Search

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Background: Florbetapir (AV45) and fluorodeoxyglucose (FDG) PET imaging are valuable techniques to detect the amyloid-β (Aβ) load and brain glucose metabolism in patients with Alzheimer’s disease (AD). Objective: The purpose of this study is to access the characteristics of Aβ load and FDG metabolism in brain for further investigating their relationships with cognitive impairment in AD patients. Methods: Twenty-seven patients with AD (average 70.6 years old, N = 13 male, N = 14 female) were enrolled in this study. These AD patients underwent the standard clinical assessment and received detailed imaging examinations of the nervous system by using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), 18F-AV45, and 18F-FDG PET scans. Results: Of 27 AD patients, 22 patients (81.5%) showed significantly increases in Aβ load and 26 patients (96.3%) had significantly reductions in FDG metabolism. The moderate AD patients had more brain areas of reduced FDG metabolism and more severe reductions in some regions compared to mild AD patients, with no differences in Aβ load observed. Moreover, the range and degree of reduced FDG metabolism in several regions were positively correlated with the total score of MMSE or MOCA, whereas the range of Aβ load did not. No correlation was found between the range of Aβ load and the range of reduced FDG metabolism in this study. Conclusion: The reduction in FDG metabolisms captured by 18F-FDG imaging can be used as a potential biomarker for AD diagnosis in the future. 18F-AV45 imaging did not present valuable evidence for evaluating AD patient in this study.

Introduction It has been reported that environmental factors such as hypoxia could contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutics like hyperbaric oxygen treatment, which improves tissue oxygen supply and ameliorates hypoxic conditions in the brain, may be an alternative therapy for AD and amnestic mild cognitive impairment (aMCI). The present work aims to investigate the potential therapeutic effect of hyperbaric oxygen treatment for AD and aMCI. Methods We recruited 42 AD, 11 aMCI, and 30 control AD patients in this study. AD and aMCI patients were treated with 40 minutes of hyperbaric oxygen once a day for 20 days and assessed by neuropsychiatric assessments including Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Activities of Daily Living (ADL) scale before and at 1‐, 3‐, and 6‐month follow‐up after treatment. Control AD patients who were not given hyperbaric oxygen treatment had similar clinical profile as hyperbaric oxygen treated AD. We examined 10 of the AD/aMCI patients with fluorodeoxyglucose positron emission tomography. Results In self‐comparison study, one course of hyperbaric oxygen treatment significantly improved the cognitive function assessed by MMSE and MoCA in AD patients after 1‐month follow‐up; such treatment also significantly improved MMSE score at 3‐month follow‐up and MoCA score at 1‐ and 3‐month follow‐up in aMCI patients. The ADL scale was significantly improved in AD patients after 1‐ and 3‐month follow‐up. Compared to the control AD patients, the MMSE and MoCA in hyperbaric oxygen treated AD patients were significantly improved after 1‐month follow‐up. Hyperbaric oxygen treatment also ameliorated the reduced brain glucose metabolism in some of the AD and aMCI patients. Conclusion Based on previous studies and our recent findings, we propose that hyperbaric oxygen treatment may be a promising alternative therapy for AD and aMCI.

The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, we developed an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, Erb-IL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8(+) T cells in the TME. We observed that the IL-21–mediated antitumor effect largely depended on the existing intratumoral CD8(+) T cells, instead of newly migrated CD8(+) T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen–specific CD8(+) T cells to achieve effective tumor control.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non-small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand-1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.

OBJECTIVES: Parkinson’s disease (PD) and the parkinsonian variant of multiple system atrophy (MSA-P) are distinct neurodegenerative disorders that share similar clinical features of parkinsonism. The morphological alterations of these diseases have yet to be understood. The purpose of this study was to evaluate gray matter atrophy in PD and MSA-P using regions of interest (ROI)-based measurements and voxel-based morphometry (VBM). METHODS: We studied 41 patients with PD, 20 patients with MSA-P, and 39 controls matched for age, sex, and handedness using an improved T1-weighted sequence that eased gray matter segmentation. The gray matter volumes were measured using ROI and VBM. RESULTS: ROI volumetric measurements showed significantly reduced bilateral putamen volumes in MSA-P patients compared with those in PD patients and controls (p

Summary Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.

Entorhinal cortex (EC), thought to be the location of the earliest lesions in Alzheimer’s disease (AD), has been widely studied in recent years. With the irreversible pathological changes of AD, there is an urgent need to find biomarkers that can be used to predict the presence of the disease before it is clinically expressed. The aim of this review is to summarize and analyze recent findings that are relevant to the important role of EC in the diagnosis of mild cognitive impairment (MCI) and mild AD and to describe a range of neuroimaging techniques used to define the EC boundary. A comprehensive literature search for articles published up to May 2015 was performed. Our research highlights the finding that atrophy in EC reflects the early pathological changes of AD and can be a strong predictor of prodromal AD. The early changes in EC are a good imaging biomarker that can be used to discriminate individuals with MCI from normal control subjects. A larger degree of atrophy in EC predicts increased disease severity, and the right EC in patients with mild AD exhibited greater changes than the left side. In addition, the EC seems to have an obvious advantage over the hippocampus as a biomarker when predicting future conversion to AD in individuals with MCI, and it may be of help in following the course of disease progression. In this review, we also summarize the main differences observed between the hippocampus and the EC when differentiating diseases. These findings will hopefully provide an opportunity for the effective prevention and early treatment of AD.