CDGSH iron–sulfur domain‐containing protein 2 (Cisd2), a protein that declines in an age‐dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two‐fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ‐mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild‐type mice. These findings highlight Cisd2‐based therapies as a potential disease‐modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Abstract. The hepatitis B virus X protein (HBx) critically modulates cell growth by inducing apoptosis or proliferation. We sought to clarify whether HBx-mediated apoptosis in a CCL13 stable cell line (Chang-HBx) with inducible HBx expression proceeds through the extrinsic (death receptormediated) and/or intrinsic (mitochondrial-mediated) pathways of apoptosis. We used western blotting, cell viability assays, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, caspase activity assays, JC-1 staining and DNA fragmentation analysis to study the role of HBx in apoptosis. The expression of the pro-apoptotic proteins Bax and Bad and the release of cytochrome c also increased slightly upon HBx induction. JC-1 staining showed a loss of mitochondrial membrane potential upon HBx induction. Additionally, induction of HBx increased the levels of cleaved caspase-9 (intrinsic pathway), caspase-8 (extrinsic pathway) and the common effector caspase-3 as measured by western blotting. This elevation of cleaved caspase-8 or caspase-3 and caspase-9 or caspase-3 decreased in the presence of caspase-8 inhibitor Z-IETD-FMK or caspase-9 inhibitor Z-LEHD-FMK, respectively. Both inhibitors also rescued cell growth, and the caspase-8 inhibitor Z-IETD-FMK prevented apoptotic phenomena including the TUNEL signal. DNA fragmentation analysis showed that these phenomena were not detected in the presence of higher concentration of inhibitors. Our data suggest that HBx induces apoptosis through both extrinsic and intrinsic pathways.

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Background: Atrial fibrillation (AF) is associated with an increased risk of heart failure, death and thromboembolism. AF is prevalent in patients with cancer. Although current guidelines suggest the application of oral anticoagulants (OACs) for thromboembolic event prevention in high-risk AF patients, owing to the high thromboembolic and bleeding risks of active-cancer patients, there is no consensus on the use of OACs in such a population. Therefore, we conducted this retrospective cohort study to investigate the applicability of the CHA2DS2-VASc score and to evaluate the efficacy and safety outcomes of OAC therapy in active-cancer patients with AF. Methods: This retrospective cohort study enrolled patients diagnosed with cancer at National Cheng Kung University Hospital between November 2012 and August 2019. The primary outcomes included all-cause mortality, thromboembolic events (stroke/transient ischemic attack and systemic emboli), acute myocardial infarction (AMI), hospitalization for HF and major bleeding events. Results: We enrolled 2429 patients with active cancer. Among these patients, 1060 patients (43.6%) had AF. After 1:2 propensity score matching, 690 cancer patients with AF were enrolled for the final analysis, grouped as follows: 225 patients taking OACs and 465 patients without OAC treatment. The OAC-treated group had lower all-cause mortality than the patients without OAC treatment (all-cause mortality rate in OAC treatment vs. non-OAC treatment: 24.4% vs. 37.4%, hazard ratio 0.58 [95% confidence interval (CI) 0.43-0.78], p < 0.001). However, there was no difference in thromboembolic events, myocardial infarction or heart failure hospitalization between the OAC-treated and non-OACtreated groups. Importantly, the risk of major bleeding composition (i.e., major gastrointestinal bleeding and intracranial hemorrhage) was similar between these two groups. Moreover, the CHA2DS2-VASc score could not predict thromboembolic events in the enrolled active-cancer patients with AF (OR 1.23, 95% CI 0.98-1.56). Conclusions: OAC treatment may significantly reduce the risk of death, without safety concerns, in active-cancer patients with AF. OAC treatment may not prevent thromboembolic events in patients with active cancer and AF. However, we found that OAC treatment is associated with improved prognosis without increasing the risks of major bleeding, despite several limitations in this study. Further studies are required to determine the optimal use of anticoagulation therapy in this high-risk population.