IMPORTANCE Microglia, the resident immune cells of the central nervous system, play an important role in the brain's response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury. OBJECTIVE To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level-, and body mass index-matched control participants. This study was conducted at an academic research institution
Proteasome is a protein degradation complex that plays a major role in maintaining cellular homeostasis. Despite extensive efforts to identify protein substrates that are degraded through ubiquitination, the regulation of proteasome activity itself under diverse signals is poorly understood. In this study, we have isolated iRhom1 as a stimulator of proteasome activity from genome-wide functional screening using cDNA expression and an unstable GFP-degron. Downregulation of iRhom1 reduced enzymatic activity of proteasome complexes and overexpression of iRhom1 enhanced it. Native-gel and fractionation analyses revealed that knockdown of iRhom1 expression impaired the assembly of the proteasome complexes. The expression of iRhom1 was increased by endoplasmic reticulum (ER) stressors, such as thapsigargin and tunicamycin, leading to the enhancement of proteasome activity, especially in ER-containing microsomes. iRhom1 interacted with the 20S proteasome assembly chaperones PAC1 and PAC2, affecting their protein stability. Moreover, knockdown of iRhom1 expression impaired the dimerization of PAC1 and PAC2 under ER stress. In addition, iRhom1 deficiency in D. melanogaster accelerated the rough-eye phenotype of mutant Huntingtin, while transgenic flies expressing either human iRhom1 or Drosophila iRhom showed rescue of the rough-eye phenotype. Together, these results identify a novel regulator of proteasome activity, iRhom1, which functions via PAC1/2 under ER stress.
The inherent instability of nucleic acids within serum and the tumor microenvironment necessitates a suitable vehicle for non-viral gene delivery to malignant lesions. A specificity-conferring mechanism is also often needed to mitigate off-target toxicity. In the present study, we report a stable and efficient redox-sensitive nanoparticle system with a unique core–shell structure as a DNA carrier for cancer theranostics. Thiolated polyethylenimine (PEI-SH) is complexed with DNA through electrostatic interactions to form the core, and glycol chitosan-modified with succinimidyl 3-(2-pyridyldithio)propionate (GCS-PDP) is grafted on the surface through a thiolate-disulfide interchange reaction to form the shell. The resulting nanoparticles, GCS-PDP/PEI-SH/DNA nanoparticles (GNPs), exhibit high colloid stability in a simulated physiological environment and redox-responsive DNA release. GNPs not only show a high and redox-responsive cellular uptake, high transfection efficiency, and low cytotoxicity in vitro, but also exhibit selective tumor targeting, with minimal toxicity, in vivo, upon systemic administration. Such a performance positions GNPs as viable candidates for molecular-genetic imaging and theranostic applications.
Carbonic anhydrase IX (CAIX) is a cell surface enzyme that is over-expressed in approximately 95% of clear cell renal cell carcinomas (ccRCCs), the most common renal cancer. CAIX is also a surrogate marker of hypoxic tumors for various human cancers; however, a clinically viable molecular imaging agent targeting CAIX is not available. We have synthesized and performed in vitro and in vivo evaluation of a dual-motif, low-molecular-weight inhibitor of CAIX, [64Cu] XYIMSR-06, for imaging CAIX expression on ccRCC tumors using positron emission tomography (PET). [64Cu] XYIMSR-06 was synthesized in two steps from reported dual-motif precursor 1. Upon radiolabeling, [64Cu] XYIMSR-06 was evaluated in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors for in vivo PET imaging and biodistribution. [64Cu] XYIMSR-06 was generated in radiochemical yields of 51.0 ± 4.5% (n = 5) and specific radioactivity of 6.0 GBq/μmol (170Ci/mmol ± 70, n = 5). Tumor could be visualized on PET images by 1 h post-injection with high tumor-to-background levels achieved within 24 h. Biodistribution studies of [64Cu] XYIMSR-06 demonstrated a maximum tumor uptake of 19.3 ± 4.51% injected dose per gram of radioactivity at 4 h. Tumor-to- blood, muscle and kidney ratios were 129.6 ± 18.8, 84.3 ± 21.0 and 2.1 ± 0.26, respectively, at 8 h post-injection. At 24 h, a tumor-to-kidney ratio of 7.1±2.5 was achieved. These findings represent increased tumor-to-background ratios at the indicated times relative to previously reported CAIX-targeted imaging agents. [64Cu] XYIMSR-06 is a promising candidate for PET imaging of CAIX expressing tumors, especially ccRCC. Citation Format: IL MINN, Soo Min Koo, Hye Soo Lee, Mary Brummet, Steven P. Rowe, Michael A. Gorin, Polina Sysa-Shah, William D. Lewis, Hye-Hyun Ahn, Yuchuan Wang, Sangeeta Ray, Ronnie C. Mease, Sridhar Nimmagadda, Mohamad E. Allaf, Martin G. Pomper, Xing Yang. A dual-motif CAIX inhibitor, [64Cu]XYIMSR-06, for PET imaging of clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4206.
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