming Unglued: The Potential to Break Apart Biofilms
    Shrout, J. D.
  • [Editors' Choice] You May Feel Some Discomfort--or Not!
    Skarke, C.
  • [Editors' Choice] Of Bugs and Men: Antibiotics, the Gut Microbiota, and Risk of Developing Allergic Asthma
    Zeki, A. A.

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