Recent amendments to regulatory frameworks have placed a greater emphasis on the utilization of in vitro testing platforms for preclinical drug evaluations and toxicity assessments. This requires advanced tissue models capable of accurately replicating liver functions for drug efficacy and toxicity predictions. Liver organoids, derived from human cell sources, offer promise as a reliable platform for drug evaluation. However, there is a lack of standardized quality evaluation methods, which hinders their regulatory acceptance. This paper proposes comprehensive quality standards tailored for liver organoids, addressing cell source validation, organoid generation, and functional assessment. These guidelines aim to enhance reproducibility and accuracy in toxicity testing, thereby accelerating the adoption of organoids as a reliable alternative or complementary tool to animal testing in drug development. The quality standards include criteria for size, cellular composition, gene expression, and functional assays, thus ensuring a robust hepatotoxicity testing platform.

BACKGROUND: A drug-eluting stent (DES) is a highly beneficial medical device used to widen or unblock narrowed blood vessels. However, the drugs released by the implantation of DES may hinder the re-endothelialization process, increasing the risk of late thrombosis. We have developed a tacrolimus-eluting stent (TES) that as acts as a potent antiproliferative and immunosuppressive agent, enhancing endothelial regeneration. In addition, we assessed the safety and efficacy of TES through both in vitro and in vivo tests. METHODS: Tacrolimus and Poly(lactic-co-glycolic acid) (PLGA) were applied to the metal stent using electrospinning equipment. The surface morphology of the stent was examined before and after coating using a scanning electron microscope (SEM) and energy dispersive X-rays (EDX). The drug release test was conducted through high-performance liquid chromatography (HPLC). Cell proliferation and migration assays were performed using smooth muscle cells (SMC).The stent was then inserted into the porcine coronary artery and monitored for a duration of 4 weeks. RESULTS: SEM analysis confirmed that the coating surface was uniform. Furthermore, EDX analysis showed that the surface was coated with both polymer and drug components. The HPCL analysis of TCL at a wavelength of 215 nm revealed that the drug was continuously released over a period of 4 weeks. Smooth muscle cell migration was significantly decreased in the tacrolimus group (54.1% ± 11.90%) compared to the non-treated group (90.1% ± 4.86%). In animal experiments, the stenosis rate was significantly reduced in the TES group (29.6% ± 7.93%) compared to the bare metal stent group (41.3% ± 10.18%). Additionally, the fibrin score was found to be lower in the TES group compared to the group treated with a sirolimus-eluting stent (SES). CONCLUSION Similar to SES, TES reduces neointimal proliferation in a porcine coronary artery model, specifically decreasing the fibrins score. Therefore, tacrolimus could be considered a promising drug for reducing restenosis and thrombosis.

Background: Since the global coronavirus disease 2019 (COVID-19) pandemic, nonpharmacological interventions (NPIs) such as extensive and comprehensive hand hygiene, mask-wearing, and social distancing have been implemented globally. This study aimed to investigate changes in respiratory viruses other than severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that occurred following the implementation of these NPIs. Methods: From January 2018 to December 2021, influenza-like illness patient specimens and specimens from the Korea Influenza and Respiratory Viruses Surveillance System were analyzed at the Incheon Metropolitan City Institute of Public Health and Environment.Oropharyngeal or nasopharyngeal swab samples from respiratory infection patients were transferred in a virus transport medium at 4°C. After RNA or DNA extraction, respiratory virus-specific genes for human influenza virus (IFV), adenovirus (ADV), parainfluenza virus (PIV), respiratory syncytial virus (RSV), human rhinovirus (hRV), human coronavirus, human bocavirus, and human metapneumovirus were detected by individual real-time reverse transcription polymerase chain reaction. Results: A total 3,334 samples were collected. After NPI was implemented, the detection of respiratory viruses other than SARS-CoV-2 decreased overall. The yearly detection rate of respiratory viruses was decreased from 69.5% (399/574) in 2018 and 73.3% (505/689) in 2019 to 19.8% (206/1,043) in 2020 and 34.9% (365/1,028) in 2021. The epidemic was more prominent in respiratory viruses such as IFV and RSV, which were considered dominant viruses, especially those with viral envelopes. Among viruses that were not considered dominant, hRV showed no clear change before and after NPI, while PIV showed a rapid increase compared to the existing dominant viruses between October–December 2021, after the increase in the number of gatherings started at the end of September and the “Relaxing COVID19 and mitigation policy,” which was implemented on November 1. Conclusion NPI seems to have influenced the isolation and transmission of respiratory viruses in South Korea. In the future, additional studies focusing on the isolation and transmission patterns of respiratory viruses following NPI are needed.

Background/Aims: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). Methods: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. Results: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. Conclusions Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Background and Objectives: The purpose of this study is to investigate the replacement of external sound processors and to help understand the economic burden experienced from cochlear implant users.Subjects and Method Among the 500 cases of cochlear implant surgery from 1992 to 2019, 336 cases from 311 patients who had used a cochlear implant for more than 1 year were enrolled. The period of cochlear implant use, replacement of the sound processor, the number, method, and reason of replacements were examined. Results: One hundred sixty cases (47.62%) replaced the sound processor at least once. There were a total of 213 replacements made in 160 cases. The most common reason for replacing the sound processors was because it could not be repaired (71 replacements, 33.33%), with their period of use being an average of 12 years. The most common replacement method of the sound processors was by purchasing with medical insurance benefits (100 replacements, 46.95%), with the usage period being an average of 11 years and 4 months. Conclusion Cochlear implant users replaced the sound processor for various reasons and the period of using one sound processor was relatively short. About half of all replacement cases were made by applying for medical insurance benefits. Others purchased directly through a sales company and paid a relatively high cost. Therefore, it is necessary to expand the medical insurance for external sound processor of cochlear implants to include exchange times considering the economic burden of cochlear implant users.

A human cell-based liver model capable of long-term expansion and mature hepatic function is a fundamental requirement for pre-clinical drug development. We previously established self-renewing and functionally mature human pluripotent stem cell-derived liver organoids as an alternate to primary human hepatocytes. In this study, we tested long-term prolonged culture of organoids to increase their maturity. Organoid growing at the edge of Matrigel started to deteriorate two weeks after culturing, and the expression levels of the functional mature hepatocyte marker ALB were decreased at four weeks of culture. Replating the organoids weekly at a 1：2 ratio in fresh Matrigel, resulted in healthier morphology with a thicker layer compared to organoids maintained on the same Matrigel and significantly increased ALB expression until three weeks, although, it decreased sharply at four weeks. The levels of the fetal hepatocyte marker AFP were considerably increased in long-term cultures of organoids. Therefore, we performed serial passaging of organoids, whereby they were mechanically split weekly at a 1：3∼1：5 ratio in fresh Matrigel. The organoids expanded so far over passage 55, or 1 year, without growth retardation and maintained a normal karyotype after long-term cryopreservation. Differentiation potentials were maintained or increased after long-term passaging, while AFP expression considerably decreased after passaging. Therefore, these data demonstrate that organoids can be exponentially expanded by serial passaging, while maintaining long-term functional maturation potential. Thus, hepatic organoids can be a practical and renewable cell source for human cell-based and personalized 3D liver models.

The general concept and initial approach to syncope patients has been mentioned in the general sections. This special sections have been described the characteristics, diagnosis, and treatment with patient education for the each syncope. It has been described in order of reflex syncope, orthostatic hypotension, postural orthostatic tachycardia syndrome (POTS), cardiac syncope, and unexplained syncope. Several clinical issues will have been dealt with in special issues. Neurological assessment is added when the patients were diagnosed with psychogenic pseudosyncope (PPS). Although many childhood syncope caused by reflex syncope, they are also presented as syncope caused by arrhythmic events in patients with congenital heart disease. In the elderly patients, syncope is because of not only a single cause of syncope but a combination of various conditions. In case of a syncope patient visiting the emergency department, a standardized systematic approach will be required to determine whether hospitalize the patient according to the risk of recurrence and the needs for the syncope management unit. We also mention recommendations on the limits of driving, exercising and social life style that are relevant to syncope in all patients. In this guideline, we reviewed the Korean published literatures and European/American guidelines on syncope. We, writing and publishing committee for evaluation and management guidelines of syncope in the Korean Society for Holter and Noninvasive Electrocardiography (KSHNE) under the Korean Heart Rhythm Society (KHRS) are very pleased to be able to publish this guideline. We also hope this guideline will be a good support to manage the syncope patients and a useful trigger for further research in Korea.
Aged ; Diagnosis ; Electrocardiography ; Emergency Service, Hospital ; Heart ; Heart Defects, Congenital ; Hope ; Humans ; Hypotension, Orthostatic ; Korea ; Life Style ; Patient Education as Topic ; Postural Orthostatic Tachycardia Syndrome ; Recurrence ; Reflex ; Syncope ; Writing

Syncope is a very common symptom that occurs in all age groups, especially in adolescents and elderly people. The cause of syncope is very diverse, and patients with syncope visit various medical departments such as general medicine, cardiology, neurology, and emergency medicine. If we do not perform appropriate diagnostic tests based on detailed history of syncope, we may have some difficulty to identify the cause of syncope. Failure to identify the cause of syncope can lead to physical trauma due to recurrence of syncope or may increase the risk of cardiovascular events in the future. However, there is no Korean guidelines for the diagnosis and treatment of syncope yet. Considering these circumstances in Korea, we prepared writing and publishing committee for evaluation and management guidelines of syncope in the Korean Society for Holter and Noninvasive Electrocardiology (KSHNE) under the Korean Heart Rhythm Society (KHRS). In this guideline, we reviewed the Korean published literatures and European / American guidelines on syncope.
Adolescent ; Aged ; Cardiology ; Diagnosis ; Diagnostic Tests, Routine ; Emergency Medicine ; Heart ; Humans ; Korea ; Neurology ; Recurrence ; Syncope ; Writing

Emerging evidence has emphasized the importance of cancer therapies targeting an abnormal metabolic state of tumor-initiating cells (TICs) in which they retain stem cell-like phenotypes and nicotinamide adenine dinucleotide (NAD⁺) metabolism. However, the functional role of NAD⁺ metabolism in regulating the characteristics of TICs is not known. In this study, we provide evidence that the mitochondrial NAD⁺ levels affect the characteristics of glioma-driven SSEA1⁺ TICs, including clonogenic growth potential. An increase in the mitochondrial NAD⁺ levels by the overexpression of the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT) significantly suppressed the sphere-forming ability and induced differentiation of TICs, suggesting a loss of the characteristics of TICs. In addition, increased SIRT3 activity and reduced lactate production, which are mainly observed in healthy and young cells, appeared following NNT-overexpressed TICs. Moreover, in vivo tumorigenic potential was substantially abolished by NNT overexpression. Conversely, the short interfering RNA-mediated knockdown of NNT facilitated the maintenance of TIC characteristics, as evidenced by the increased numbers of large tumor spheres and in vivo tumorigenic potential. Our results demonstrated that targeting the maintenance of healthy mitochondria with increased mitochondrial NAD⁺ levels and SIRT3 activity could be a promising strategy for abolishing the development of TICs as a new therapeutic approach to treating aging-associated tumors.
Glioblastoma* ; Lactic Acid ; Metabolism ; Mitochondria ; NAD ; NADP Transhydrogenases ; Phenotype ; Tics ; Up-Regulation*

Multiple sclerosis (MS) is a T-lymphocyte-mediated autoimmune disease that is characterized by inflammation in the central nervous system (CNS). Although many disease-modifying therapies (DMTs) are presumed effective in patients with MS, studies on the efficacy and safety of DMTs for preventing MS relapse are limited. Therefore, we tested the immunosuppressive anti-inflammatory effects of oral-formulated tacrolimus (FK506) on MS in a mouse model of experimental autoimmune encephalomyelitis (EAE). The mice were randomly divided into 3 experimental groups: an untreated EAE group, a low-dose tacrolimus-treated EAE group, and a high-dose tacrolimus-treated EAE group. After autoimmunization of the EAE mice with myelin oligodendrocyte glycoprotein, symptom severity scores, immunohistochemistry of the myelination of the spinal cord, and western blotting were used to evaluate the EAE mice. After the autoimmunization, the symptom scores of each EAE group significantly differed at times. The group treated with the larger tacrolimus dose had the lowest symptom scores. The tacrolimus-treated EAE groups exhibited less demyelination and inflammation and weak immunoreactivity for all of the immunization biomarkers. Our results revealed that oral-formulated tacrolimus inhibited the autoimmunization in MS pathogenesis by inactivating inflammatory cells.
Animals ; Autoimmune Diseases ; Biomarkers ; Blotting, Western ; Central Nervous System ; Demyelinating Diseases ; Encephalomyelitis, Autoimmune, Experimental* ; Humans ; Immunization ; Immunohistochemistry ; Inflammation ; Mice* ; Multiple Sclerosis ; Myelin Sheath ; Myelin-Oligodendrocyte Glycoprotein ; Neuromyelitis Optica ; Recurrence ; Spinal Cord ; Tacrolimus*