Browsing by Author "Shapiro, Scott"

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    Aging- and Tumor-Mediated Increase in CD8+CD28- T Cells Might Impose a Strong Barrier to Success of Immunotherapy in Glioblastoma
    (American Association of Immunologists, 2021-06-08) Huff, Wei X.; Bam, Marpe; Shireman, Jack M.; Kwon, Jae Hyun; Song, Leo; Newman, Sharlé; Cohen-Gadol, Aaron A.; Shapiro, Scott; Jones, Tamara; Fulton, Kelsey; Liu, Sheng; Tanaka, Hiromi; Liu, Yunlong; Wan, Jun; Dey, Mahua; Neurological Surgery, School of Medicine
    Clinical use of various forms of immunotherapeutic drugs in glioblastoma (GBM), has highlighted severe T-cell dysfunction such as exhaustion in GBM patients. However, reversing T-cell exhaustion using immune checkpoint inhibitors in GBM clinical trials has not shown significant overall survival benefit. Phenotypically, CD8+ T cells with downregulated CD28 co-receptors, low CD27 expression, increased CD57 expression, and telomere shortening, are classified as senescent T cells. These senescent T cells are normally seen as part of aging and also in many forms of solid cancers. Absence of CD28 on T-cells leads to several functional irregularities including reduced TCR diversity, incomplete activation of T cells, and defects in antigen induced proliferation. In the context of GBM, presence and/or function of these CD8+CD28− T-cells is unknown. In this clinical correlative study, we investigated the effect of aging as well as tumor microenvironment on CD8+ T-cell phenotype as an indicator of its function in GBM patients. We systematically analyzed and describe a large population of CD8+CD28− T-cells in both the blood and tumor infiltrating lymphocytes of GBM patients. We found that phenotypically these CD8+CD28− T-cells represent a distinct population compared to exhausted T-cells. Comparative transcriptomic and pathway analysis of CD8+CD28− T cell populations in GBM patients revealed that tumor microenvironment might be influencing several immune related pathways and thus further exaggerating the age associated immune dysfunction in this patient population.
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    Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury
    (Wolters Kluwer, 2022) Herr, Seth A.; Shi, Liangqin; Gianaris, Thomas; Jiao, Yucheng; Sun, Siyuan; Race, Nick; Shapiro, Scott; Shi, Riyi; Neurological Surgery, School of Medicine
    Lipid peroxidation-derived aldehydes, such as acrolein, the most reactive aldehyde, have emerged as key culprits in sustaining post-spinal cord injury (SCI) secondary pathologies leading to functional loss. Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2 (ALDH2), a key oxidoreductase and powerful endogenous anti-aldehyde machinery, is likely important for protecting neurons from aldehydes-mediated degeneration. Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator (Alda-1), we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2. Over an acute 2 day period post injury, we found that ALDH2 expression was significantly lowered post-SCI, but not so in rats given Alda-1. This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction, which was revealed in co-immunoprecipitation experiments. We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord, and reduced cyst pathology. In addition, Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI. Finally, ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure. It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims. All animal work was approved by Purdue Animal Care and Use Committee (approval No. 1111000095) on January 1, 2021.
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    Efficacy of pre-operative stereotactic radiosurgery followed by surgical resection and correlative radiobiological analysis for patients with 1-4 brain metastases: study protocol for a phase II trial
    (Biomed Central, 2018-12-20) Huff, Wei X.; Agrawal, Namita; Shapiro, Scott; Miller, James; Kulwin, Charles; Shah, Mitesh; Savage, Jesse J.; Payner, Troy; Vortmeyer, Alexander; Watson, Gordon; Dey, Mahua; Neurological Surgery, School of Medicine
    BACKGROUND: Stereotactic radiosurgery (SRS) has emerged as a common adjuvant modality used with surgery for resectable brain metastases (BMs). However, the optimal sequence of the multi-modality therapy has not been established. The goal of the study is to evaluate 6-month local control utilizing pre-operative SRS followed by surgical resection for patients with 1-4 brain metastases. METHODS: This prospective, single arm, phase II trial will recruit patients with up to 4 brain metastases and at least one resectable lesion. All lesions will be treated with SRS and symptomatic lesions will be resected within 1-4 days after SRS. Patients will be monitored for 6-month local control, in-brain progression free survival, distant in-brain failure, rate of leptomeningeal spread, radiation necrosis and overall survival. Additionally, we will also perform correlative radiobiological molecular studies to assess the effect of radiation dosing on the tumor tissue and clinical outcomes. We expect that pre-operative SRS to the gross tumor prior to surgical resection will improve local control and decrease leptomeningeal failure. DISCUSSION: Our study is the second prospective trial to investigate the efficacy of pre-operative SRS in the treatment of multiple BMs. In addition, the correlative molecular studies will be the first to investigate early response of BMs at a cellular and genetic level in response to radiation doses and potentially provide molecular prognostic markers for local control and overall survival.