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Background The prognostic implication of mildly reduced ejection fraction (mrEF) after acute myocardial infarction has not been clearly demonstrated. We investigated the long‐term risk of cardiovascular death and its predictors in patients with mrEF following acute myocardial infarction. Methods and Results A total of 18 668 patients who presented with acute myocardial infarction were included in 2 prospective, multicenter registries. The incidence of adverse cardiovascular events according to the left ventricular ejection fraction (EF) strata at index admission were evaluated. A score system consisting of clinical variables were developed to predict long‐term cardiovascular death in the mrEF group. There were 2548 patients with reduced EF (EF ≤40%), 4266 patients with mrEF (EF 41%–49%), and 11 854 patients with preserved EF (EF ≥50%). During a median follow‐up period of 37.9 months, the cardiovascular death rate was 22.3% in the reduced EF group, 10.3% in the mrEF group, and 7.3% in the preserved EF group (P65 years, hypertension, stroke, severe renal insufficiency, and Killip class ≥3 were independent predictors for cardiovascular death. Presence of >2 predictors best discriminated the high‐risk patients for cardiovascular death with an area under the curve of 0.746. Incidence of cardiovascular death in the high‐risk mrEF group was comparable with the rEF group, while it was lower in the low‐risk mrEF group than in the pEF group. Conclusions Patients with mrEF after acute myocardial infarction had a modest risk of cardiovascular death. Clinical predictors could help discriminate a high‐risk subpopulation with cardiovascular death risks comparable with those in the reduced EF group.

Background Little is known about the characteristics and long‐term clinical outcomes of patients with heart failure with improved ejection fraction (HFimpEF) after acute myocardial infarction. Methods and Results From a multicenter, consecutive cohort of patients with acute myocardial infarction undergoing percutaneous coronary intervention, patients with an initial echocardiogram with left ventricular ejection fraction ≤40% and at least 1 follow‐up echocardiogram after 14 days and within 2 years of the initial event were considered for analyses. HFimpEF was defined as an initial left ventricular ejection fraction ≤40% and serial left ventricular ejection fraction >40% with an increase of ≥10% from baseline at follow‐up. Independent factors predicting HFimpEF were identified, and clinical outcomes of patients with HFimpEF were compared with those without improvement. From an initial cohort of 10 719 patients with acute myocardial infarction, 191 patients with HFimpEF and 256 patients with non‐HFimpEF who had initial and follow‐up echocardiographic data were analyzed. The median follow‐up duration was 4.5 (interquartile range, 2.9–5.0) years. The factors predicting HFimpEF were lower peak creatine kinase myocardial band, smaller left ventricular dimensions, lower ratio between early mitral inflow velocity and mitral annular early diastolic velocity ′, and the use of β blockers or renin–angiotensin system blockers at discharge. HFimpEF was associated with a significantly decreased risk of all‐cause death compared with non‐HFimpEF (hazard ratio, 0.377 [95% CI, 0.234–0.609]; P

Abstract Background About 3%–5% of non‐small cell lung cancer (NSCLC) presents positive anaplastic lymphoma kinase (ALK). Recently, several target agents have been approved as a treatment for ALK‐positive NSCLC. This study aimed to analyze the real‐world efficacy and outcome when administered crizotinib, the first approved target agent for ALK‐positive NSCLC, according to first‐ or late‐line treatment. Methods A total of 290 patients with ALK‐positive advanced NSCLC who were treated with crizotinib in 15 institutions in South Korea from January 2009 to December 2018 were enrolled. Results The median age of patients was 57.0 years, and 50.3% were male. The median follow‐up duration was 29.3 months. Among them, 113 patients received crizotinib as first‐line therapy. The objective response rate (ORR) was 60.1% (57.0% for first‐line recipients, 61.8% for second−/later‐line). Median (95% CI) progression‐free survival (PFS) was 13.7 (11.6–17.0) months. For first‐line recipients, overall survival (OS) was 26.3 (17.6–35.0) months. No significant difference in ORR, PFS and OS, according to the setting of crizotinib initiation, was observed. In a multivariate Cox regression analysis, old age, male gender, initially metastatic, and number of metastatic organs were associated with poor PFS and OS. The most common adverse events were nausea and vomiting, and severe adverse event leading to dose adjustment was hepatotoxicity. Conclusions ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials. Our findings could aid in the efficient management of ALK‐positive lung cancer patients.

Abstract Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β‐glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin‐induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β‐Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β‐glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β‐glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury‐mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury‐mediated disorders.

Abstract Background Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy‐induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha‐like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy‐induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy‐induced cachexia in tumour‐bearing mice. Methods Anti‐GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15‐induced signalling was evaluated using western blotting. To investigate the in vivo function of A11, a tumour‐bearing mouse model was established by inoculating 8‐week‐old male C57BL/6 mice with B16F10 cells (n = 10–16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis. Results A11 reduced serum response element‐luciferase reporter activity up to 74% (P

Abstract Intracellular C‐terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP‐C31 that is suspected to be involved in the pathology of AD. But details about the role of APP‐C31 in the development of the disease are not known. Here, this work reports that APP‐C31 directly interacts with the N‐terminal and self‐recognition regions of amyloid‐β40 (Aβ40) to form transient adducts, which facilitates the aggregation of both metal‐free and metal‐bound Aβ40 peptides and aggravates their toxicity. Specifically, APP‐C31 increases the perinuclear and intranuclear generation of large Aβ40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aβ40‐induced degeneration of neurites and inflammation are also intensified by APP‐C31 in human neurons and murine brains. This study demonstrates a new function of APP‐C31 as an intracellular promoter of Aβ40 amyloidogenesis in both metal‐free and metal‐present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.

Abstract Climate change is globally affecting rainfall patterns, necessitating the improvement of drought tolerance in crops. Sorghum bicolor is a relatively drought‐tolerant cereal. Functional stay‐green sorghum genotypes can maintain green leaf area and efficient grain filling during terminal post‐flowering water deprivation, a period of ~10 weeks. To obtain molecular insights into these characteristics, two drought‐tolerant genotypes, BTx642 and RTx430, were grown in replicated control and terminal post‐flowering drought field plots in California's Central Valley. Photosynthetic, photoprotective, and water dynamics traits were quantified and correlated with metabolomic data collected from leaves, stems, and roots at multiple timepoints during control and drought conditions. Physiological and metabolomic data were then compared to longitudinal RNA sequencing data collected from these two genotypes. The unique metabolic and transcriptomic response to post‐flowering drought in sorghum supports a role for the metabolite galactinol in controlling photosynthetic activity through regulating stomatal closure in post‐flowering drought. Additionally, in the functional stay‐green genotype BTx642, photoprotective responses were specifically induced in post‐flowering drought, supporting a role for photoprotection in the molecular response associated with the functional stay‐green trait. From these insights, new pathways are identified that can be targeted to maximize yields under growth conditions with limited water.

Abstract Introduction The PACIFIC study demonstrated that durvalumab consolidation therapy significantly improved progression‐free survival (PFS) and overall survival (OS) in patients with unresectable stage III non‐small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). However, there was no clinical benefit in both PFS and OS in epidermal growth factor receptor (EGFR) mutation‐positive patient groups in a post hoc exploratory analysis. Moreover, the clinical effects of immune checkpoint inhibitors (ICIs) in EGFR mutation‐positive stage IV NSCLC were demonstrated to be poor. Personalized treatment according to the mutation status is also required in stage III NSCLC. Lazertinib, a third‐generation EGFR tyrosine kinase inhibitor (TKI), is newly developed and approved for use in Korea. Methods This prospective, open, single‐arm, multicenter, phase II clinical trial aims to evaluate the efficacy and safety of lazertinib as a consolidative therapy after CCRT treatment in unresectable, EGFR mutation‐positive NSCLC stage III patients. The primary endpoint of this study is PFS, and the secondary endpoints are OS, objective response rate (ORR), duration of response (DoR), time to death or distant metastasis (TTDM), and safety profiles. Discussion Our study may extend the indications for third‐generation EGFR‐TKIs to treat patients with stage III NSCLC. Moreover, using this drug to treat stage III NSCLC would emphasize the value of mutation analysis and personalized medicine.

Abstract Regeneration of over 10 mm long peripheral nerve defects remains a challenge due to the failure of regeneration by prolonged axotomy and denervation occurring in long‐term recovery. Recent studies reveal that conductive conduits and electrical stimulation accelerate the regeneration of long nerve defects. In this study, an electroceutical platform combining a fully biodegradable conductive nerve conduit and a wireless electrical stimulator is proposed to maximize the therapeutic effect on nerve regeneration. Fully biodegradable nerve conduit fabricated using molybdenum (Mo) microparticles and polycaprolactone (PCL) can eliminate the unwanted effects of non‐degradable implants, which occupy nerve paths and need to be removed through surgery increasing the risk of complications. The electrical and mechanical properties of Mo/PCL conduits are optimized by controlling the amounts of Mo and tetraglycol lubricant. The dissolution behavior and electrical conductivity of biodegradable nerve conduits in the biomimetic solutions are also evaluated. In in vivo experiments, the integrated strategy of a conductive Mo/PCL conduit with controlled therapeutic electrical stimulation shows accelerated axon regeneration for long sciatic nerve defects in rats compared to the use of the Mo/PCL conduit without stimulation and has a significant therapeutic effect based on the results obtained from the functional recovery test.

Abstract Background Studies on the application of targeted therapies for patients with non‐small cell lung cancer (NSCLC) who harbor rare genetic mutations are ongoing. In the present study, we investigated the real‐world data of NSCLC patients who harbor rare mutations. Methods We retrospectively analyzed patients with advanced or metastatic nonsquamous NSCLC aged >20 years with confirmed rare mutations (BRAF, ROS1, MET, RET, HER2, FGFR, and NTRK) from January 2015 to September 2020 at nine tertiary hospitals. In addition, we validated the lung cancer PCR panel kit in patients with confirmed mutations by NGS. Results Among 118 patients included, 88 received platinum‐based chemotherapy as first‐line chemotherapy. The progression‐free survival of patients with BRAF, ERBB2, MET, RET, and ROS1 mutations was 10.9 months (95% confidence interval [CI]: 1.3–20.5), 5.3 months (95% CI: 3.0–7.5), 7.2 months (95% CI: 3.6–10.9), 11.4 months (95% CI: 9.2–13.6), and 10.0 months (95% CI: 3.7–16.4) respectively (p = 0.041). The median overall survival (OS) was not reached in patients with ROS1 mutations; however, in BRAF, ERBB2, MET, and RET mutant patients, median OS was 14.1 months (95% CI: 10.1–14.1), 34.5 months (95% CI: 13.2–36.9), 22.7 months (95% CI: 1.7–24.0), and 29.8 months (95% CI: 28.9–61.3), respectively (p = 0.006). Of the 27 tissue samples, 26 (96.3%) showed the same PCR panel kit result with NGS. Conclusions First‐line platinum‐based chemotherapy showed durable benefit in patients with advanced or metastatic nonsquamous NSCLC harboring rare genetic mutation other than EGFR or ALK.

Expanding on previous demonstrations of the therapeutic effects of adeno‐associated virus (AAV) carrying small‐hairpin RNA (shRNA) in downregulating the mechanistic target of rapamycin (mTOR) in in vivo retinal vascular disorders, vascular endothelial growth factor (VEGF)‐stimulated endothelial cells were treated with AAV2‐shmTOR to examine the role of mTOR inhibition in retinal angiogenesis. AAV2‐shmTOR exposure significantly reduced mTOR expression in human umbilical vein endothelial cells (HUVECs) and decreased downstream signaling cascades of mTOR complex 1 (mTORC1) and mTORC2 under VEGF treatment. Moreover, the angiogenic potential of VEGF was significantly inhibited by AAV2‐shmTOR, which preserved endothelial integrity by maintaining tight junctions between HUVECs. These data thus support previous in vivo studies and provide evidence that AAV2‐shmTOR induces therapeutic effects by inhibiting the neovascularization of endothelial cells.

Abstract When a thermoelectric (TE) material is deposited with a secondary TE material, the total Seebeck coefficient of the stacked layer is generally represented by a parallel conductor model. Accordingly, when TE material layers of the same thickness are stacked vertically, the total Seebeck coefficient in the transverse direction may change in a single layer. Here, an abnormal Seebeck effect in a stacked two‐dimensional (2D) PtSe2/PtSe2 homostructure film, i.e., an extra in‐plane Seebeck voltage is produced by wet‐transfer stacking at the interface between the PtSe2 layers under a transverse temperature gradient is reported. This abnormal Seebeck effect is referred to as the interfacial Seebeck effect in stacked PtSe2/PtSe2 homostructures. This effect is attributed to the carrier‐interface interaction, and has independent characteristics in relation to carrier concentration. It is confirmed that the in‐plane Seebeck coefficient increases as the number of stacked PtSe2 layers increase and observed a high Seebeck coefficient exceeding ≈188 µV K−1 at 300 K in a four‐layer‐stacked PtSe2/PtSe2 homostructure.

Abstract T cell‐derived small extracellular vesicles (sEVs) exhibit anti‐cancer effects. However, their anti‐cancer potential should be reinforced to enhance clinical applicability. Herein, we generated interleukin‐2‐tethered sEVs (IL2‐sEVs) from engineered Jurkat T cells expressing IL2 at the plasma membrane via a flexible linker to induce an autocrine effect. IL2‐sEVs increased the anti‐cancer ability of CD8+ T cells without affecting regulatory T (Treg) cells and down‐regulated cellular and exosomal PD‐L1 expression in melanoma cells, causing their increased sensitivity to CD8+ T cell‐mediated cytotoxicity. Its effect on CD8+ T and melanoma cells was mediated by several IL2‐sEV‐resident microRNAs (miRNAs), whose expressions were upregulated by the autocrine effects of IL2. Among the miRNAs, miR‐181a‐3p and miR‐223‐3p notably reduced the PD‐L1 protein levels in melanoma cells. Interestingly, miR‐181a‐3p increased the activity of CD8+ T cells while suppressing Treg cell activity. IL2‐sEVs inhibited tumour progression in melanoma‐bearing immunocompetent mice, but not in immunodeficient mice. The combination of IL2‐sEVs and existing anti‐cancer drugs significantly improved anti‐cancer efficacy by decreasing PD‐L1 expression in vivo. Thus, IL2‐sEVs are potential cancer immunotherapeutic agents that regulate both immune and cancer cells by reprogramming miRNA levels.

Abstract Background To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between non‐vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF), this retrospective study was conducted using the Korean Health Insurance Review & Assessment Service (HIRA) claims database. Methods Patients with AF who initiated NOACs (apixaban, dabigatran, and rivaroxaban) from July 1, 2015 to November 30, 2016 were included. We applied inverse probability of treatment weighting (IPTW) method using propensity score to make weighted populations having similar characteristics between groups. Hazard ratio (HR) of S/SE and MB were estimated by Cox proportional hazard model. Results Of the 39 783 patients with AF, 10 564; 11 418; and 17 801 used apixaban, dabigatran, and rivaroxaban, respectively. The mean CHA2DS2‐VASc and HAS‐BLED scores were 4.59 ~ 4.69 and 3.58 ~ 3.62, respectively, among all patients after applying IPTW. For S/SE, there were no significant differences between NOACs (HR [95% confidence interval (CI)]): apixaban vs dabigatran (0.99 [0.87‐1.13]), apixaban vs rivaroxaban (0.95 [0.84‐1.07]), and dabigatran vs rivaroxaban (0.96 [0.85‐1.08]). For MB (HR [95% CI]), both apixaban (0.77 [0.68‐0.86]) and dabigatran (0.88 [0.79‐0.98]) had a significantly lower risk compared with rivaroxaban. Apixaban also had a significantly lower risk of MB compared with dabigatran (0.87 [0.76‐0.99]). Conclusions In real‐world practice among Korean AF patients with relatively high risk of stroke and bleeding, there were no significant differences in the risk of S/SE between all NOAC comparisons. Apixaban was associated with lower risk of MB than dabigatran and rivaroxaban.

Abstract Precise control of the local electronic structure and properties of electrocatalysts is important for enhancing the multifunctionality and durability of electrocatalysts and for correlating the structure/chemistry with the catalytic properties. Herein, we report electronically coupled metallic hybrids of NiFe layered double hydroxide nanosheet/Ti3C2 MXene quantum dots deposited on a nitrogen‐doped graphene surface (LDH/MQD/NG) for high‐performance flexible Zn–air batteries (ZABs). As verified from the Mott–Schottky and Nyquist plots, as well as spectroscopic, electrochemical, and computational analyses, the electronic and chemical coupling of LDH/MQD/NG modulates the local electronic and surface structure of the active LDH to provide metallic conductivity and abundant active sites, leading to significantly improved bifunctional activity and electrocatalytic kinetics. The rechargeable ZABs with LDH/MQD/NG hybrids are superior to the previous LDH‐based ZABs, demonstrating a high power density (113.8 mW cm−2) and excellent cycle stability (150 h at 5 mA cm−2). Moreover, the corresponding quasi solid‐state ZABs are completely flexible and practical, affording a high power density of 57.6 mW cm−2 even in the bent state, and in real‐life operation of tandem cells for powering various electronic devices.

Abstract Objectives The optimal sequence for the administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non‐small cell lung cancer (NSCLC) is still unclear. This study aimed to evaluate the efficacy of sequential afatinib and osimertinib treatment in patients with NSCLC harboring EGFR mutations. Materials and methods Electronic records of patients with EGFR‐mutated NSCLC, who were administered afatinib and osimertinib (group A) or other chemotherapy (group B) between October 2014 and 2019, across 16 hospitals in South Korea were reviewed. The primary outcome, time on treatment (TOT), secondary outcome, and overall survival (OS) were estimated using the Kaplan–Meier method and log‐rank test. Multivariate analyses were performed using the Cox proportional hazards model. Results Of the 737 patients who received frontline afatinib treatment, 324 with complete records were selected (group A: 126, group B: 198). All patients in group A were T790M positive after afatinib, while patients in group B were all negative or unknown. The median TOT was 35.4 months (95% confidence interval [CI]: 27.7−45.6) in group A and 20.8 months (95% CI: 19.4−24.0) in group B. The median TOT with afatinib was 13.0 months (95% CI: 12.0−13.9) overall and 15.7 months (95% CI: 13.9−17.3) in group A. The 2‐ and 3‐year survival rates were 86.0 and 69.3% in group A and 75.9 and 55.3% in group B, respectively. Conclusion Sequential afatinib and osimertinib treatment resulted in better survival rates than treatment with afatinib followed by other chemotherapies.

Background Antithrombotic agents to treat patients with acute myocardial infarction can cause bleeding, which may reveal undiagnosed cancer. However, the relationship between bleeding and new cancer diagnosis and the prognostic impact is still unclear. Methods and Results We analyzed the new cancer diagnosis, Bleeding Academic Research Consortium 2, 3, or 5 bleeding, and all‐cause death of 10 364 patients with acute myocardial infarction without a history of previous cancer in a multicenter acute myocardial infarction registry. During a median of 4.9 years, 1109 patients (10.7%) experienced Bleeding Academic Research Consortium 2, 3, or 5 bleeding, and 338 patients (3.3%) were newly diagnosed with cancer. Bleeding Academic Research Consortium 2, 3, or 5 bleeding was associated with an increased risk of new cancer diagnosis (subdistribution hazard ratio [sHR] 3.29 [95% CI, 2.50–4.32]). In particular, there were robust associations between gastrointestinal bleeding and new gastrointestinal cancer diagnosis (sHR, 19.96 [95% CI, 11.30–29.94]) and between genitourinary bleeding and new genitourinary cancer diagnosis (sHR, 28.95 [95% CI, 14.69–57.07]). The risk of all‐cause death was not lower in patients diagnosed with new gastrointestinal cancer after gastrointestinal bleeding (hazard ratio [HR], 4.05 [95% CI, 2.04–8.02]) and diagnosed with new genitourinary cancer after genitourinary bleeding (HR, 2.79 [95% CI, 0.81–9.56]) than in patients newly diagnosed with cancer without previous bleeding. Conclusions Clinically significant bleeding, especially gastrointestinal and genitourinary bleeding, in patients with AMI was associated with an increased risk of new cancer diagnoses. However, the bleeding preceding new cancer detection was not associated with better survival. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02385682 and NCT02806102.

Abstract Introduction This study aimed to investigate alterations in whole‐brain functional connectivity after a concussion using graph‐theory analysis from global and local perspectives and explore the association between changes in the functional network properties and cognitive performance. Methods Individuals with mild traumatic brain injury (mTBI, n = 29) within a month after injury, and age‐ and sex‐matched healthy controls (n = 29) were included. Graph‐theory measures on functional connectivity assessed using resting state functional magnetic resonance imaging data were acquired from each participant. These included betweenness centrality, strength, clustering coefficient, local efficiency, and global efficiency. Multi‐domain cognitive functions were correlated with the graph‐theory measures. Results In comparison to the controls, the mTBI group showed preserved network characteristics at a global level. However, in the local network, we observed decreased betweenness centrality, clustering coefficient, and local efficiency in several brain areas, including the fronto‐parietal attention network. Network strength at the local level showed mixed‐results in different areas. The betweenness centrality of the right parahippocampus showed a significant positive correlation with the cognitive scores of the verbal learning test only in the mTBI group. Conclusion The intrinsic functional connectivity after mTBI is preserved globally, but is suboptimally organized locally in several areas. This possibly reflects the neurophysiological sequelae of a concussion. The present results may imply that the network property could be used as a potential indicator for clinical outcomes after mTBI.

Abstract Herein, we report the case of a 48‐year‐old woman with metastatic thymoma who developed fulminant myositis with cardiotoxicity after one cycle of pembrolizumab treatment. She presented with severe muscle weakness and dyspnea, and her laboratory test results revealed increased muscle and cardiac enzyme levels. Despite an urgent initiation of systemic steroids, her muscle weakness and hypercapnia worsened, for which intravenous immunoglobulin G was initiated. However, hypercapnia did not improve, but the patient recovered completely after plasma exchange. Patients with thymic neoplasms could be susceptible to fulminant forms of immune‐related adverse effects because they lack normal thymic physiology. Clinicians must not hesitate to consider immunoglobulin G administration and plasma exchange therapy as the next treatment steps for steroid‐refractory patients.

Abstract Patient‐derived cancer models that reconstitute the characteristics of the tumor microenvironment may facilitate efforts in precision immune‐oncology and the discovery of effective anticancer therapies. Organoids that have recently emerged as robust preclinical models typically contain tumor epithelial cells and lack the native tumor immune microenvironment. A patient‐derived organotypic tumor spheroid (PDOTS) is a novel and innovative ex vivo system that retains key features of the native tumor immune microenvironment. Here, we established and characterized a series of colorectal cancer PDOTS models for use as a preclinical platform for testing effective immunotherapy and its combinations with other drugs. Partially dissociated (> 100 μm in diameter) tumor tissues were embedded in Matrigel‐containing organoid media and subsequently formed into organoid structures within 3 to 7 days of culture. The success rate of growing PDOTS from fresh tissues was ~86%. Morphological analysis showed that the PDOTSs varied in size and structure. Immunofluorescence and flow cytometry analysis revealed that the PDOTSs retained autologous tumor‐infiltrating lymphoid cells and tumor‐infiltrating lymphoid cells were continually decreased through serial passages. Notably, PDOTSs from tumors from a high‐level microsatellite instability‐harboring patient were sensitive to anti‐PD‐1 or anti‐PD‐L1 antibodies. Our results demonstrate that the PDOTS model in which the tumor immune microenvironment is preserved may represent an advantageous ex vivo system to develop effective immune therapeutics.

Abstract Afatinib is an ErbB family blocker approved for the treatment of epidermal growth factor receptor mutation‐positive nonsmall‐cell lung cancer. A pivotal trial demonstrated significant clinical benefits with manageable toxicity of afatinib as a second‐line treatment option in squamous cell carcinoma of the lung (SCC) which led to approval in >60 countries. However, these results were derived from a controlled study conducted in selected patients and are not necessarily representative of the real‐world use of this drug. In addition, data on afatinib use after immunotherapy in this clinical setting are lacking. The aim of this study is to evaluate the treatment outcomes and safety of afatinib as a second‐ or later‐line treatment for SCC and to identify potential predictive biomarkers. As a real‐world observational study, 130 eligible patients with advanced SCC, who progressed after platinum‐based chemo‐ and immunotherapy, will be enrolled. Treatment outcomes and safety data will be collected for both the retrospective and prospective cohorts, and molecular profiling using tissue and plasma will be performed for the prospective cohort. The primary endpoint is time to treatment failure, and the secondary endpoints are objective response rate, progression‐free survival, overall survival, and safety. Comparison of clinical outcomes with respect to the different programmed death‐ligand 1 expression and molecular characteristics will also be carried out. This study will provide additional evidence on the usefulness of afatinib as a subsequent treatment, as well as feasible molecular biomarkers to predict its efficacy in this clinical setting.

Abstract Background In this study, we investigated the risk factors of acquired T790M mutation among patients with lung adenocarcinoma with epidermal growth factor receptor (EGFR) tyrosine mutation who were treated with EGFR‐tyrosine kinase inhibitors (TKIs). The aim was to identify the clinical impact of rebiopsy. Methods This multicenter, retrospective cohort study was conducted in South Korea from January 2007 to June 2017. Patients with adenocarcinoma with EGFR mutation who underwent rebiopsy and were treated with EGFR‐TKIs were included. Results Of a total of 352 patients, T790M mutation was identified in 156 (41.9%) at the time of rebiopsy. The median duration from initial biopsy to rebiopsy was 17 months. Univariate logistic regression analysis revealed associations of exon 19 deletion (odds ratio [OR], 1.643; p = 0.026), absence of L858R (OR, 0.627; p = 0.042), and previous EGFR‐TKI treatment duration (OR, 1.039; p

Abstract Background Mutation analysis of circulating tumor DNA (ctDNA) is used for diagnosing lung cancer. This trial aimed to assess the efficacy of afatinib in treatment‐naïve patients with lung cancer harboring epidermal growth factor receptor mutations (EGFRm, exon 19 deletions or exon 21 point mutations) detected based on ctDNA. Methods The primary objective was the objective response rate (ORR) in the response evaluable (RE) population. EGFRm analysis of ctDNA was performed using PANA Mutype. Of the 331 patients screened, ctDNA was positive in 21% (68/331) in the detection of activating EGFRm. Among 81 subjects with tumor EGFRm, 48 showed matched EGFRm in their ctDNA (59% sensitivity). Results Therapy with afatinib 40 mg was initiated in 21 (female, 17; adenocarcinoma, 20) patients (intention‐to‐treat, ITT); dose modifications were made in 15 (71%). The ORR was 74% in the RE population (14/19); 11 patients showed EGFRm only in ctDNA (Group A), whereas 10 exhibited the same EGFRm in their ctDNA and tumor DNA (Group B). There was no significant difference in ORR between Groups A and B (80% and 67% RE, respectively). Median progression‐free survival (PFS) was 12.0 months, and no significant difference was observed according to the final afatinib dose, type of EGFRm, and Group A versus B. After progression, T790M mutation was found in 40% (6/15) of patients, and osimertinib was used as a second‐line treatment. Conclusions Afatinib showed similar ORR and PFS in patients with lung cancer harboring EGFRm in their ctDNA regardless of tumor EGFRm results. Key points Significant findings of the study Afatinib showed favorable ORR and PFS regardless of the tumor EGFR mutation status results, similar to the findings of previous trials assessing afatinib as first‐line treatment of EGFR‐mutated non‐small cell lung cancer based on tumor genotyping. What this study adds Our findings emphasize that the survival benefit of afatinib treatment can be achieved not only by appropriate dose reduction with frequent and detailed monitoring of toxicities, but also by using noninvasive (ctDNA) assays in a real‐world setting.

Abstract Although post‐synthetic anion exchange allows halide perovskite quantum dots to easily change the optical bandgap of materials, additional exchange of shorter ligands is required to use them as active materials in optoelectronic devices. In this study, a novel all‐in‐one process exchanging ligands and halide anions in film‐state for facile color tuning and patterning of cesium lead halide perovskite colloidal quantum dot (PeQD) light‐emitting diodes (LEDs) is proposed. The proposed all‐in‐one process significantly enhances the performances of PeQD LEDs by passivating the PeQD with shorter ligands. In addition, the all‐in‐one process is repeated more stably in the film state. Red, green, and blue LEDs with extremely narrow emission spectra using cesium lead bromide PeQDs and appropriate butylammonium halide solutions are fabricated. Furthermore, the proposed all‐in‐one process in film‐state facilitated rapid color change in localized areas, thereby aiding in realizing fine patterns of narrow widths (300 µm) using simple contact masks. Consequently, various paint‐over red/green/blue patterns in PeQD LEDs by applying halide solutions additively are fabricated.

Background Chronic vasodilator therapy with long‐acting nitrate is frequently used to treat vasospastic angina. However, the clinical benefits of this approach are controversial. We investigated the prognostic impact of vasodilator therapy in patients with vasospastic angina from the multicenter, prospective VA‐KOREA (Vasospastic Angina in KOREA) registry. Methods and Results We analyzed data from 1895 patients with positive intracoronary ergonovine provocation test results. The patients were divided into 4 groups: no vasodilator (n=359), nonnitrate vasodilator (n=1187), conventional nitrate (n=209), and a combination of conventional nitrate and other vasodilators (n=140). The primary end point was a composite of cardiac death, acute coronary syndrome, and new‐onset arrhythmia at 2 years. Secondary end points were the individual components of the primary end point, all‐cause death, and rehospitalization due to recurrent angina. The groups did not differ in terms of the risk of the primary end point. However, the acute coronary syndrome risk was significantly higher in the conventional nitrate (hazard ratio [HR], 2.49; 95% CI, 1.01–6.14; P=0.047) and combination groups (HR, 3.34; 95% CI, 1.15–9.75, P=0.027) compared with the no‐vasodilator group, as assessed using the inverse probability of treatment weights. Subgroup analyses revealed prominent adverse effects of nitrate in patients with an intermediate positive ergonovine provocation test result and in those with low Japanese Coronary Spasm Association scores. Conclusions Long‐acting nitrate‐based chronic vasodilator therapy was associated with an increased 2‐year risk of acute coronary syndrome in patients with vasospastic angina, especially in low‐risk patients.

Abstract The flow‐cell design offers prospect for transition to commercial‐relevant high current density CO2 electrolysis. However, it remains to understand the fundamental interplay between the catalyst, and the electrolyte in such configuration toward CO2 reduction performance. Herein, the dramatic influence of electrolyte alkalinity in widening potential window for CO2 electroreduction in a flow‐cell system based on SnS nanosheets is reported. The optimized SnS catalyst operated in 1 m KOH achieves a maximum formate Faradaic efficiency of 88 ± 2% at −1.3 V vs reversible hydrogen electrode (RHE) with the current density of ≈120 mA cm−2. Alkaline electrolyte is found suppressing the hydrogen evolution across all potentials which is particularly dominant at the less negative potentials, as well as CO evolution at more negative potentials. This in turn widens the potential window for formate conversion (>70% across −0.5 to −1.5 V vs RHE). A comparative study to SnOx counterpart indicates sulfur also acts to suppress hydrogen evolution, although electrolyte alkalinity resulting in a greater suppression. The boosting of the electrochemical potential window, along with high current densities in SnS derived catalytic system offers a highly attractive and promising route toward industrial‐relevant electrocatalytic production of formate from CO2.

Background In tandem stenoses, nonhyperemic pressure ratio pullback is the preferred method to fractional flow reserve (FFR), based on the assumption of stable resting coronary flow. This study aimed to evaluate temporal changes of coronary circulatory indexes in tandem stenoses before and after angioplasty for proximal stenosis. Methods and Results Coronary tandem stenoses were created by porcine restenosis model with 2 bare metal stents in the left anterior descending artery. Four weeks later, changes in distal coronary pressure (Pd), averaged peak velocity, microvascular resistance, transstenotic pressure gradient across distal stenosis, resting Pd/aortic pressure, and FFR were measured before and 1, 5, 10, 15, and 20 minutes after balloon angioplasty for proximal stenosis. After angioplasty, there were significant changes in both resting and hyperemic Pd, averaged peak velocity, microvascular resistance, and transstenotic pressure gradient across distal stenosis (all P values

Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.

Purpose. Particulate matter (PM) is increasing every year in Asia. It is not fully understood how the airway is affected when inhaling PM. We investigated the correlation between particulate matter with a diameter of less than 10 μm (PM10) and fractional exhaled nitric oxide (FeNO) to determine whether PM causes airway inflammation. Material and Methods. We analyzed patients who visited our outpatient clinic and tested FeNO from January 2016 to December 2017 at the Korea University Guro Hospital. PM10 data were provided by the government of the Republic of South Korea, and measuring station of PM10 is located 800 meters from the hospital. We analyzed the correlation between PM10 and FeNO by a Pearson correlation analysis and by a multivariate linear regression analysis. To identify the most correlated times, we analyzed the correlation between the FeNO and PM10 daily average from the day of visit to 4 days before visit. Results. FeNO positively correlated with PM10 at two days before hospital visit in the Pearson correlation (Pearson correlation coefficient = 0.057; P-value = 0.023) and in the multivariate linear regression analysis (B = 0.051, P-value = 0.026). If the PM10 increased by 100 μg/m3, the FeNO result was expected to rise to 8.3 ppb in healthy people without respiratory disease. Conclusion. The positive correlation was found in both healthy people and asthmatic patients. Therefore, PM10 can increase airway inflammation.

Systemic lupus erythematosus (SLE) is an autoimmune disease, which is characterized by hyperactivation of T and B cells. Human mesenchymal stem cells (hMSCs) ameliorate the progression of SLE in preclinical studies using lupus-prone MRL.Faslpr mice. However, whether hMSCs inhibit the functions of xenogeneic mouse T and B cells is not clear. To address this issue, we examined the in vitro effects of hMSCs on T and B cells isolated from MRL.Faslpr mice. Naïve hMSCs inhibited the functions of T cells but not B cells. hMSCs preconditioned with IFN-γ (i) inhibited the proliferation of and IgM production by B cells, (ii) attracted B cells for cell–cell interactions in a CXCL10-dependent manner, and (iii) inhibited B cells by producing indoleamine 2,3-dioxygenase. In summary, our data demonstrate that hMSCs exert therapeutic activity in mice in three steps: first, naïve hMSCs inhibit the functions of T cells, hMSCs are then activated by IFN-γ, and finally, they inhibit B cells.

Background Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous disease entity. Its prognosis and predictor of mortality remain unclear. This study aimed to compare the prognosis between MINOCA and myocardial infarction with obstructive coronary artery disease and identify factors related to all‐cause death in MINOCA using a nation‐wide, multicenter, and prospective registry. Methods and Results Among 13 104 consecutive patients enrolled, patients without previous history of significant coronary artery disease who underwent coronary angiography were selected. The primary outcome was 2‐year all‐cause death. Secondary outcomes were cardiac death, noncardiac death, reinfarction, and repeat revascularization. Patients with MINOCA (n=396) and myocardial infarction with obstructive coronary artery disease (n=10 871) showed similar incidence of all‐cause death (9.1% versus 8.8%; hazard ratio [HR], 1.04; 95% CI, 0.74–1.45; P=0.83). Risks of cardiac death, noncardiac death, and reinfarction were not significantly different between the 2 groups (HR, 0.82; 95% CI, 0.53–1.28; P=0.38; HR, 1.55; 95% CI, 0.93–2.56; P=0.09; HR, 1.23; 95% CI, 0.65–2.31; P=0.38, respectively). MINOCA patients had lower incidence of repeat revascularization (1.3% versus 7.2%; HR, 0.17; 95% CI, 0.07–0.41; P