Hydroxychloroquine Attenuates hERG Channel by Promoting the Membrane Channel Degradation: Computational Simulation and Experimental Evidence for QT-Interval Prolongation with Hydroxychloroquine Treatment.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has led to millions of confirmed cases and deaths worldwide and has no approved therapy. Currently, more than 700 drugs are tested in the COVID-19 clinical trials, and full evaluation of their cardiotoxicity risks is in high demand. METHODS: We mainly focused on hydroxychloroquine (HCQ), one of the most concerned drugs for COVID-19 therapy, and investigated the effects and underlying mechanisms of HCQ on hERG channel via molecular docking simulations. We further applied the HEK293 cell line stably expressing hERG-wild-type channel (hERG-HEK) and HEK293 cells transiently expressing hERG-p.Y652A or hERG-p.F656A mutants to validate our predictions. Western blot analysis was used to determine the hERG channel, and the whole-cell patch clamp was utilized to record hERG current (IhERG). RESULTS: HCQ reduced the mature hERG protein in a time- and concentration-dependent manner. Correspondingly, chronic and acute treatment of HCQ decreased the hERG current. Treatment with brefeldin A (BFA) and HCQ combination reduced hERG protein to a greater extent than BFA alone. Moreover, disruption of the typical hERG binding site (hERG-p.Y652A or hERG-p.F656A) rescued HCQ-mediated hERG protein and IhERG reduction. CONCLUSION: HCQ can reduce the mature hERG channel expression and IhERG via enhancing channel degradation. The QT prolongation effect of HCQ is mediated by typical hERG binding sites involving residues Tyr652 and Phe656.

Global Burden of Aortic Aneurysm and Attributable Risk Factors from 1990 to 2017.

Background: To date, our understanding of the global aortic aneurysm (AA) burden distribution is very limited. Objective: To assess a full view of global AA burden distribution and attributable risk factors from 1990 to 2017. Methods: We extracted data of AA deaths, disability-adjusted life years (DALYs), and their corresponding age-standardized rates (ASRs), in general and by age/sex from the 2017 Global Burden of Disease (GBD) study. The current AA burden distribution in 2017 and its changing trend from 1990 to 2017 were separately showed. The spatial divergence was discussed from four levels: global, five social-demographic index regions, 21 GBD regions, and 195 countries and territories. We also estimated the risk factors attributable to AA related deaths. Results: Globally, the AA deaths were 167,249 with an age-standardized death rate (ASDR) of 2.19/100,000 persons in 2017, among which the elderly and the males accounted for the majority. Although reductions in ASRs were observed in developed areas, AA remained an important health issue in those relatively underdeveloped areas and might be much more important in the near future. AA may increasingly affect the elderly and the female population. Similar patterns of AA DALYs burden were noted during the study period. AA burden attributable to high blood pressure and smoking decreased globally and there were many heterogeneities in their distribution. Discussion: AA maintained an incremental public health issue worldwide. The change pattern of AA burden was heterogeneous across locations, ages, and sexes and it is paramount to improve resource allocation for more effective and targeted prevention strategies. Also, prevention of tobacco consumption and blood pressure control should be emphasized.

Computed tomography imaging of macrophage phagocytic activity in abdominal aortic aneurysm.

Inflammation plays a major role in the pathogenesis of several vascular pathologies, including abdominal aortic aneurysm (AAA). Evaluating the role of inflammation in AAA pathobiology and potentially outcome in vivo requires non-invasive tools for high-resolution imaging. We investigated the feasibility of X-ray computed tomography (CT) imaging of phagocytic activity using nanoparticle contrast agents to predict AAA outcome. Methods: Uptake of several nanoparticle CT contrast agents was evaluated in a macrophage cell line. The most promising agent, Exitron nano 12000, was further characterized in vitro and used for subsequent in vivo testing. AAA was induced in Apoe-/- mice through angiotensin II (Ang II) infusion for up to 4 weeks. Nanoparticle biodistribution and uptake in AAA were evaluated by CT imaging in Ang II-infused Apoe-/- mice. After imaging, the aortic tissue was harvested and used from morphometry, transmission electron microscopy and gene expression analysis. A group of Ang II-infused Apoe-/- mice underwent nanoparticle-enhanced CT imaging within the first week of Ang II infusion, and their survival and aortic external diameter were evaluated at 4 weeks to address the value of vessel wall CT enhancement in predicting AAA outcome. Results: Exitron nano 12000 showed specific uptake in macrophages in vitro. Nanoparticle accumulation was observed by CT imaging in tissues rich in mononuclear phagocytes. Aortic wall enhancement was detectable on delayed CT images following nanoparticle administration and correlated with vessel wall CD68 expression. Transmission electron microscopy ascertained the presence of nanoparticles in AAA adventitial macrophages. Nanoparticle-induced CT enhancement on images obtained within one week of AAA induction was predictive of AAA outcome at 4 weeks. Conclusions: By establishing the feasibility of CT-based molecular imaging of phagocytic activity in AAA, this study links the inflammatory signal on early time point images to AAA evolution. This readily available technology overcomes an important barrier to cross-sectional, longitudinal and outcome studies, not only in AAA, but also in other cardiovascular pathologies and facilitates the evaluation of modulatory interventions, and ultimately upon clinical translation, patient management.

Epidemiological features and survival outcomes in patients with malignant pulmonary blastoma: a US population-based analysis.

BACKGROUND: Pulmonary blastoma (PB) is a rare lung primary malignancy with poorly understood risk factors and prognosis. We sought to investigate the epidemiologic features and long-term outcomes of PB. METHODS: A population-based cohort study was conducted to quantify the death risk of PB patients. All subjects diagnosed with malignant PB from 1988 to 2016 were screened from the Surveillance, Epidemiology and End Results database. Cox regression model of all-cause death and competing risk analysis of cause-specific death were performed. RESULTS: We identified 177 PB patients with a median survival of 108 months. The 5 and 10-year survival rate in all PB patients were 58.2 and 48.5%, as well as the 5 and 10-year disease-specific mortality were 33.5 and 38.6%. No sex or race disparities in incidence and prognosis was observed. The death risk of PB was significantly associated with age at diagnosis, clinical stage, histologic subtype and surgery treatment (p<0.01). On multivariable regression analyses, older age, regional stage and no surgery predicted higher risk of both all-cause and disease-specific death in PB patients. CONCLUSION: We described the epidemiological characteristics of PB and identified its prognostic factors that were independently associated with worse clinical outcome.

The Risk of Second Primary Malignancies in Patients With Lung Neuroendocrine Tumors: A Population-Based Study on SEER Database.

PURPOSE: We investigated the at-risk sites of second primary malignancies (SPMs) and evaluate the risk factors of SPMs among lung neuroendocrine tumors (LNETs) survivors by using the surveillance, epidemiology, and end results (SEER) database. METHODS: Propensity-score matching was performed to conduct a case-control study from the surveillance, epidemiology, and end results (SEER) database. Cox regression analysis and multiple primary standardized incidence ratios were performed to investigate the risk factors of occurrence of SPMs among patients with LNETs. RESULTS: Of 3,206 patients with LNETs after matching, 539 developed SPMs. The risk of developing SPMs was higher in older patients (55-74 vs ≦54: hazard ratios [HR] 1.875; age ≧75 vs ≦54: HR 2.713), higher-stage of LNETs (regional vs localized: HR 1.387; distant vs localized: HR 2.732) and recent periods of diagnosis (2004-2014 vs 1984-1993: HR 1.735). Patients with SCLC, TC and LENEC had a higher risk for SPMs compared to general population. Lung and bronchus, larynx and some digestive organs had higher risk for SPMs while some sex hormone related organs like prostate, breast, and female reproductive system had a lower incidence of SPMs. CONCLUSIONS: Patients with LNETs had overall higher risks of SPMs than general population. Different types of second primary malignancies occurred in different periods after LNETs were diagnosed. Further investigations are required to screen different second primary malignancies for those with primary LNETs.

IgA nephropathy with leucocytoclastic vasculitis.

Leucocytoclastic vasculitis is a rare type of allergic disease caused by immune complexes. IgA nephropathy is a glomerulopathy characterized by recurrent episodes of gross haematuria or microscopic haematuria and IgA deposition in the glomerular mesangial region. IgA nephropathy complicating leucocytoclastic vasculitis is rare documented. We present a case of IgA nephropathy in a 47-year-old woman with leucocytoclastic vasculitis and discuss the clinical and pathological data, aiming to promote the diagnosis and treatment of this specific clinical manifestation.

Association of genetic polymorphisms in MIF with breast cancer risk in Chinese women.

Macrophage migration inhibitory factor (MIF) has been reported to associate with increased cancer risk in several cancers. However, the role of MIF in breast cancer (BC) susceptibility remains unknown. For the first time, we conducted a case-control study to assess the potential association of three common MIF gene variants (rs755622, rs1803976, rs11548059) with BC susceptibility in Chinese women. Total 560 breast cancer patients and 583 age- and sex-matched healthy individuals were recruited from Northwest China, and the DNA was genotyped by Sequenom MassARRAY. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed to estimate the associations. We found that C/G, C/C, and C/G-C/C genotype carriers in MIF rs755622 have a significantly increased risk of BC (C/G vs. G/G: OR = 1.36, 95% CI = 1.07-1.75, P = 0.014; C/C vs. GG: OR = 2.01, 95% CI = 1.06-3.79, P = 0.029; C/G-C/C vs. G/G: OR = 1.42 95% CI = 1.11-1.80, P = 0.004). Further analyses indicate that the BC risk is associated with Ki-67 status, and the rs755622 polymorphism increases breast cancer risk among elder patients (≥49 years). There is no association between BC risk and other two polymorphisms (rs1803976 and rs11548059) by overall analysis and stratified analysis. In conclusion, MIF rs755622 polymorphism increases BC susceptibility in Chinese population, especially among elder patients.