and Relevance: Alternative methods provide ethical and rational approaches to developmental toxicity assessment. When integrated into regulatory science, they can contribute to early safety decisions in clinical development and public health. Coordinated efforts by stakeholders in technology advancement, implementation support, and guideline revision are essential for broader adoption.

Sepsis-associated acute kidney injury (SA-AKI) is a prominent sepsis complication, often resulting in adverse clinical outcomes. Hyperbaric oxygen therapy (HBOT), known for its anti-inflammatory characteristics, antioxidant effects, and ability to deliver high oxygen tension to hypo-perfused tissues, offers potential benefits for SA-AKI. This study investigated whether HBOT improved renal injury in sepsis and elucidated its underlying mechanisms. Methods: A lipopolysaccharide (LPS)-induced endotoxemia model was established using 8-week-old C57BL/6 mice. Thirty minutes post-LPS administration, a group of mice underwent HBOT at a 2.5 atmospheric pressure absolute with 100% oxygen for 60 minutes. After 24 hours, all mice were euthanized for measurements. Results: Our results demonstrated that HBOT effectively mitigated renal tubular cell apoptosis. Additionally, HBOT significantly reduced phosphorylated p53 proteins and cytochrome C levels, suggesting that HBOT may attenuate renal apoptosis by impeding p53 activation and cytochrome C release. Notably, HBOT preserved manganese-dependent levels of superoxide dismutase, an antioxidant enzyme, compared to the LPS group. Furthermore, transforming growth factor beta (TGF-β)/Smad4 and alpha smooth muscle actin expressions were significantly reduced in the LPS + HBOT group. Conclusion: An early single session of HBOT exhibited renoprotective effects in LPS-induced endotoxemia mice models by suppressing p53 activation and cytochrome C levels to mitigate apoptosis. The observed TGF-β decrease, downstream Smad expression reduction, and antioxidant capacity preservation following HBOT may contribute to these effects.

Background: Research is continuously being conducted on the relationship between the airway and malocclusion. The nose, asthe upper part of the respiratory pathway, plays a critical role. While various international studies employ the Nasal Index classification for nasal morphology, domestic research remains scarce. This research investigates the proportions of nasal morphology in malocclusion patients utilizing a 3D software. Methods: The study evaluated 100 malocclusion patients in their 20s (40 Class I, 34 Class II, 26 Class III). Cone-beam computedtomography was used with the Mimics (ver. 22; Materialise) 3D program to model the skull and soft tissues of the patients in three views: coronal, sagittal, and frontal. Results: The results showed that in Class I, there were 5 leptorrhine (long and narrow) cases, 30 mesorrhine (moderate shape)cases, and 5 platyrrhine (broad and short) cases. In Class II, there were 3 leptorrhine, 25 mesorrhine, and 6 platyrrhine cases.In Class III, there were 2 leptorrhine, 21 mesorrhine, and 3 platyrrhine cases. Conclusion The findings of this study indicate that there is no significant correlation between the size of the nose and malocclusionin patients. Additionally, additional research related to this study is expected to be necessary.

Purpose: Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. Conclusion A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Objective: To develop an integrated and comprehensive community-based mental healthcare model, opinions were collected on various issues from practitioners in mental health service institutions currently offering mental healthcare services in Seoul through a focus group interview, qualitative research method, and Delphi survey. Methods: The focus group interview was conducted with six practitioners from mental health welfare centers and six hospital-based psychiatrists. A questionnaire of opinions on the mental healthcare model was filled by these practitioners and psychiatrists. A Delphi survey was additionally conducted with a panel of 20 experts from a community mental health welfare center and hospital-based psychiatrists. Results: The focus group interview results showed the need for integrated community-based mental healthcare service and the need to establish a system for managing mental and physical health in an integrated manner. Based on the survey results, the current status of community-based mental healthcare services was investigated, and the direction of the revised model was established. The Delphi survey was then conducted to refine the revised model. Conclusion The present study presents the Seoul-type community-based mental healthcare model with integrated services between a psychiatric hospital with a mental health welfare center as well as combined mental and physical health services. This is ultimately expected to help people with mental illnesses live healthy lives by meeting their needs as community members.

Background: The nose is located at the center of the face, and it is possible to determine race, sex, and the like. Research usingthe nasal index (NI) classification method to classify the shape of the nose is currently in progress. However, domestic research is required as most research is being conducted abroad. In this study, we used a 3D program to confirm the ratio of the nose shape of Koreans. Methods: One hundred patients (50 males and 50 females) in their 20s were evaluated (IRB approval no. DKUDH IRB 2020-01-007).Cone beam computed tomography was performed using the Mimics ver.22 (Materialise Co., Leuven, Belgium) 3D program to model the patient’s skull and soft tissues into three views: coronal, sagittal, and frontal. To confirm the ratio of measurement metrics, analysis was performed using the SPSS ver. 23.0 (IBM Co., Armonk, NY, USA) program. Results: Ten leptorrhine (long and narrow) type, 76 mesorrhine (moderate shape) type, and 14 platyrrhine (broad and short) type noses were observed. In addition, as a result of sex comparison, five males had the leptorrhine (long and narrow) type, 40 mesorrhine (moderate shape), and five platyrrhine (broad and short) types. For females, five patients had the leptorrhine (long and narrow) type, 36 patients had the mesorrhine (moderate shape) type, and nine patients had the platyrrhine (broad and short) type. Conclusion This study will be helpful when performing nose-related surgeries and procedures in clinical practice and for similarstudies in the future.

Background: Sexual dimorphism is important for sex determination in the field of forensics. However, sexual dimorphism is commonly assessed using cone beam computed tomography (CBCT) rather than three-dimensional (3D) modeling software; therefore, studies using a more accurate measurement approach are necessary. This study assessed the sexual dimorphism of the MS using a 3D modeling program to obtain information that could contribute to the fields of surgery and forensics. Methods: The CBCT data of 60 patients (age, 20∼29 y; 30 males and 30 females) admitted to the Department of Orthodontics at the Dankook University School of Dentistry were provided in Digital Imaging and Communications in Medicine (DICOM) format.The left MS and right MS were modeled based on the DICOM files using the Mimics (version 22; Materialise, Leuven, Belgium) 3D program and converted to stereolithography (STL) files used to measure the width, length, and height of the MS, infraorbital foramen (IOF), right MS, and left MS. The average of three repeated measurements was calculated, and a reliability test was performed to ensure data reliability (Cronbach’s α =0.618). A canonical discriminant analysis was performed using a standard approach (left: Box’s M=0.096; right: Box’s M=0.115). Results: Males had greater values for all parameters (MS width, MS length, MS height, IOF, right MS, left MS) than females. The discriminant analysis identified six independent variables (MS width, MS height, MS length, IOF, right MS, left MS) that could identify sex. The left MS and right MS correctly identified the sex of 81.7% and 71.7% of the patients, respectively, with the left MS having higher accuracy. Conclusion This study confirmed that, for Korean individuals, the left MS has a better ability to identify sex than the right MS. These results may contribute to sex identification in the fields of surgery and forensics.

Background: Hypoxia causes oxidative stress and affects cardiovascular function and the programming of cardiovascular disease. Melatonin promotes antioxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase. Objectives: This study aims to investigate the correlation between melatonin and hypoxia induction in cardiomyocytes differentiation. Methods: Mouse embryonic stem cells (mESCs) were induced to myocardial differentiation.To demonstrate the influence of melatonin under hypoxia, mESC was pretreated with melatonin and then cultured in hypoxic condition. The cardiac beating ratio of the mESCderived cardiomyocytes, mRNA and protein expression levels were investigated. Results: Under hypoxic condition, the mRNA expression of cardiac-lineage markers (Brachyury, Tbx20, and cTn1) and melatonin receptor (Mtnr1a) was reduced. The mRNA expression of cTn1 and the beating ratio of mESCs increased when melatonin was treated simultaneously with hypoxia, compared to when only exposed to hypoxia. Hypoxia-inducible factor (HIF)-1α protein decreased with melatonin treatment under hypoxia, and Mtnr1a mRNA expression increased. When the cells were exposed to hypoxia with melatonin treatment, the protein expressions of phospho-extracellular signal-related kinase (p-ERK) and Bcl-2-associated X proteins (Bax) decreased, however, the levels of phospho-protein kinase B (p-Akt), phosphatidylinositol 3-kinase (PI3K), B-cell lymphoma 2 (Bcl-2) proteins, and antioxidant enzymes including Cu/Zn-SOD, Mn-SOD, and catalase were increased.Competitive melatonin receptor antagonist luzindole blocked the melatonin-induced effects. Conclusions This study demonstrates that hypoxia inhibits cardiomyocytes differentiation and melatonin partially mitigates the adverse effect of hypoxia in myocardial differentiation by regulating apoptosis and oxidative stress through the p-AKT and PI3K pathway.

Background: Hypoxia causes oxidative stress and affects cardiovascular function and the programming of cardiovascular disease. Melatonin promotes antioxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase. Objectives: This study aims to investigate the correlation between melatonin and hypoxia induction in cardiomyocytes differentiation. Methods: Mouse embryonic stem cells (mESCs) were induced to myocardial differentiation.To demonstrate the influence of melatonin under hypoxia, mESC was pretreated with melatonin and then cultured in hypoxic condition. The cardiac beating ratio of the mESCderived cardiomyocytes, mRNA and protein expression levels were investigated. Results: Under hypoxic condition, the mRNA expression of cardiac-lineage markers (Brachyury, Tbx20, and cTn1) and melatonin receptor (Mtnr1a) was reduced. The mRNA expression of cTn1 and the beating ratio of mESCs increased when melatonin was treated simultaneously with hypoxia, compared to when only exposed to hypoxia. Hypoxia-inducible factor (HIF)-1α protein decreased with melatonin treatment under hypoxia, and Mtnr1a mRNA expression increased. When the cells were exposed to hypoxia with melatonin treatment, the protein expressions of phospho-extracellular signal-related kinase (p-ERK) and Bcl-2-associated X proteins (Bax) decreased, however, the levels of phospho-protein kinase B (p-Akt), phosphatidylinositol 3-kinase (PI3K), B-cell lymphoma 2 (Bcl-2) proteins, and antioxidant enzymes including Cu/Zn-SOD, Mn-SOD, and catalase were increased.Competitive melatonin receptor antagonist luzindole blocked the melatonin-induced effects. Conclusions This study demonstrates that hypoxia inhibits cardiomyocytes differentiation and melatonin partially mitigates the adverse effect of hypoxia in myocardial differentiation by regulating apoptosis and oxidative stress through the p-AKT and PI3K pathway.

Purpose: Pharmacological inhibition of mutant isocitrate dehydrogenase (IDH) reduces R-2-hydroxyglutarate (2-HG) levels and restores cellular differentiation in vivo and in vitro. The IDH2 inhibitor enasidenib (AG-221) has been approved by the FDA as a first-in-class inhibitor for the treatment of relapsed or refractory (R/R) IDH2-mutant acute myeloid leukemia (AML). In this study,the effects of a combination of all-trans retinoic acid (ATRA) and AG-221 on AML cell differentiation was explored, along with the mechanisms employed by IDH2-mutant cells in AML. Materials and Methods: We treated the human AML cell line, IDH2-mutant-TF-1, and primary human AML cells carrying IDH2 mutation with 30 μM AG-221 and 100 nM ATRA, alone or in combination. Results: Combined treatment with AG-221 and ATRA inhibited 2-HG production and resulted in synergistic effects on differentiation among IDH2-mutant AML cells and primary AML cells expressing IDH2 mutation. Combined treatment with AG-221 and ATRA altered autophagic activity. AG-221 and ATRA treatment-induced differentiation of IDH2-mutant AML cells was associated with autophagy induction, without suppressing autophagy flux at maturation and degradation stages. A RAF-1/MEK/ERK pathway was founded to be associated with AG-221 and ATRA-induced differentiation in IDH2-mutant AML cells. IDH-associated changes in histone methylation markers decreased after AG-221 and ATRA combination treatment. Conclusion Our preliminary evidence indicates that the addition of ATRA to treatments with IDH2 inhibitor may lead to further improvements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments with IDH2 inhibitor alone.