A simple metastatic brain cancer model using human embryonic stem cell-derived cerebral organoids.

Every year, hundreds of thousands of people die because of metastatic brain cancer. Most metastatic cancer research uses 2D cell culture or animal models, but they have a few limitations, such as difficulty reproducing human tissue structures. This study developed a simple 3D in vitro model to better replicate brain metastasis using human cancer cells and human embryonic stem cell-derived cerebral organoids (metastatic brain cancer cerebral organoid [MBCCO]). The MBCCO model successfully reproduced metastatic cancer processes, including cell adhesion, proliferation, and migration, in addition to cell-cell interactions. Using the MBCCO model, we demonstrated that lung-specific X protein (LUNX) plays an important role in cell proliferation and migration or invasion. We also observed astrocyte accumulation around and their interaction with cancer cells through connexin 43 in the MBCCO model. We analyzed whether the MBCCO model can be used to screen drugs by measuring the effects of gefitinib, a well-known anticancer agent. We also examined the toxicity of gefitinib using normal cerebral organoids (COs). Therefore, the MBCCO model is a powerful tool for modeling human metastatic brain cancer in vitro and can also be used to screen drugs.

Multiple Combination of Angelica gigas Extract and Mesenchymal Stem Cells Enhances Therapeutic Effect.

Alternative medicines attract attention because stroke is rarely expected to make a full recovery with the most advanced medical technology. Angelica gigas (AG) is a well-known herbal medicine as a neuroprotective agent. The present study introduced mesenchymal stem cells (MSCs) to identify for the advanced treatment of the cerebrovascular disease. The objective of this research is validation of the enhanced effects of multiple combined treatment of AG extract with MSCs on stroke through angiogenesis. Our results confirmed that AG extract with MSCs improved the neovascularization increasing expression of angiogenesis-regulated molecules. The changes of brain and the behavioral ability showed the increased effects of AG extract with MSCs. As a result, AG extract and MSCs may synergistically increase the therapeutic potential by enhancing neovascularization. This mixed approach provides a new experimental protocol of herbal medicine therapy for the treatment of a variety of diseases including stroke, trauma, and spinal cord injury.

Effect of chongmyungtang, a traditional Korean polyherbal formula, on the Pharmacokinetic profiles of donepezil in rats.

Chongmyungtang (CMT) is a famous Korean herbal medicine for improving learning and memory, which has been reported to have anti-cholinergic and neuroprotective effects. Therefore, drug-drug interactions were examined between CMT and donepezil as a first screening of combination therapy for cognitive deficits. Rats received oral co-administration of donepezil with distilled water as a control or donepezil with CMT as a combination. The distilled water or CMT was co-administered at intervals within 5min after donepezil or 1.5h intervals. The plasma samples were analyzed for donepezil concentration and its pharmacokinetic parameters of Tmax, Cmax, AUC, t1/2 and MRTinf. In the single co-administration at intervals within 5min, donepezil was detected lower in the combination than control at 0.5h and 2h post-treatment (P<0.05). In addition, the combination showed significant increases in MRTinf compared to the control (P<0.05). This suggests drug-drug interactions between donepezil and CMT in the co-administration within 5 min. However, no meaningful differences were found in the pharmacokinetic profiles of donepezil by single dosing with CMT at 1.5h intervals and even by the repeated dosing for a week at 1.5h intervals potential combination therapy of donepezil with CMT.

The consequences of ISO 45001: preliminary analysis of cases in Korea.

OBJECTIVES: Using cases in the Korean workplace, this study preliminarily investigated whether ISO 45001-certified and non-certified workplaces differ in 4 aspects of occupational safety and health (OSH) management. METHODS: Data were obtained from the 2021 Survey on the Status of Safety and Health in the Workplace in Korea. This study used a matched-pair analysis of certified and non-certified workplaces. RESULTS: The results suggest that although ISO 45001-certified workplaces have a more safety-friendly internal institutional context than non-certified workplaces, there is no significant difference in the number of injuries and fatalities. CONCLUSIONS: The results indicate that ISO 45001-certified workplaces do not achieve better OSH performance than non-certified workplaces because ISO 45001 remains in the early stages of expansion, and certification does not require the achievement of OSH performance. A longitudinal analysis is needed to confirm the accurate outcomes of ISO 45001 certification.

Relationship Between Perceived Discrimination and Somatic Symptom Disorder Among Young Adults With Immigrant Background in South Korea.

Insufficient research has compared the impact of subtle and overt discrimination on somatic symptom disorder (SSD) among young adults with immigrant backgrounds in South Korea, a country that is becoming increasingly racially and ethnically diverse. Therefore, this study sought to examine this. A cross-sectional survey was conducted in January 2022 involving 328 young adults aged 25 to 34 years who had at least one foreign-born parent or were foreign-born immigrants. We used ordinary least squares (OLS) regression with SSD as the dependent variable. The results showed that subtle and overt discrimination were positively associated with SSD among young immigrant adults. Subtle discrimination seems more strongly related to SSD among Korean-born immigrant adults (N = 198) than foreign-born immigrant young adults (N = 130). This result partially supported the theory that both forms of discrimination were differently related to increased SSD tendencies by place of birth.

Seasonal characteristics of atmospheric water-soluble organic nitrogen in PM2.5 in Seoul, Korea: Source and atmospheric processes of free amino acids and aliphatic amines.

The seasonal characteristics of atmospheric water-soluble organic nitrogen (WSON) in particulate matter with a diameter of 2.5 µm or smaller (PM2.5) were analyzed focusing on sources and atmospheric processing. Daily collected samples over 23 h (10:00-9:00) from 7 August 2018 to 31 December 2019 on quartz filters with a high-volume sampler at the Korea Institute of Science and Technology (KIST) in Seoul were considered. The most common species in the Seoul atmosphere included Glycine (5.45 ± 9.81 ng/m3) among free amino acids (FAAs) and trimethylamine (TMA) (5.35 ± 3.80 ng/m3) among aliphatic amines (AAs). The top 10 WSON species (93.6% of all WSON species) were categorized into three groups based on correlation analysis considering meteorological data, (e.g., temperature, rainfall, relative humidity (RH), wind speed) gaseous pollutants (e.g., SO2, CO, NO2) and mass concentration of PM10 and PM2.5. Those three groups are G1 (Glycine, Alanine, and Threonine), G2 (Gln Glutamine, Lys Lysine, and Glutamic acid) and G3 (Trimethylamine (TMA), dimethylamine (DMA), and methylamine (MA)), where G1, G2 and G3 accounted for 31.1%, 8.8% and 51.1%, respectively, of the total species. Among these three groups, G1 and G3 are from combustion sources, and G2 shows secondary features generated by photochemical reactions involving ozone. Although both G1 and G3 exhibited features influenced by combustion sources, the AA species (TMA, DMA, and MA) in G3 demonstrated typical features enhanced under high-humidity conditions, suggesting not only primary sources but also secondary formation at the local scale influence to the AA in G3 group. Based on long-term measurements more than a year, our findings suggest that complex and diverse sources of atmospheric WSON are in Seoul, Korea both from primary and secondary, which may affect its environmental, climate and health.

Post-Marketing Pooled Safety Analysis for CT-P13 Treatment of Patients with Immune-Mediated Inflammatory Diseases in Observational Cohort Studies.

BACKGROUND: At EU marketing authorisation, safety data for CT-P13 (biosimilar infliximab) were limited, particularly in some indications, and uncommon adverse events (AEs) could not be evaluated among relatively small analysis populations. OBJECTIVES: Our objective was to investigate the overall safety profile and incidence rate of AEs of special interest (AESIs), including serious infections and tuberculosis, in CT-P13-treated patients. METHODS: Data were pooled from six observational studies representing authorised indications of CT-P13 (ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, adult and paediatric Crohn's disease and ulcerative colitis). Patients were analysed by indication and treatment (patients who received CT-P13 or those who switched from reference infliximab to CT-P13 ≤ 6 months prior to enrolment or during the study). RESULTS: Overall, 4393 patients were included (n = 3677 CT-P13 group; n = 716 switched group); 64.03% of patients had inflammatory bowel disease and 6.31% of patients were antidrug antibody positive. Overall, 32.94% and 9.58% of patients experienced treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs, respectively. Across indications, TEAEs were more frequent with CT-P13 than with the switched group. Infections including tuberculosis were the most frequent serious AESI overall (2.48%) and by treatment group or indication. In total, 14 patients (0.32%) reported active tuberculosis. Overall incidence rates per 100 patient-years (95% confidence interval) were 3.40 (2.788-4.096) for serious infections including tuberculosis and 0.44 (0.238-0.732) for active tuberculosis. Infusion-related reactions were the second most frequent AESI following infection including tuberculosis. CONCLUSION: The CT-P13 safety profile appears consistent with previous studies for CT-P13 and reference infliximab, supporting the favourable risk/benefit balance for CT-P13 treatment.

Validation of a HeLa Mx2/Luc reporter cell line for the quantification of human type I interferons.

Although antiviral assays have been the most widely available biological assays for interferons (IFNs), they are less sensitive and provide considerable interassay variation. In this study, we demonstrate a new reporter cell line, which is based on HeLa cells transfected with a plasmid containing a human Mx2 promoter driving a luciferase (Luc) cDNA. To characterize the specific gene expression profiles induced by interferon alpha, we analyzed the microarray results of interferon response gene expression induced by IFN-alpha2a or IFN-alpha2b treatment with HeLa cells. We found that the Mx2 gene increased the most by treatment with both IFN-alpha2a and IFN-alpha2b. Based on this result, we designed a reporter cell line, HeLa-Mx2, suitable for determination of IFN-alpha. HeLa cells were stably transfected with the luciferase gene under the control of Mx2 promoter. The expression of luciferase can be easily measured for luminescence using a 96-well luminometer and has been correlated with the concentration of added IFN and cell density. In the validation results, our reporter cell line had specificity for type I IFN, but the significant effects of a number of other cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-2, IL-5, IL-6 and GM-CSF, or type II interferon (IFN-gamma) were not observed. Moreover, the robustness of our cell line is demonstrated by the lack of an effect of the HeLa-Mx2 cell culture's age on the performance of the reporter gene assay. The reporter gene assay demonstrated reproducible dose-response curves for IFN-alpha2a in the range of 1-10,000 IU/ml. The 95% confidential limit and total coefficient of variation estimates ranged between 96 and 116 and 10.51% in the reducible range mentioned above, respectively. In conclusion, we established a stable IFN-responsible HeLa-Mx2 cell line, which has advantages with regard to simplicity, selectivity, and reliability over conventional cytopathic effect reduction assays used to quantify IFN-alpha activity.

Simultaneous emission of orthogonal handedness in circular polarization from a single luminophore.

The direct emission of circularly polarized (CP) light improves the efficiency of an organic light-emitting diode and characterizes the secondary structure of proteins. In most cases, CP light is generated from a luminescent layer containing chiral characteristics, thereby generating only one kind of CP light in an entire device. Here, we propose direct CP light emissions using a twisted achiral conjugate polymer without any chiral dopant as an emitting layer (EML). The twisted structure is induced in the mesogenic conjugate polymer due to its elasticity by applying different alignment directions to its upper and lower interfaces. Furthermore, we demonstrate the simultaneous emission of orthogonal CP light in a single luminescent device by patterning different alignment directions on the surfaces of the EML. The light source with multipolarization including the orthogonal CP states is applicable to many applications in biosensors and optical devices.

Salvia miltiorrhiza enhances the survival of mesenchymal stem cells under ischemic conditions.

OBJECTIVES: To validate the enhanced therapeutic effect of Salvia miltiorrhiza Bunge (SM) for brain ischemic stroke through the anti-apoptotic and survival ability of mesenchymal stem cells (MSCs). METHODS: The viability and the expression level of cell apoptotic and survival-related proteins in MSCs by treatment of SM were assessed in vitro. In addition, the infarcted brain region and the behavioural changes after treatment of MSCs with SM were confirmed in rat middle cerebral artery occlusion (MCAo) models. KEY FINDINGS: We demonstrated that SM attenuates apoptosis and improves the cell viability of MSCs. In the rat MCAo model, the recovery of the infarcted region and positive changes of behaviour are observed after treatment of MSCs with SM. CONCLUSIONS: The therapy using SM enhances the therapeutic effect for brain ischemic stroke by promoting the survival of MSCs. This synergetic effect thereby proposes a new experimental approach of traditional Chinese medicine and stem cell-based therapies for patients suffering from a variety of diseases.

Transforming growth factor-ß1 bioassay involving matrix metalloproteinase-2 induction.

The transforming growth factor-ß1 (TGF-ß1) bioassay developed in this study monitors increased luciferase activity in MCF10A cells containing the matrix metalloproteinase-2 (MMP-2) promoter with a luciferase reporter and treated with increasing TGF-ß1 concentrations. The response was linear in the concentration range from 75 to 2,500 pg/mL. The abilities of 3 types of TGF-ß in inducing MMP-2 were different. The luciferase activity induced by TGF-ß1 was about 2 times more than that by TGF-ß2 and TGF-ß3. The MMP-2 promoter bioassay showed greater reproducibility (coefficient of variation [CV] 10%) than the previously developed anticell proliferation assay of TF-1 cell (CV 16%) and the MMP-2 zymogram assay (CV 40%).

Shengmai-san-mediated enhancement of regenerative responses of spinal cord axons after injury in rats.

Shengmai-san (SMS) is a traditional Chinese medicine used to treat diverse symptoms including cardiovascular and neurological disorders. Here we investigated the effects of SMS on regenerative responses of spinal cord axons in rats that were given contusion injury at the lower thoracic level. The injury cavity was confined to a restricted area by SMS treatment, and the signals of glial scar protein chondroitin sulphate proteoglycan (CSPG) and inflammatory cell marker protein CD11beta were heavily observed within the injury cavity in SMS-treated animals. Anterograde tracing of DiI-labeled corticospinal tract (CST) axons revealed increases in collateral arborization around and within the injury cavity and caudal elongation by SMS treatment. Furthermore, SMS treatment facilitated neurite elongation of dorsal root ganglion (DRG) sensory neurons that were co-cultured with non-neuronal cells prepared from injured spinal cord. Phospho-Erk1/2 was strongly induced in both spinal cord and motor cortical areas after spinal cord injury (SCI), and it was further unregulated in the motor cortex by SMS treatment. In contrast, upregulation of cell division cycle 2 (Cdc2) production by SMS treatment was limited to a local, SCI area. These data suggest that SMS may play an active role in regenerative responses and facilitate axonal regrowth after SCI.