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Yun Seob Jung,1 Byung Hak Jin,2 Ju Eun Choi,2 Min Soo Park,2 Young-Woo Kim,3 Hyung Won Kang,4 Sunyoung Cho,5 Choon Ok Kim2 1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; 2Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Korea; 3School of Korean Medicine, Dongguk University, Gyeongju, Korea; 4College of Korean Medicine, Wonkwang University, Iksan, Korea; 5IntegroMediLab Co., Ltd, Seoul, KoreaCorrespondence: Choon Ok Kim, Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Korea, Tel +82-2-2228-0455, Fax +82-2-2227-7890, Email delivery98@yuhs.acPurpose: Herbal medicines are occasionally used in combination with conventional antidepressants to mitigate various depression-associated symptoms. However, there is limited information on herb–antidepressant interactions. In this study, we investigated the pharmacokinetic (PK) effects of four herbal medicines (Gami-soyosan, Banhasasim-tang, Ojeok-san, and Bojungikgi-tang) on escitalopram, a commonly used antidepressant.Patients and Methods: In this open-label, fixed-sequence, three-period, crossover study, 18 participants were enrolled and divided into two groups. Each group received a 10 mg oral dose of escitalopram in period 1. Participants took escitalopram once daily and their assigned herbal medicines thrice a day for 7 d in periods 2 (group 1: Gami-soyosan, group 2: Ojeok-san) and 3 (group 1: Banhasasim-tang; group 2: Bojungikgi-tang). The primary endpoints were Cmax,ss and AUCtau,ss of escitalopram. Cmax,ss and AUCtau,ss in period 1 were obtained using nonparametric superposition from single-dose data. The PK endpoints were classified according to the CYP2C19 phenotype.Results: Of 18 participants, 16 completed the study. Systemic exposure to escitalopram resulted in a minor increase in the presence of each herbal medicine. The geometric mean ratios (GMRs, combination with herbal medicines/escitalopram monotherapy) and their 90% confidence intervals (CIs) for Cmax,ss and AUCtau,ss were as follows: Gamisoyosan– 1.1454 (0.9201, 1.4258) and 1.0749 (0.8084, 1.4291), Banhasasim-tang– 1.0470 (0.7779, 1.4092) and 1.0465 (0.7035, 1.5568), Ojeok-san– 1.1204 (0.8744, 1.4357) and 1.1267 (0.8466, 1.4996), and Bojungikgi-tang– 1.1264 (0.8594, 1.4762) and 1.1400 (0.8515, 1.5261), respectively. Furthermore, no significant differences in the GMRs of Cmax,ss and AUCtau,ss were observed across different CYP2C19 phenotypes in any of the groups.Conclusion: The co-administration of escitalopram with Gami-soyosan, Banhasasim-tang, Ojeok-san, or Bojungikgi-tang did not exert significant PK effects on escitalopram. These findings provide valuable insights into the safe use of herbal medicines along with escitalopram.Keywords: CYP2C19 phenotype, herb–drug interaction, antidepressant, geometric mean ratio

Ji Eun Park,1,* Mi Jeong Hong,2,3,* Shin Yup Lee,1,4 Jang Hyuck Lee,2,4 Jin Eun Choi,2,3 Hyo-Gyoung Kang,2,3 Sook Kyung Do,2,3 Ji Yun Jeong,5 Kyung Min Shin,6 Won Kee Lee,7 Sun Ha Choi,1 Yong Hoon Lee,1 Hye won Seo,1 Seung Soo Yoo,1 Jaehee Lee,1 Seung Ick Cha,1 Chang Ho Kim,1 Jae Yong Park1,2 1Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 3Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 4BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; 5Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 6Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 7Department of Medical Informatics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea*These authors contributed equally to this workCorrespondence: Shin Yup Lee; Jae Yong ParkDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of KoreaTel +82-53-200-2632Fax +82-53-200-2027Email shinyup@knu.ac.kr; jaeyong@knu.ac.krIntroduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have represented the prototype of targeted therapy in NSCLC. Patients with EGFR-mutant lung adenocarcinoma extract an extraordinary clinical benefit from EGFR-TKIs. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual’s response to TKIs. We investigated whether genetic variants in miRNA binding sites are associated with the clinical outcome of EGFR-TKIs in lung adenocarcinoma patients.Methods: One hundred SNPs at miRNA binding sites in cancer-related genes were selected for the analysis using the crosslinking, ligation and sequencing of hybrids (CLASH) and CancerGenes database. qRT-PCR and luciferase assays were conducted to evaluate the functional relevance of the SNPs.Results: NUP62 rs9523A>G were significantly associated with worse response to EGFR-TKIs, overall survival (OS), and progression-free survival (PFS). The other three SNPs (DVL2 rs2074216G>A, ARF1 rs11541557G>T, and UHRF1 rs2261988C>A) were significantly associated with worse OS and PFS. The rs9523A>G was significantly associated with decreased NUP62 expression in tumor tissues. In addition, a significantly decreased luciferase activity was noted in NUP62 rs9523 G allele compared to A allele.Conclusion: Genetic variants in miRNA binding sites, especially NUP62 rs9523A>G, may be useful in predicting the clinical outcomes of EGFR-mutant lung adenocarcinoma patients treated with EGFR-TKIs.Keywords: lung adenocarcinoma, EGFR-TKI, clinical outcome, miRNA binding site, polymorphism

Exploring the unique physical properties of oxide perovskites necessitates their growth on diverse single‐crystal substrates. The thin‐film growth of perovskite SrMnO3 (SMO) has been a particular focus of research due to its emerging room‐temperature multiferroicity. Herein, the epitaxial thin films of (110)‐oriented SMO are grown on the piezoelectric (110)‐oriented (1–x)Pb(Mg1/3Nb2/3)O3–xPbTiO3 (PMN‐PT) substrate. The effects of the thickness and oxygen annealing on the crystal structure, stoichiometry, and ferroelectric properties of the SMO thin film are systematically investigated. The tensile strain produced by the lattice mismatch between the bulk SMO and the PMN‐PT substrate causes an expansion of the c‐lattice parallel to the in‐plane direction of the substrate. The films show larger a‐, b‐, and c‐lattice parameters than the bulk material, resulting in volume expansion of the unit cell. This lattice expansion is attributed to the generation of oxygen vacancies driven by the reduced formation energy caused by the high elastic strain. Piezoelectric force microscopy reveals that the SMO film contains domains with strain‐mediated in‐plane and vacancy‐mediated out‐of‐plane polarization. Furthermore, the piezoelectric response of the PMN‐PT substrate effectively modulates the biaxial tensile strain in the SMO film, offering a potential strategy for controlling the crystal structure and ferroelectric properties of SMO. [ABSTRACT FROM AUTHOR]

The discovery of ferroelectricity in HfO2 ultrathin films has gathered considerable interest from the microelectronic industry owing to their compatibility with complementary metal oxide semiconductor technology. However, a significant challenge in utilizing HfO2 thin films for commercial devices is the wakeup effect, which is an increase in polarization with the number of electric field cycles in HfO2-based capacitors. Despite efforts to develop wakeup-free HfO2 thin films, the root cause of this effect remains elusive. Some studies attribute it to the tetragonal (T) to orthorhombic (O) phase transformation, while others suggest it is due to the redistribution of oxygen vacancies within the HfO2 layer during electric field cycling. This study investigated the phase transformation dynamics and oxygen vacancy distributions in TiN/Hf0.5Zr0.5O2/TiN capacitors subjected to electric field cycling using in situ grazing incidence synchrotron x-ray diffraction and ex situ x-ray photoelectron spectroscopy. The as-grown HZO films were crystallized in a mixed phase consisting of monoclinic (M), tetragonal, and orthorhombic fractions. The T-phase volume fraction decreased continuously up to 10k electric field cycles. In contrast, the O-phase fraction increased within the first 100 cycles and then stabilized with further cycling. The redistribution of oxygen vacancies occurred continuously throughout the cycling process. The results revealed that continuous oxygen vacancy redistribution during electric field cycling resulted in phase transformation between the T-, O-, and M-phases. The study provides insight into the phase transformation dynamics and oxygen vacancy redistribution in TiN/Hf0.5Zr0.5O2/TiN capacitors during electric field cycling, shedding light on the underlying mechanisms of the wakeup effect. [ABSTRACT FROM AUTHOR]