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Abstract Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

Abstract Background Clinical applications of RNA interference for cancer treatment and immune therapy require the development of simultaneous therapy and imaging systems for microRNA. This research was performed to fabricate the miRNA34a-loaded magnetic nanoparticles and investigate its anticancer effects against triple-negative breast cancer (TNBC) in mice model. Results Using two types of polymers to improve their water dispersibility and gene delivery, iron oxide magnetic nanoparticles were prepared for delivery of miRNA34a. The iron oxide magnetic nanoparticles were delivered to TNBC cells, and their efficacy was evaluated in vitro and in vivo. Delivery of miRNA34a reduced TNBC cell migration and decreased the expression of PD-L1 at the mRNA and protein levels. In animal experiments, delivery of miRNA34a reduced tumor growth, and immunostaining and algorithmic analysis confirmed the decrease in PD-L1 expression. Conclusion This study is the first to modulate PD-L1 by delivering miRNA34a with magnetic nanoparticles, and the results suggest that miRNA34a can be delivered effectively using magnetic nanoparticles and has potential as a molecular imaging contrast agent.

Abstract Background Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. Methods We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. Results We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p

Abstract Manganese oxide (MnO) nanocubes were fabricated and their surface were modified by ligand encapsulation or ligand exchange, to render them water-soluble. And then, MnO formed the hollow structure by etching using acidic solution (phthalate buffer, pH 4.0). Depending on the ligand of the MnO surface, it increases the interaction between MnO and water molecules. Also, the hollow structure of MnO, as well as the ligand, can greatly enhance the accessibility of water molecules to metal ions by surface area-to-volume ratio. These factors provide high R1 relaxation, leading to strong T1 MRI signal. We have confirmed T1-weighted MR contrast effect using 4-kinds of MnO nanocubes (MnOEn, MnOEnHo, MnOEx and MnOExHo). They showed enough a MR contrast effect and biocompatibility. Especially, among them, MnOExHo exhibited high T1 relaxivity (r1) (6.02 mM−1 s−1), even about 1.5 times higher sensitivity than commercial T1 MR contrast agents. In vitro/in vivo studies have shown that MnOExHo provides highly sensitive T1-weighted MR imaging, thereby improving diagnostic visibility at the disease site.

Abstract Background Gastric cancer is a considerable burden for worldwide patients. And diffuse gastric cancer is the most insidious subgroup with poor survival. The phenotypic characterization of the diffuse gastric cancer cell line can be useful for gastric cancer researchers. In this article, we aimed to characterize the diffuse gastric cancer cells with MRI and transcriptomic data. We hypothesized that gene expression pattern is associated with the phenotype of the cells and that the heterogeneous enhancement pattern and the high tumorigenicity of SNU484 can be modulated by the perturbation of the highly expressed gene. Methods We evaluated the 9.4 T magnetic resonance imaging and transcriptomic data of the orthotopic mice models from diffuse gastric cancer cells such as SNU484, Hs746T, SNU668, and KATO III. We included MKN74 as an intestinal cancer control cell. After comprehensive analysis integrating MRI and transcriptomic data, we selected CD34 and validated the effect by shRNA in the BALB/c nude mice models. Results SNU484, SNU668, Hs746T, and MKN74 formed orthotopic tumors by the 5 weeks after cell injection. The diffuse phenotype was found in the SNU484 and Hs746T. SNU484 was the only tumor showing the heterogeneous enhancement pattern on T2 images with a high level of CD34 expression. Knockdown of CD34 decreased the round-void shape in the H&E staining (P = 0.028), the heterogeneous T2 enhancement, and orthotopic tumorigenicity (100% vs 66.7%). The RNAseq showed that the suppressed CD34 is associated with the downregulated gene-sets of the extracellular matrix remodeling. Conclusion Suppression of CD34 in the human-originated gastric cancer cell suggests that it is important for the round-void histologic shape, heterogeneous enhancement pattern on MRI, and the growth of gastric cancer cell line.

The roots of Panax notoginseng (PN) are commonly used as a therapeutic agent to stop hemorrhage and as a tonic to promote health in traditional Korean medicine. Stroke triggers an inflammatory response that not only plays a central role in the pathogenesis of cerebral ischemia, but also induces secondary damage. This study was designed to investigate the neuroprotective effects of the methanol extract of PN on the infarct volume induced by middle cerebral artery occlusion (MCAO) (90-min occlusion and 24-h reperfusion) in rat brains. The PN extract (50 mg/kg, i.p.) was administered 2 h after the onset of MCAO. The PN-treated groups had a reduction in infarct volume by 23.82 ± 8.9%. In the PN extract–treated groups, the microglial density was significantly decreased in the peri-infarct region; the underlying mechanism was inhibition of inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, via blocking of the NF-κB pathway. Furthermore, in vitro studies showed that the PN extract significantly reduced the production of iNOS-derived NO and COX-2– derived prostaglandin E2 through the regulation of gene transcription levels in primary microglia and BV-2 cells. These results suggest that anti-inflammatory and microglial activation inhibitory effects of the PN extract may contribute to its neuroprotective effects in brain ischemia. Keywords:: inflammation, microglia, Panax notoginseng, stroke

IntroductionAdolescents may perpetrate cyberbullying in cyberspace, which they perceive as a medium of social communication, and cyberbullying perpetration is closely related to adolescent behavior, mental health, and development. This study aimed to examine the relationship of certain factors related to cyberbullying in adolescents using the framework of Jessor’s problem behavior theory.MethodsThis cross-sectional study investigated the mediating effect of adolescent self-esteem and smartphone addiction in the relationship between positive parenting and adolescent cyberbullying perpetration. The secondary analysis used data from the 2018 Korean Children and Youth Panel Survey. The data on positive parenting, adolescent self-esteem, smartphone addiction, and perpetration of cyberbullying of 2,394 Korean adolescents (boys: 1,297, 54.2%) were analyzed. Hayes’ PROCESS macro program was used to confirm the mediating role.ResultsThe results revealed that 26.5% (n = 634) of adolescents had perpetrated cyberbullying. Positive parenting did not directly relate to cyberbullying perpetration. Adolescent self-esteem and smartphone addiction played a mediating role between positive parenting and adolescent cyberbullying.DiscussionIndividual adolescent characteristics and parent/family system characteristics should be considered in policies aimed at preventing adolescent cyberbullying perpetration, preceded by the management of appropriate smartphone use. Improving young people’s self-esteem and teaching them how to use smartphones correctly can help prevent cyberbullying.

The Korean Neonatal Network (KNN), which is celebrating its 10th anniversary, currently has more than 100 staff and researchers from >70 neonatal intensive care units nationwide in Korea. More than 85% to 90% of the population of very low birth weight infants in Korea are registered yearly, and more than half are followed up for up to 3 years at the KNN. A total of >19,000 cases have been accumulated through a strict data quality management process of the KNN. Based on this, >100 research projects have been proposed, >70 peer-reviewed papers have been published in leading international journals, and the cornerstone of the quality improvement project has been launched. In addition, we recently expanded the number of subjects for registration to very premature infants

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very longchain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy. [ABSTRACT FROM AUTHOR]

Porcine embryonic stem cells (pESCs) have become an advantageous experimental tool for developing therapeutic applications and producing transgenic animals. However, despite numerous reports of putative pESC lines, deriving validated pESC lines from embryos produced in vitro remains difficult. Here, we report that embryo aggregation was useful for deriving pESCs from in vitro-produced embryos. Blastocysts derived from embryo aggregation formed a larger number of colonies and maintained cell culture stability. Our derived cell lines demonstrated expression of pluripotent markers (alkaline phosphatase, Oct4, Sox2, and Nanog), an ability to form embryoid bodies, and the capacity to differentiate into the three germ layers. A cytogenetic analysis of these cells revealed that all lines derived from aggregated blastocysts had normal female and male karyotypes. These results demonstrate that embryo aggregation could be a useful technique to improve the efficiency of deriving ESCs from in vitro-fertilized pig embryos, studying early development, and deriving pluripotent ESCs in vitro in other mammals. [ABSTRACT FROM AUTHOR]

Abstract Objectives/aims With the Euro-Qol-5 dimension (EQ-5D) system, we investigated the relationship between the number of remaining teeth and QoL using data from the Korean National Health and Nutrition Examination Survey (KNHANES), 2010–2012. A total of 17,417 participants, more than 19 years old, were finally included in this study (men = 7394 and women = 10,023). Through this study, we have discovered that the remaining teeth affect overall health and that the fewer number of them may indicate a lower quality of life, as well. The quality of life according to the number of remaining teeth was assessed among Koreans using the Euro-Qol-5 dimension (EQ-5D) system. Method The Euro-Qol-5 dimension (EQ-5D) system was used to measure the health-related QoL. Its five dimensions included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The respondents were asked to choose one of the followings: G 1, no problems; G 2, some problems; and G 3, problematic, to best describe their health status for the five dimensions. Then, we assigned low QoL to G2 + G3 and high QoL to G1. We used age, gender, economic income, educational level, residence, and marital status for the demographic variables and, drinking, smoking, exercise, BMI, and metabolic syndrome for health behaviors. Multiple logistic regression analysis was performed to examine the odds ratios (ORs) and confidence intervals (CIs) for the high QoL (G1) on the five categories of EQ-5D according to the number of remaining teeth. On the basis of the 0–15 remaining teeth group, we drew a comparison of the QoL between the 16–20 and 21–28 remaining teeth groups. Results Subjects with 21–28 remaining teeth had higher QoL scores and had higher ORs of high QoL, especially for mobility (OR = 1.256, 95% CI = 1.056–1.495), self-care (OR = 1.441, 95% CI = 1.096–1.894), and usual activities (OR = 1.241, 95% CI = 1.022–1.508, respectively), than those with 0–15 remaining teeth after adjusting for age, sex, body mass index, smoking, drinking, exercise, income, education, and metabolic syndrome. ORs from the high QoL had the tendency to increase as the number of remaining teeth increased (all p for trend

Abstract The mesenchymal cancer phenotype is known to be clinically related to treatment resistance and a poor prognosis. We identified gene signature-based molecular subtypes of gastric cancer (GC, n = 547) based on transcriptome data and validated their prognostic and predictive utility in multiple external cohorts. We subsequently examined their associations with tumor microenvironment (TME) features by employing cellular deconvolution methods and sequencing isolated GC populations. We further performed spatial transcriptomics analysis and immunohistochemistry, demonstrating the presence of GC cells in a partial epithelial-mesenchymal transition state. We performed network and pharmacogenomic database analyses to identify TGF-β signaling as a driver pathway and, thus, a therapeutic target. We further validated its expression in tumor cells in preclinical models and a single-cell dataset. Finally, we demonstrated that inhibition of TGF-β signaling negated mesenchymal/stem-like behavior and therapy resistance in GC cell lines and mouse xenograft models. In summary, we show that the mesenchymal GC phenotype could be driven by epithelial cancer cell-intrinsic TGF-β signaling and propose therapeutic strategies based on targeting the tumor-intrinsic mesenchymal reprogramming of medically intractable GC.

The initial response to a marine accident can play a key role to minimize the accident. Therefore, various decision support systems have been developed using sensors, simulations, and active response equipment. In this study, we developed an algorithm to predict damage locations using ship motion data with bidirectional long short-term memory (BiLSTM), a type of recurrent neural network. To reflect the low frequency ship motion characteristics, 200 time-series data collected for 100 s were considered as input values. Heave, roll, and pitch were used as features for the prediction model. The F1-score of the BiLSTM model was 0.92; this was an improvement over the F1-score of 0.90 of a prior model. Furthermore, 53 of 75 locations of damage had an F1-score above 0.90. The model predicted the damage location with high accuracy, allowing for a quick initial response even if the ship did not have flood sensors. The model can be used as input data with high accuracy for a real-time progressive flooding simulator on board.

Somatic cell nuclear transfer (SCNT) is an alternative potential tool for the conservation of endangered. In this study, somatic cells were collected from a purebred 9-month-old male mastiff and an 11-month-old female mastiff. Oocytes that had been matured in vivo were retrieved from outbred dogs by laparoscopy. We used cycling cells as donor cells for SCNT. A total of 289 oocytes were reconstructed with each male or female somatic cell and then fused/activated simultaneously by electrical stimulation. Finally, 224 embryos were transferred to 16 recipients that had been synchronized naturally. The efficiency of delivery of cloned dogs (7.1%) was threefold higher than in previous reports. Moreover, one surrogate delivered four identical cloned female Tibetan Mastiff puppies; another three surrogates each delivered triplets. Microsatellite analysis demonstrated the genotypic identity of the cloned puppies. Thus, our study has demonstrated techniques that improve significantly the overall efficiency of SCNT in the canine species. [ABSTRACT FROM AUTHOR]