Evaluation of connectivity map-discovered celastrol as a radiosensitizing agent in a murine lung carcinoma model: Feasibility study of diffusion-weighted magnetic resonance imaging

<div><p>This study was designed to identify potential radiosensitizing (RS) agents for combined radio- and chemotherapy in a murine model of human lung carcinoma, and to evaluate the <i>in vivo</i> effect of the RS agents using diffusion-weighted magnetic resonance imaging (DW-MRI). Radioresistance-associated genes in A549 and H460 cells were isolated on the basis of their gene expression profiles. Celastrol was selected as a candidate RS by using connectivity mapping, and its efficacy in lung cancer radiotherapy was tested. Mice inoculated with A549 carcinoma cells were treated with single ionizing radiation (SIR), single celastrol (SC), or celastrol-combined ionizing radiation (CCIR). Changes in radiosensitization over time were assessed using DW-MRI before and at 3, 6, and 12 days after therapy initiation. The tumors were stained with hematoxylin and eosin at 6 and 12 days after therapy. The percentage change in the apparent diffusion coefficient (ADC) value in the CCIR group was significantly higher than that in the SC and SIR group on the 12^th day (Mann–Whitney U-test, p = 0.05; Kruskal–Wallis test, p < 0.05). A significant correlation (Spearman’s rho correlation coefficient of 0.713, p = 0.001) was observed between the mean percentage tumor necrotic area and the mean ADC values after therapy initiation. These results suggest that the novel radiosensitizing agent celastrol has therapeutic effects when combined with ionizing radiation (IR), thereby maximizing the therapeutic effect of radiation in non–small cell lung carcinoma. In addition, DW-MRI is a useful noninvasive tool to monitor the effects of RS agents by assessing cellularity changes and sequential therapeutic responses.</p></div

Dependence of the In-Plane Thermal Conductivity of Graphene on Grain Misorientation

The thermal transport across the grain boundary (GB) is inevitably encountered for large-area polycrystalline graphene. However, the influence of GB configuration on thermal transport is not well understood. Here we investigated the effect of grain misorientation angle on the in-plane thermal conductivity (κ) of suspended graphene by using the optothermal Raman technique. Graphene with well-defined grain orientation was synthesized on an electropolished, annealed, and oxygen plasma-treated single-crystalline Cu(111) substrate by low-pressure chemical vapor deposition. The κ was primarily dependent on the grain size of single-, bi-, and polycrystalline graphene, consistent with the Boltzmann transport model. Surprisingly, κ of bicrystalline graphene dramatically decreased with a slight misorientation (<4°) between two neighboring grains. This phonon-boundary scattering was successfully simulated by the GB misorientation model. The GB length or shape also affected κ as a tertiary parameter. The GB misorientation angle and length, in addition to the grain size, were determining factors of κ, which may be applicable for other two-dimensional materials

The top 30 drugs for A549 and H460 cells that were selected using connectivity map.

<p>The top 30 drugs for A549 and H460 cells that were selected using connectivity map.</p

Identification of candidate radiosensitizers using a connectivity map.

<p>Genes with a false discovery rate-adjusted p value (p < 0.05) and a fold change >1.5 were considered DEGs. Connectivity mapping between A549 and H460 cells gene signatures is shown. Four drugs show overlap in the top 30 drug list for both lung cancer cell lines.</p

Histologic analysis of the tumor response.

<p>(A) The mean percentage tumor necrotic fraction was determined from hematoxylin and eosin- (H&E) stained sections after ionizing radiation (IR), celastrol, and combined IR celastrol therapy at day 6 and 12 after treatment initiation (original magnification, ×100). (B) Graph of the percentage necrotic area in H&E-stained sections. Tumors treated with the combined IR and celastrol therapy showed a significantly (p = 0.05) larger necrotic area at day 6 and 12 than that observed in the IR and celastrol mono-treatment groups. *p = 0.05 (statistically significant). SIR, single ionizing radiation; SC, single celastrol; CCIR, celastrol-combined ionizing radiation.</p

Characteristics of each group classified by the results of provocation test.

<p>Characteristics of each group classified by the results of provocation test.</p

Data_Sheet_1_Impact of frailty on early rhythm control outcomes in older adults with atrial fibrillation: A nationwide cohort study.docx

PurposeRhythm-control therapy administered early following the initial diagnosis of atrial fibrillation (AF) has superior cardiovascular outcomes compared to rate-control therapy. Frailty is a key factor in identifying older patients’ potential for improvement after rhythm-control therapy. This study evaluated whether frailty affects the outcome of early rhythm-control therapy in older patients with AF.MethodsFrom the Korean National Health Insurance Service database (2005–2015), we collected 20,611 populations aged ≥65 years undergoing rhythm- or rate-control therapy initiated within 1 year of AF diagnosis. Participants were emulated by the EAST-AFNET4 trial, and stratified into non-frail, moderately frail, and highly frail groups based on the hospital frailty risk score (HFRS). A composite outcome of cardiovascular-related mortality, myocardial infarction, hospitalization for heart failure, and ischemic stroke was compared between rhythm- and rate-control.ResultsEarly rhythm-control strategy showed a 14% lower risk of the primary composite outcome in the non-frail group [weighted incidence 7.3 vs. 8.6 per 100 person-years; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.79–0.93, p ConclusionAlthough the degree attenuated with increasing frailty, the superiority of cardiovascular outcomes of early rhythm-control in AF treatment was maintained without increased risk for safety outcomes. An individualized approach is required on the benefits of early rhythm-control therapy in older patients with AF, regardless of their frailty status.</p

Correlation between the mean ADC change and percentage tumor necrotic fraction.

<p>The mean ADC values correlated with the percentage tumor necrotic fraction calculated from the H&E-stained sections from the A549 tumors. Spearman’s rank-order correlation test was applied to calculate the Spearman correlation coefficient (rho = 0. 713, p = 0.001). The solid lines are the result of the linear regression on the data.</p

A new test for diagnosing vasovagal syncope: Standing after treadmill test with sublingual nitrate administration

<div><p>Introduction</p><p>Increased adrenergic tone might be an additional trigger of orthostatic stress of vasovagal syncope (VVS). Exercise before standing might provide increased sensitivity compared to standing using a sublingual nitroglycerines protocol during tilt table testing. The aim of this study was to evaluate the diagnostic value of treadmill testing before standing with nitroglycerin administration.</p><p>Methods and results</p><p>A total of 36 patients with syncope or presyncope were enrolled for the test. VVS was confirmed in 29 patients according to the Calgary Score (≥ -2), including 20 patients who were likely to have typical (classical) VVS. All 36 subjects were subjected to a novel provocation test consisting of treadmill test using the Bruce protocol followed by standing with administration of 300 μg sublingual nitroglycerin. Consequently, syncope or presyncope occurred in 22 patients of the 36 patients. The sensitivity and a specificity of the test for Calgary score based VVS was 82.7% and 85.75%, respectively. Reproducibility rate for typical VVS was 90% (18 of 20). In all symptomatic patients, systolic blood pressure dropped to < 90 mmHg and symptom occurred a mean of 6.7 ± 2.3 minutes after the nitroglycerine administration. No patient required anticholinergics injection to restore vital signs.</p><p>Conclusions</p><p>Treadmill test with administration of sublingual nitroglycerines might be safely used to reproduce syncope in patients with VVS. More clinical experience and confirmation are needed to validate this protocol.</p></div

The effect of celastrol-combined IR treatment on cell survival and proliferation.

<p>The clonogenic survival was significantly decreased in both (A) A549 and (B) H460 cells exposed to an IR of 2–6 Gy and celastrol treatment (p ≤ 0.05). DMOG did not significantly reduce the survival of A549 and H460 cells exposed to these IR doses (p > 0.05). IR, ionizing radiation; DMOG, dimethyloxalylglycine.</p