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This file contains Supplemental figures, tables, and legends that accompany the main figures, as indicated in each legend. There are 3 supplemental tables and 6 supplemental figures. Table S1. List of potential target of the GNS compounds that were profiled in Figure 1 of the main text. Table S2. Half-maximal inhibitor concentration of the EGFR inhibitors tested. Table S3. Blood-brain-barrier penetration of the GNS compounds as assessed by the indicated pharmacokinetic measurements. Figure S1. Structural modeling studies show the binding characteristics of the indicated EGFR inhibitors. Figure S2. The effects of each EGFR inhibitor in the cell lines expressing mutant or wild type EGFR. Figure S3. In vivo effects of the GNS compounds. Figure S4. In vivo anti-tumor effects of the GNS compounds. Figure S5. In vivo anti-tumor effects of the GNS compounds in intracranial EGFR-mutant lung cancer. Figure S6. In vivo anti-tumor effects of the indicated EGFR inhibitors in intracranial EGFR-mutant lung cancer.

The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200–11. ©2017 AACR.

Supplementary Table from The Reversible Fourth-Generation EGFR Tyrosine Kinase Inhibitor OBX02–011 Overcomes C797S-Mediated Resistance in Lung Cancer

Supplementary Table 1 from Pierce1, a Novel p53 Target Gene Contributing to the Ultraviolet-Induced DNA Damage Response

Background: Obesity has been linked to atrial fibrillation (AF) burden and severity, and epidemiological studies suggest that AF is more prevalent in whites than Asian. We aimed to investigate whether obesity mediates associations with AF in Europe and Asia using patient-level data comparisons of two cohort studies. Methods: Using Korean National Health Insurance Service’s Health Screening (NHIS-HealS) and U.K. Biobank data, we included 401,206 Korean and 477,926 British aged 40–70 years without previous AF who received check-ups. The incidence and risk of AF were evaluated regarding different body mass index (BMI) values. Results: The obese proportion (BMI³30.0 kg/m2, 2.8% vs. 24.3%, PP for interactionConclusions: Obesity was associated with AF in both populations. British subjects had a greater incidence of AF related to the high proportion of obese individuals, but the risk of AF was also increased when participants into obese categories.

Supplementary Figure Legends 1-6 from Pierce1, a Novel p53 Target Gene Contributing to the Ultraviolet-Induced DNA Damage Response

To assess the utility of machine learning (ML) algorithms in predicting clinically relevant atrial high-rate episodes (AHREs), which can be recorded by a pacemaker. We aimed to develop ML-based models to predict clinically relevant AHREs based on the clinical parameters of patients with implanted pacemakers in comparison to logistic regression (LR). We included 721 patients without known atrial fibrillation or atrial flutter from a prospective multicenter (11 tertiary hospitals) registry comprising all geographical regions of Korea from September 2017 to July 2020. Predictive models of clinically relevant AHREs were developed using the random forest (RF) algorithm, support vector machine (SVM) algorithm, and extreme gradient boosting (XGB) algorithm. Model prediction training was conducted by seven hospitals, and model performance was evaluated using data from four hospitals. During a median follow-up of 18 months, clinically relevant AHREs were noted in 104 patients (14.4%). The three ML-based models improved the discrimination of the AHREs (area under the receiver operating characteristic curve: RF: 0.742, SVM: 0.675, and XGB: 0.745 vs. LR: 0.669). The XGB model had a greater resolution in the Brier score (RF: 0.008, SVM: 0.008, and XGB: 0.021 vs. LR: 0.013) than the other models. The use of the ML-based models in patient classification was associated with improved prediction of clinically relevant AHREs after pacemaker implantation.

We aimed to evaluate the long-term risk of ischemic stroke/systemic embolism of hyperthyroidism-related AF.This retrospective population-based cohort study included records of 1,034,099 atrial fibrillation patients between 2005 and 2016 from the Korean National Health Insurance Service database. After exclusion, we identified 615,724 oral anticoagulation-naïve patients aged ≥18 years with new-onset non-valvular atrial fibrillation, of whom 20,773 had hyperthyroidism-related atrial fibrillation. After 3:1 propensity score matching, ischemic stroke and systemic embolism occurrences were compared between hyperthyroidism-related and non-hyperthyroidism-related ("nonthyroidal") atrial fibrillation patients.After exclusion, we identified 615,724 oral anticoagulation-naïve AF patients of whom 20,773 had hyperthyroidism-related AF. Median follow-up duration was 5.9 years. Hyperthyroidism-related AF patients had significantly higher risks of ischemic stroke and systemic embolism than nonthyroidal AF patients (1.83 vs 1.62 per 100-person year, hazard ratio[HR], 1.13; 95% confidence interval[CI], 1.07 to 1.19; P0.001). This risk was 36% higher in hyperthyroidism-related than in nonthyroidal AF patients within 1 year of atrial fibrillation diagnosis (3.65 vs 2.67 per 100-person year, HR, 1.36; 95% CI, 1.24 - 1.50; P0.001). This difference was also observed in the CHAHyperthyroidism-related AF patients have high risks of ischemic stroke and systemic embolism like nonthyroidal AF, especially when initially diagnosed. This risk is reduced by treating hyperthyroidism.

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 < 0.001] than rate-control strategy. A consistent trend toward a lower risk of early rhythm-control was observed in the moderately frail (HR 0.91, 95% CI 0.81–1.02, p = 0.09) and highly frail (HR 0.93, 95% CI 0.75–1.17, p = 0.55) groups.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.

Anemia is a well-known risk factor for cardiovascular disease. However, there are limited data on whether anemia on admission is a long-term prognostic factor in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention. We sought to evaluate the prevalence and prognostic consequences of anemia in patients with ACS treated with percutaneous coronary intervention in Korea. We retrospectively enrolled 1930 consecutive patients. Among the anemic population (hemoglobin [Hb] 13 g/dL in men, and 12 g/dL in women), we classified patients with Hb ≥ 7 g/dL,10 d/dL as moderate anemia, other cases classified as mild anemia. Among patients with normal hemoglobin levels, we classified those with Hb 16.5 g/dL in men, and 16.0 g/dL in women, as having high hemoglobin. We examined the relationship between anemia with all-cause mortality and secondary outcomes - including cardiovascular mortality, myocardial infarction, stroke, and repeat revascularization. We classified 3.3%, 21.5%, and 5.3% of patients as moderate anemia, mild anemia, and high hemoglobin, respectively. During a median follow-up of 67.2 (interquartile range; 46.8-88.5) months, 74 (3.8%) patients died. Compared with patients with normal hemoglobin, we detected a significantly increased risk for all-cause mortality in patients with anemia (adjusted hazard ratios for moderate and mild anemia, respectively: 8.26 [95% confidence interval: 3.98-17.15], P .001 and 2.60 [1.54-4.40], P .001). Among patients with ACS, anemia is prevalent and is strongly associated with increased mortality and cardiovascular events. Clinical trials will prospectively evaluate the efficacy of treatment for anemia on the outcomes of patients with ACS.

C1q/tumor necrosis factor–related protein 9 (CTRP9) is an adipokine and has high potential as a therapeutic target. However, the role of CTRP9 in cardiovascular disease pathogenesis remains unclear. We found CTRP9 to induce HDAC7 and p38 MAPK phosphorylation via tight regulation of AMPK in vascular endothelial cells, leading to angiogenesis through increased MEF2 activity. The expression of CTRP9 and atheroprotective MEF2 was decreased in plaque tissue of atherosclerotic patients and the ventricle of post-infarction mice. CTRP9 treatment inhibited the formation of atherosclerotic plaques in ApoE KO and CTRP9 KO mice. In addition, CTRP9 induced significant ischemic injury prevention in the post-MI mice. Clinically, serum CTRP9 levels were reduced in patients with MI compared with healthy controls. In summary, CTRP9 induces a vasoprotective response via the AMPK/HDAC7/p38 MAPK pathway in vascular endothelial cells, whereas its absence can contribute to atherosclerosis and MI. Hence, CTRP9 may represent a valuable therapeutic target and biomarker in cardiovascular diseases.

The placenta regulates maternal-fetal communication, and its defect leads to significant pregnancy complications. The maternal and embryonic circulations are primitively connected in early placentation, but the function of the placenta during this developmentally essential period is relatively unknown. We thus performed a comparative proteomic analysis of the placenta before and after primary placentation and found that the metabolism and transport of lipids were characteristically activated in this period. The placental fatty acid (FA) carriers in specific placental compartments were upregulated according to gestational age, and metabolomic analysis also showed that the placental transport of FAs increased in a time-dependent manner. Further analysis of two mutant mice models with embryonic lethality revealed that lipid-related signatures could reflect the functional state of the placenta. Our findings highlight the importance of the nutrient transport function of the primary placenta in the early gestational period and the role of lipids in embryonic development. Summary Sentence The placenta is activated characteristically in terms of lipid transport during primary placentation, and the lipid-related signatures closely reflect the functional state of the placenta.

Objective : Accurate measurement of T1 slope (a component of T1s minus cervical lordosis [CL]) is often constrained by anatomical limitations. In this situation, efforts should be made to find the exact meaning of T1s-CL and whether there are any alternatives to it.Methods : We enrolled 117 patients who received two-level anterior cervical discectomy and fusion (ACDF). Occipital slope, C2 slope (C2s), C7 slope (C7s), T1, O-C2 angle (O-C2A), C2-7 angle (C2-7A), O-C7 angle (O-C7A), T1s-CL, C7-T1 angle (C7-T1A), and C2-7 sagittal vertical axis were measured. We determined 16° (T1s-CL) as the reference point for dividing subjects into the mismatch group and the balance group, and a comparative analysis was performed.Results : The mean value of C7-T1A was constantly maintained within 2.6° peri-operatively. In addition, C2s and T1s-CL showed the same absolute change (Δ|0.8|°). The mean values of T1s-CL of the mismatch and balance groups were 23.0° and 7.6°, respectively. The five factors with the largest differences between the two groups were as follows : C2s (Δ13.3°), T1s-CL (Δ15.4°), O-C2A (Δ8.7°), C2-7A (Δ14.7°), and segmental angle (Δ7.9°) before surgery. Only four factors showed statistically significant change between the two groups after ACDF : T1s-CL (Δ4.0° vs. Δ0.2°), C2s (Δ3.2° vs. Δ0.7°), O-C2A (Δ2.6° vs. Δ1.3°), C2-7A (Δ6.3° vs. Δ1.3°). A very strong correlation between T1s-CL and C2s was also found (r=|0.88–0.96|).Conclusion : C2s itself may be the essential key to represent T1s-CL. The amounts and directions of change of these two factors (T1s-CL and C2s) were also almost identical. The above phenomenon was re-confirmed once again through the correlation analysis.

Functional neuronal computing systems that support information diversification require high-density memory with selector devices to reduce leakage current in cross-point architectures, which drives us to develop a functional switching layer that operates as three distinct devices, namely non-volatile memory, selector, and synaptic devices, using a GeTe-based single material system. In this study, amorphous Ag-GeTe switching layers are engineered by doping with Te species to achieve either resistive switching (RS) or threshold switching properties. The Ag/Ag-GeTe/Ag memory device exhibits multilevel characteristics via a tunable compliance current approach. By comparison, Ag/Ag-GeTex/Ag selector device provides excellent selectivity (>106) with a very low OFF-current (∼10−11 A). The RS mechanism for memory and selector devices is interrogated by using conductive atomic force microscopy. Moreover, the Ag/Ag-GeTe/Ag RS device mimics a cohort of basic and complex synaptic plasticity properties, including potentiation-depression and four-spike time-dependent plasticity rules that include asymmetric Hebbian, asymmetric anti-Hebbian, symmetric Hebbian, and symmetric anti-Hebbian learning rules. The capability of the synaptic devices to detect image edges is demonstrated by using a convolution neural network. The present work showcases the multi-functionality of Ag-GeTe materials, which will likely emerge as a prominent candidate for high-density cross-point architecture-based neuromorphic computing systems.

Background Cytidine-5′-diphosphate choline (CDP-choline) has been suggested to exert neuroprotective and neuroreparative effects and may be beneficial for patients with stimulant dependence. This randomized, double-blind, placebo-controlled study in methamphetamine (MA) dependence investigated effects of CDP-choline on the brain structures and their associations with craving and MA use. Methods MA users (n = 44) were randomized to receive 2 g/day of CDP-choline (n = 22) or placebo (n = 22) for 8 weeks. Patients underwent brain magnetic resonance imaging (MRI) at baseline and 8-week follow-up. Healthy individuals (n = 27) were also examined using brain MRI at the same interval. Voxel-based morphometry analysis was conducted to examine changes in gray matter (GM) volumes and their associations with craving and MA use. Results Craving for MA was significantly reduced after the 8 week-treatment with CDP-choline (p = 0.01), but not with the placebo treatment (p = 0.10). There was no significant difference in the total number of MA-negative urine samples between the two groups (p = 0.19). With CDP-choline treatment, GM volumes in the left middle frontal gyrus (p = 0.001), right hippocampus (p = 0.009), and left precuneus (p = 0.001) were significantly increased compared to the placebo and control groups. Increased GM volumes in the left middle frontal gyrus with CDP-choline treatment were associated with reduced craving for MA (Spearman's ρ = −0.56, p = 0.03). In addition, the right hippocampal volume increases were positively associated with the total number of MA-negative urine results in the CDP-choline group (Spearman's ρ = 0.67, p = 0.006). Conclusion Our findings suggest that CDP-choline may increase GM volumes of MA-dependent patients, which may be related to decreases in MA use and craving.

Background The efficacy of implantable cardioverter defibrillators (ICDs) for primary prevention is controversial in patients with nonischemic heart failure (HF). We evaluated the mortality and predictors of mortality in patients with prophylactic ICD implantation for ischemic and nonischemic HF. Methods From 2008 to 2017, 1097 patients (667, nonischemic HF and 430, ischemic HF) who underwent prophylactic ICD implantation, were identified from the Korean National Health Insurance Service database. We used propensity score overlap weighting to correct the differences between two groups. Results Those with ischemic HF were older (67.0 ± 10.1 vs 61.8 ± 14.2 years), more often male (71.4% vs 63.7%), and had more comorbidities than patients with nonischemic HF. During a median follow‐up of 37.3 months (interquartile range [IQR], 14.2‐53.8 months), all‐cause mortality was higher in unweighted patients with ischemic HF than in those with nonischemic HF (10.9 vs 6.4 per 100 person‐years; hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.38‐2.20; P, In contemporary HF patients undergoing prophylactic ICD implantation in Korea, all‐cause, cardiac, and non‐cardiac mortality rates were similar between patients with non‐ischemic and ischemic HF when weighting is performed to account for differences in patient characteristics. Therefore, the benefit of prophylactic ICD therapy in HF patients should not be restricted to ischemic patients.

BACKGROUND Modified orbitozygomatic craniotomy is characterized by simplicity and wide exposure. The purpose of the present study was to describe a modified orbitozygomatic approach without resecting the zygomatic arch for large parasellar tumor surgeries. METHODS Between April 2016 and December 2019, seven patients with parasellar tumor underwent surgiest with a modified orbitozygomatic approach. Surgical procedures, clinical outcomes, and complications were analyzed. RESULTS This study included 3 meningiomas, 2 pituitary adenomas, 1 chondrosarcoma, and 1 schwannoma. Modified orbitozygomatic craniotomy provides a wider surgical freedom in the opticocarotid and prechiasmatic cistern than frontotemporal craniotomy without orbitotomy, Total, subtotal, and partial resections were achieved for 3, 2, and 2 patients, respectively. Reasons for partial resections were tight adhesion to the carotid artery and encasing of the carotid artery. Permanent morbidities developed in one patient with 3rd nerve palsy and one patient with hemiparesis. CONCLUSION Modified orbitozygomatic approach can provide the shortest access to the interpeduncular cistern with a minimum brain retraction. Surgeons who experience surgical challenge during the conventional approach for parasellar tumor resection are recommended to learn the modified orbitozygomatic approach.

Inflammation plays a pivotal role in acute ischemic stroke, and various inflammatory markers are known to predict prognosis of acute ischemic stroke. This study aimed to evaluate the prognostic value of systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) after mechanical thrombectomy (MT) for acute ischemic stroke caused by large artery occlusion.The study enrolled 440 patients who underwent MT for large artery occlusion. SIRI and SII were calculated using laboratory data on admission. Prognosis was estimated with modified Rankin Scale at 3 months, and favorable clinical outcome was defined by a modified Rankin Scale score of 0-2. Receiver operating characteristic analysis was used to calculate the optimal cutoff values of SIRI and SII for predicting clinical outcome. Multivariate analysis was used to assess the relationship of SIRI and SII with clinical outcome.In receiver operating characteristic analysis, the optimal cutoff values for SIRI and SII were 2.9 and 853, respectively (area under the curve 0.799, 95% confidence interval [CI] 0.756-0.843, P0.001 and area under the curve 0.679, 95% CI 0.643-0.745, P0.001, respectively). Multivariate analysis revealed that SIRI2.9 (odds ratio 2.27, 95% CI 1.29-5.17, P = 0.019) and SII853 (OR 1.82, 95% CI 1.16-3.10, P = 0.031) were independent predictors of favorable clinical outcome after MT.Decreased SIRI and SII were associated with favorable clinical outcome after MT. SIRI and SII represent potential prognostic factors in patients undergoing MT for large artery occlusion.

Background Catheter ablation is more effective than antiarrhythmic drug therapy alone in patients with atrial fibrillation (AF). However, there are limited data on the outcomes of AF ablation according to sex. The purpose of this study was to evaluate gender differences in the actual outcomes after catheter ablation for atrial fibrillation. Methods Of 801,710 patients with AF in the Korean National Health Insurance Service database, we identified 9175 patients without valvular heart disease who underwent AF ablation between 2006 and 2015 and assessed 30-day safety and one-year effectiveness outcomes according to sex. Results Of the 9175 patients who underwent AF ablation, 2206 (24%) were female. Women, compared to men, were older (60.8 ± 10.2 vs. 56.0 ± 10.5 years), had higher CHA2DS2-VASc (3.5 ± 1.7 vs. 2.0 ± 1.6), higher HAS-BLED (2.6 ± 1.3 vs. 2.4 ± 1.2), and higher Charlson comorbidity index scores (3.8 ± 2.6 vs. 3.1 ± 2.5) (p Conclusion Women who underwent AF ablation did not differ from men in terms of the risk of complications and all-cause hospitalization in this study. The small increased risk in women reported in previous studies may be related to residual confounding, particularly from insufficient control for age and comorbidities.