The Wikstroemia genus is highly regarded in traditional Asian medicine for its diverse therapeutic applications, including the treatment of inflammatory and infectious conditions. Among its members,Wikstroemia trichotoma (Thunb.) Makino remains a promising medicinal resource which is yet to be chemicallycharacterized. To ensure the chemical consistency of W. trichotoma, we developed and validated the first HPLC method for the simultaneous quantification of three major marker compounds: chlorogenic acid (1), miconioside B (2), and matteucinol 7-O-apiofuranosyl(1→6)-glucopyranoside (3). Chromatographic separation was achieved on a C18 column using a gradient elution system of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Detection was optimized using a photodiode array (PDA) detector at 280 and 325 nm, based on the absorption maxima of the markers. The method was validated in accordance with the International Council for Harmonisation (ICH) and the Ministry of Food and Drug Safety (MFDS) guidelines. The results demonstrated high linearity (r2 > 0.999), with limits of detection and quantitation ranging from 4.28–6.42 and 12.97–19.47 μg/ mL, respectively. Intra- and inter-day precision (% RSD ≤ 1.83%) and accuracy (recoveries of 92.5–101.7%) were within acceptable limits. Quantitative analysis revealed the contents of 1, 2, and 3 in the W. trichotoma extract to be 19.9, 139.8, and 264.9 mg/g, respectively. This study provides a reliable analytical framework for the standardization, quality control, and future pharmacological evaluation of W. trichotoma.

Background/Aims: Biliary tract cancer (BTC) is a rare malignancy with poor prognosis. We investigated genomic determinants of clinical benefit from gemcitabine, cisplatin, and nab-paclitaxel (GAP) versus gemcitabine and cisplatin (GC) in advanced BTC. Methods: Clinical and genomic data using TruSight Oncology 500 were analyzed from patients treated with GAP (N=198) or GC (N=89) as first-line therapy. Results: With a median follow-up of 33.0 months, GAP modestly improved progression-free survival (PFS) (hazard ratio [HR] 0.764; 95% confidence interval [CI] 0.591–0.989) without significant overall survival (OS) difference compared to GC. Genomic profiling revealed frequent alterations in TP53 (35.2%), KRAS (16.4%), SMAD4 (10.5%), and TNFRSF14 (10.5%), involving RTK/RAS (44.3%), TP53 (41.8%), and PI3K (20.2%) pathways. Single-gene mutations did not predict treatment benefit. However, pathway-level analysis identified PI3K pathway activation as significantly associated with inferior PFS (HR 2.148; 95% CI 1.478–3.124) and OS (HR 2.096; 95% CI 1.413–3.109) in patients receiving GAP, an effect not observed with GC. Importantly, GAP conferred clinical benefit only in patients without PI3K pathway activation, while no survival advantage was seen in those with such alterations (Pinteraction=0.023 for PFS, Pinteraction=0.003 for OS). Similar results were obtained in the independent validation cohort treated with GAP (N=103) or GC (N=64) for BTC. Conclusions Genomic profiling using next-generation sequencing identified PI3K pathway activation as key molecular determinant that differentiates patient outcomes between GAP and GC treatments in advanced BTC.

Background: Although many studies have been conducted on the association between the intercondylar notch size and the risk of anterior cruciate ligament (ACL) injury, few studies have examined its relationship with the condition after surgical treatment.Therefore, this study aimed to investigate the surgical outcomes of anatomical single-bundle ACL reconstruction according to intercondylar notch volumes. Methods: Medical records of patients who underwent anatomical single-bundle ACL reconstruction using a tibialis anterior allograft between 2015 and 2019 were retrospectively reviewed. For each sex, eligible patients were classified into two groups based on their percentile of intercondylar notch volumes, which were measured using postoperative three-dimensional computed tomography images (group S, ≤ 50th percentile of included patients; group L, > 50th percentile of included patients). Additional grouping was performed based on the group’s percentiles of normalized values of intercondylar notch volumes to body heights.Between-group comparative analyses were performed on the perioperative data and surgical outcomes in both objective and subjective aspects. Results: One hundred patients were included in the study. For male patients, there were no differences in the overall surgical outcomes between groups, whereas group L showed a significantly greater knee anteroposterior (AP) laxity than group S at the final follow-up (p = 0.042 for the side-to-side differences [SSD] at the maximum manual force). Similarly, there were no differences in the female patients in the overall surgical results between the groups, whereas group L showed a significantly greater knee AP laxity at the final follow-up (p = 0.020 for the SSD at 134 N; p = 0.011 for the SSD at the maximum manual force). Additional analyses based on the normalized values of the intercondylar notch volume showed consistent results for male patients, and additional grouping for female patients was identical to the existing grouping. Conclusions The surgical outcomes of anatomical single-bundle ACL reconstruction in patients with relatively small intercondylar notch volumes were comparable to those with large notch volumes, but rather showed favorable outcomes in postoperative knee AP laxity.

Leucine-rich repeat kinase 2 (LRRK2), a large GTP-regulated serine/threonine kinase, is well-known for its mutations causing late-onset Parkinson’s disease. However, the role of LRRK2 in glioblastoma (GBM) carcinogenesis has not yet been fully elucidated. Here, we discovered that LRRK2 was overexpressed in 40% of GBM patients, according to tissue microarray analysis, and high LRRK2 expression correlated with poor prognosis in GBM patients. LRRK2 and stemness factors were highly expressed in various patient-derived GBM stem cells, which are responsible for GBM initiation. Canonical serum-induced differentiation decreased the expression of both LRRK2 and stemness factors.Given that LRRK2 is a key regulator of glioma stem cell (GSC) stemness, we developed DNK72, a novel LRRK2 kinase inhibitor that penetrates the blood-brain barrier. DNK72 binds to the phosphorylation sites of active LRRK2 and dramatically reduced cell proliferation and stemness factors expression in in vitro studies. Orthotopic patient-derived xenograft mouse models demonstrated that LRRK2 inhibition with DNK72 effectively reduced tumor growth and increased survival time. We propose that LRRK2 plays a significant role in regulating the stemness of GSCs and that suppression of LRRK2 kinase activity leads to reduced GBM malignancy and proliferation. In the near future, targeting LRRK2 in patients with high LRRK2-expressing GBM could offer a superior therapeutic strategy and potentially replace current clinical treatment methods.

Background: Benign bladder tumors are rare disease entities, and insufficient studies have assessed their epidemiological characteristics. The authors investigated the prevalence of benign bladder tumors by retrospectively investigating pathology reports of transurethral resection of bladder tumor (TURBT) procedures over the past 20 years. Methods: We analyzed 1,674 pathology reports of TURBT conducted in 1,160 patients from January 1, 2000, to April 30, 2022. The prevalence of benign tumors and histological classification according to the presence of primary (group 1) and recurrent (group 2) bladder lesions were retrospectively investigated. Results: The mean age of patients was 65.2±11.5 years, and 1,284 cases (79.1%) were in men. Benign bladder tumors comprised 278 cases (248 patients) accounting for about 17.1% of the total TURBT cases (278/1,624). Furthermore, 184 patients (16.0%, 184/1,147) belonged to group 1 and 78 patients (27.4%, 78/285) belonged to group 2. Among all benign lesions that underwent TURBT, cystitis was the most common (41.0%, 114/278), and this rate was higher in group 2 (64/184 [34.8%] vs. 50/94 [53.2%], p<0.001). The prevalence of non-neoplastic lesions was higher in group 1 (44/184 [23.9] vs. 11/94 [11.7%], p<0.001). There was no difference in the prevalence of noninvasive urothelial neoplasms between the two groups (22/184 [12.0%] vs. 8/94 [8.5%], p=0.86). Conclusions The probability of benign lesions in TURBT was 17.1%, among which cystitis was the most common. When TURBT was performed for recurrent lesions, the frequency of benign tumors was higher than that of primary benign bladder tumors.

Background/Aims: Human adenovirus type 55 (HAdV-55), an emerging epidemic strain, has caused several large outbreaks in the Korean military since 2014, and HAdV-associated acute respiratory illness (HAdV-ARI) has been continuously reported thereafter. Methods: To evaluate the epidemiologic characteristics of HAdV-ARI in the Korean military, we analyzed respiratory virus polymerase chain reaction (RV-PCR) results, pneumonia surveillance results, and severe HAdV cases from all 14 Korean military hospitals from January 2013 to May 2018 and compared these data with nationwide RV surveillance data for the civilian population. Results: A total of 14,630 RV-PCRs was performed at military hospitals. HAdV (45.4%) was the most frequently detected RV, followed by human rhinovirus (12.3%) and influenza virus (6.3%). The percentage of the military positive for HAdV was significantly greater than the percentage of civilians positive for HAdV throughout the study period, with a large outbreak occurring during the winter to spring of 2014 to 2015. The outbreak continued until the end of the study, and non-seasonal detections increased over time. The reported number of pneumonia patients also increased during the outbreak. Case fatality rate was 0.075% overall but 15.6% in patients with respiratory failure. The proportion of severe patients did not change significantly during the study period. Conclusions A large HAdV outbreak is currently ongoing in the Korean military, with a trend away from seasonality, and HAdV-55 is likely the predominant strain. Persistent efforts to control the outbreak, HAdV type-specific surveillance, and vaccine development are required.

Sodium 2-mercaptoethanesulfonate (mesna) is a protective agent that is widely used in medicine because of its antioxidant effects. Recently, reactive oxygen species (ROS) were shown to increase pigmentation. Thus, ROS scavengers and inhibitors of ROS production may suppress melanogenesis. Forkhead box-O3a (FoxO3a) is an antimelanogenic factor that mediates ROS-induced skin pigmentation. In this study, we aimed to investigate the whitening effect of mesna and the signaling mechanism mediating this effect. Human melanoma (MNT-1) cells were used in this study. mRNA and protein expression were measured by real-time quantitative PCR and Western blotting analysis to track changes in FoxO3a-related signals induced by mesna. An immunofluorescence assay was performed to determine the nuclear translocation of FoxO3a. When MNT-1 melanoma cells were treated with mesna, melanin production and secretion decreased. These effects were accompanied by increases in FoxO3a activation and nuclear translocation, resulting in downregulation of four master genes of melanogenesis: MITF, TYR, TRP1, and TRP2. We found that mesna, an antioxidant and radical scavenger, suppresses melanin production and may therefore be a useful agent for the clinical treatment of hyperpigmentation disorders.

Some drugs cause phototoxicity in humans when exposed to light, thus there is a need for an in vivo phototoxicity test to evaluate them. However, an in vivo phototoxicity test method to evaluate this has not been established. This study aimed to establish an in vivo phototoxicity test method for transdermally administered drugs. For this, we evaluated the phototoxicity using Sprague-Dawley (SD) rats for transdermal administered drugs and we studied the appropriate UVA dose using 8-methoxypsalen, which is a well-known phototoxic drug. We found that a UVA dose of 15 J/cm2 was dose and time dependent response compared to other UVA doses. We performed the Minimum Erythema Dose (MED) test because UVB can cause skin irritation by itself and selected 0.01 J/cm2 as an appropriate dose of UVB. Using the selected UVA and UVB doses, we performed a phototoxicity study of 6 pharmaceutical drugs, which included phototoxic and non-phototoxic drugs. As a result of the phototoxicity test, 100% accuracy was obtained when compared with previous studies. In addition, we performed histopathology to confirm the new findings. We found that histopathology can be used as an additional indicator of phototoxicity test for transdermally administered drugs.

Some drugs cause phototoxicity in humans when exposed to light, thus there is a need for an in vivo phototoxicity test to evaluate them. However, an in vivo phototoxicity test method to evaluate this has not been established. This study aimed to establish an in vivo phototoxicity test method for transdermally administered drugs. For this, we evaluated the phototoxicity using Sprague-Dawley (SD) rats for transdermal administered drugs and we studied the appropriate UVA dose using 8-methoxypsalen, which is a well-known phototoxic drug. We found that a UVA dose of 15 J/cm2 was dose and time dependent response compared to other UVA doses. We performed the Minimum Erythema Dose (MED) test because UVB can cause skin irritation by itself and selected 0.01 J/cm2 as an appropriate dose of UVB. Using the selected UVA and UVB doses, we performed a phototoxicity study of 6 pharmaceutical drugs, which included phototoxic and non-phototoxic drugs. As a result of the phototoxicity test, 100% accuracy was obtained when compared with previous studies. In addition, we performed histopathology to confirm the new findings. We found that histopathology can be used as an additional indicator of phototoxicity test for transdermally administered drugs.

Sodium 2-mercaptoethanesulfonate (mesna) is a protective agent that is widely used in medicine because of its antioxidant effects. Recently, reactive oxygen species (ROS) were shown to increase pigmentation. Thus, ROS scavengers and inhibitors of ROS production may suppress melanogenesis. Forkhead box-O3a (FoxO3a) is an antimelanogenic factor that mediates ROS-induced skin pigmentation. In this study, we aimed to investigate the whitening effect of mesna and the signaling mechanism mediating this effect. Human melanoma (MNT-1) cells were used in this study. mRNA and protein expression were measured by real-time quantitative PCR and Western blotting analysis to track changes in FoxO3a-related signals induced by mesna. An immunofluorescence assay was performed to determine the nuclear translocation of FoxO3a. When MNT-1 melanoma cells were treated with mesna, melanin production and secretion decreased. These effects were accompanied by increases in FoxO3a activation and nuclear translocation, resulting in downregulation of four master genes of melanogenesis: MITF, TYR, TRP1, and TRP2. We found that mesna, an antioxidant and radical scavenger, suppresses melanin production and may therefore be a useful agent for the clinical treatment of hyperpigmentation disorders.