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Immune checkpoint therapies, such as programmed cell death ligand 1 (PD-L1) blockade, have shown remarkable clinical benefit in many cancers by restoring the function of exhausted T cells. Hence, the identification of novel PD-L1 regulators and the development of their inhibition strategies have significant therapeutic advantages. Here, we conducted pooled shRNA screening to identify regulators of membrane PD-L1 levels in lung cancer cells targeting druggable genes and cancer drivers. We identified WNK lysine deficient protein kinase 3 (WNK3) as a novel positive regulator of PD-L1 expression. The kinase-dead WNK3 mutant failed to elevate PD-L1 levels, indicating the involvement of its kinase domain in this function. WNK3 perturbation increased cancer cell death in cancer cell–immune cell coculture conditions and boosted the secretion of cytokines and cytolytic enzymes, promoting antitumor activities in CD4+ and CD8+ T cells. WNK463, a pan-WNK inhibitor, enhanced CD8+ T-cell-mediated antitumor activity and suppressed tumor growth as a monotherapy as well as in combination with a low-dose anti-PD-1 antibody in the MC38 syngeneic mouse model. Furthermore, we demonstrated that the c-JUN N-terminal kinase (JNK)/c-JUN pathway underlies WNK3-mediated transcriptional regulation of PD-L1. Our findings highlight that WNK3 inhibition might serve as a potential therapeutic strategy for cancer immunotherapy through its concurrent impact on cancer cells and immune cells.

With the enforcement of the Hospice and Palliative Care and Decisions on Life-Sustaining Treatment for Patients at the End-of-Life Act in 2018, interest in the quality of death in South Korea is increasing. However, few studies have provided an updated perspective on a good death. This integrative review describes the attributes of a good death from the perspective of South Korean older adults. Among the 32 studies included in this review, 16 main themes representing good death were identified. Themes of maintaining dignity, not burdening others, living a meaningful life, being pain-free, and being prepared to die were commonly reported attributes of a good death in other cultures; themes further reflected in Korean culture were filial piety and parenting. In contrast, older adult characteristics such as low income and education level, bereavement experience, disease uncertainty, and depressive symptoms were associated with high levels of fear of death or negative attitudes, such as trying to avoid suffering through death. This review provides insights into the health care provider's approach to older people at the end of their life in South Korea. Consequently, this can help determine potential unmet needs that can be improved.

The extracellular matrix (ECM) of the tumor microenvironment undergoes constant remodeling that alters its biochemical and mechano-physical properties. Non-enzymatic glycation can induce the formation of advanced glycation end-products (AGEs), which may cause abnormal ECM turnover with excessively cross-linked collagen fibers. However, the subsequent effects of AGE-mediated matrix remodeling on the characteristics of stromal cells in tumor microenvironments remain unclear. Here, we demonstrate that AGEs accumulated in the ECM alter the fibroblast phenotype within a three-dimensional collagen matrix. Both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction signaling were up-regulated in glycated collagen matrix, leading to fibroblast activation to acquire a cancer-associated fibroblast (CAF)-like phenotype. These effects were blocked with neutralizing antibodies against RAGE or the inhibition of focal adhesion (FA) signaling. An AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711), also reduced the transformation of fibroblasts into the CAF-like phenotype because of its dual inhibitory role in the AGE-modified matrix. Apart from targeting the AGE-RAGE interaction directly, the decreased matrix stiffness attenuated fibroblast activation by inhibiting the downstream cellular response to matrix stiffness. Our results suggest that indirect/direct targeting of accumulated AGEs in the ECM has potential for targeting the tumor stroma to improve cancer therapy. STATEMENT OF SIGNIFICANCE: Advanced glycated end-products (AGEs)-modified extracellular matrix (ECM) is closely associated with pathological states and is recognized as a critical factor that precedes tumorigenesis. While increased matrix stiffness is known to induce fibroblast activation, less is known about how both biochemical and mechano-physical changes in AGE-mediated matrix-remodeling cooperate to produce a myofibroblastic cancer-associated fibroblast (CAF)-like phenotype. For the first time, we found that both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction were up-regulated in glycated collagen matrix, leading to fibroblast activation. We further demonstrated that an AGE cross-link breaker, ALT-711, reduced the CAF-like transformation because of its dual inhibitory role in the AGE-modified matrix. Our findings offer promising extracellular-reversion strategies targeting the non-enzymatic ECM glycation, to regulate fibroblast activation.

Objective Along with aging, the elderly population with cancers is increasing. The costs of end-of-life (EOL) care are particularly high among cancer patients. The purpose of this study was to investigate the trends in medical costs in the last year of life among older adults with cancer. Design, setting, and participants: Using the Health Insurance Review and Assessment Services (HIRA) database for the period 2016–2019, we identified older adults aged ≥ 65 years who had a primary diagnosis of cancers and high-intensity treatment at least once in the intensive care unit (ICU) of tertiary hospitals. Main outcomes and measures: High-intensity treatment was defined as receiving at least one of the following treatments: cardiopulmonary resuscitation, mechanical ventilation, extracorporeal membrane oxygenation, hemodialysis, and transfusion. The EOL medical treatment costs were calculated by dividing periods 1, 2, 3, 6, and 12 months from the time of death, respectively. Results The mean total EOL medical expense per older adult during the year before death was $33,712. The cost of EOL medical expenses for three months and one month before subjects’ death accounted for 62.6% ($21,117) and 33.8% ($11,389) of total EOL costs, respectively. Among subjects who died while receiving high-intensity treatment in the ICU, the costs associated with medical treatments that occurred during the last month before death were 42.4% ($13,841) of the total EOL expenses during the year. Conclusion The findings indicate that EOL care expenditures for the older population with cancer are highly concentrated until the last month. The intensity of medical care is an important and challenging issue in terms of care quality and cost suitability. Efforts are needed to properly use medical resources and provide optimal EOL care for older adults with cancer.

공유경제 플랫폼이 갖는 교차 네트워크 외부성은 끼워팔기를 통한 독점력 전이현상의 위험성을 내포한다. 본 연구는 공유경제 플랫폼에서 끼워팔기를 통한 독점력 전이현상이 어떠한 형태로 일어나는지 분석하고 이에 대한 정책을 제언한다. 게임이론의 호텔링 모형을 확장하여 공유경제 플랫폼 시장을 분석하며, 공유경제 플랫폼에서 수요자와 공급자를 연결하는 것이 중요하다는 점에 착안하여 매칭확률을 반영한 모형을 제시한다. 소비자가 각 플랫폼에 대해 느끼는 이동비용이 작은 경우 초기 가입자를 많이 확보한 플랫폼이 시장을 독점하게 되는 독점력 전이현상이 나타나지만, 이동비용이 충분히 클 경우 독점력 전이가 일어나지 않을 수 있다. 이처럼 이동비용에 따라 독점력 전이현상이 다르게 나타날 뿐만 아니라, 시장 전체 소비자의 선호도가 특정 플랫폼에서 더 크면, 독점력 전이의 효과를 누리기 위한 초기 가입자의 규모가 달라지므로, 규제의 기준이 시장의 상황에 따라 다르게 적용이 되어야 한다. 공유경제 플랫폼에서의 독점에 대한 규제는 기존의 고전적인 산업조직론의 접근은 물론, 4차 산업혁명 시대의 새로운 시장 상황에 대한 전문성을 가지고 접근해야 한다. 본 논문은 공동규제의 방식을 통해 정부가 제시한 범위 내에서 피규제자가 참여하여 규제제도의 확립에 전문성을 확충하는 방향을 제언한다.

One of the factors related to the pathogenesis of Alzheimer’s disease, a disease characterized by gradual cognitive and memory impairment, is an inflammatory process induced by the amyloid-β-mediated activation of microglia. In the present study, an extract of the Chrysanthemum boreale (Makino) Makino (CB) flower, which has inhibitory effects on inflammation and the production of phosphorylated tau in cells, was investigated for its ameliorative effect on memory dysfunction in scopolamine-treated Alzheimer’s disease models. The CB-extract-diet-administered groups, which were treated chronically with scopolamine (intraperitoneal), showed increased spontaneous alterations (12.5–15.5% increase) in the Y-maze test and latency to escape (3.7–6.7-fold increase) in the passive avoidance test, compared to the negative control (NC) group. Rats administered the CB extract also showed a higher tendency (66–86% increase) of hippocampal brain-derived neurotrophic factor expression than NC rats. Moreover, the ratio of phosphorylated extracellular signal-regulated kinase/extracellular signal-regulated kinase in the CB-extract-administered group was lower (48.0–52.2%) than that (100%) in the NC group. In the Morris water maze test conducted on the fifth day, the free-swimming times of the CB-extract-administered mice that were also treated with scopolamine for a short time (5 d) increased (51.7–56.1%) significantly compared to those of the NC mice. Finally, high-performance liquid chromatography analysis confirmed that isochlorogenic acid A, linarin, and chlorogenic acid are the major phenolic components of the CB extract. These results suggest that the extract of CB flowers might be useful as a functional material with memory-enhancing effects.

Pulmonary fibrosis (PF) is known as a chronic and irreversible disease characterized by excessive extracellular matrix accumulation and lung architecture changes. Large efforts have been made to develop prospective treatments and study the etiology of pulmonary fibrotic diseases utilizing animal models and spherical organoids. As part of these efforts, we created an all-inkjet-printed three-dimensional (3D) alveolar barrier model that can be used for anti-fibrotic drug discovery. Then, we developed a PF model by treating the 3D alveolar barrier with pro-fibrotic cytokine and confirmed that it is suitable for the fibrosis model by observing changes in structural deposition, pulmonary function, epithelial–mesenchymal transition, and fibrosis markers. The model was tested with two approved anti-fibrotic drugs, and we could observe that the symptoms in the disease model were alleviated. Consequently, structural abnormalities and changes in mRNA expression were found in the induced fibrosis model, which were shown to be recovered in all drug treatment groups. The all-inkjet-printed alveolar barrier model was reproducible for disease onset and therapeutic effects in the human body. This finding emphasized that the in vitro artificial tissue with faithfully implemented 3D microstructures using bioprinting technology may be employed as a novel testing platform and disease model to evaluate potential drug efficacy.

Despite recent innovations and advances in early diagnosis, the prognosis of advanced gastric cancer remains poor due to a limited number of available therapeutics. Here, we employed pharmacogenomic analysis of 37 gastric cancer cell lines and 1345 small-molecule pharmacological compounds to investigate biomarkers predictive of cytotoxicity among gastric cancer cells to the tested drugs. We discovered that expression of CCNA2, encoding cyclin A2, was commonly associated with responses to polo-like kinase 1 (PLK1) inhibitors (BI-2536 and volasertib). We also found that elevated CCNA2 expression is required to confer sensitivity to PLK1 inhibitors through increased mitotic catastrophe and apoptosis. Further, we demonstrated that CCNA2 expression is elevated in KRAS mutant gastric cancer cell lines and primary tumors, resulting in an increased sensitivity to PLK1 inhibitors. Our study suggests that CCNA2 is a novel biomarker predictive of sensitivity to PLK1 inhibitors for the treatment of advanced gastric cancer, particularly cases carrying KRAS mutation.

Premise Atractylodes japonica (Asteraceae) is endemic to East Asia, where its rhizomes are used in traditional medicine. To investigate the genetic diversity of this species, we developed polymorphic microsatellite markers. Methods and results We obtained a total of 175,825 simple sequence repeat (SSR) loci using the Illumina HiSeq 2500 system. Eighteen polymorphic SSR primer pairs were selected to determine heterozygosity levels and allele numbers in 80 individuals from four A. japonica populations. The levels of observed and expected heterozygosity ranged from 0.000 to 1.000 and from 0.133 to 0.892, respectively. Cross-amplification in the related species A. macrocephala and A. lancea was successful in 15 and 14 of the 18 markers, respectively. Conclusions These microsatellite markers will be useful for future studies involving A. japonica population genetics and breeding.

Age-related cognitive decline (ARCD) leads to deterioration of the quality of life in the elderly. Because emerging evidence suggests age-related illness is associated with gene regulation, it is necessary to understand the factors related to ARCD from an epigenetic perspective to aim for successful cognitive aging (SCA). This study aimed to identify biomarkers for SCA by comparing peripheral blood DNA methylation profiles of community-dwelling older adults with SCA and normal cognitive aging (NCA). We selected 14 SCA participants with scores for all cognitive functions (four domains, namely global cognitive, memory, attention, and executive function) above the average of normative values in Korean older adults and 15 NCA participants from the Korean Frailty Aging Cohort Study (KFACS). We performed methylation microarrays to compare the level of DNA methylation at CpG sites in the SCA and NCA groups. We also validated our findings using gene expression analysis. We found significant differences in eight differentially methylated genes (DMGs)-two hypermethylated genes (IL26 and LOC101060542) and six hypomethylated genes (CEND1, GNAT2, SNORD95, miR885, LOC255167, and HK2). CEND1 (fold change = 5.67) and miR885 (fold change = 8.91) were validated as having significantly different gene expressions between the SCA and NCA groups. Therefore, we postulate them to be potentially promising biomarkers to explain SCA attainment. These findings provide preliminary evidence for understanding SCA and assessing cognitive health in aging.

The provenance of the Central Yellow Sea Mud (CYSM) in the Yellow Sea has been attracted a great deal of attention over the last three decades, but a consensus is not yet reached. In this study, 101 surface sediment samples collected from the CYSM were investigated to determine provenance and transport mechanisms in the area using the clay minerals and major element components. The Huanghe sediments are characterized by higher smectite, but the Changjiang sediments are more abundant illite contents. Western Korean rivers contain more kaolinite and chlorite than do Chinese rivers. The Chinese rivers have higher Fe2O3, MgO, and CaO than the Korean rivers at the same Al2O3 concentration. Therefore, the clay minerals and major element concentrations can be useful indicator for the source. Based on our results, we suggest that the surface sediments in CYSM were composed mainly of Changjiang sediments, mixed a partly with sediments from the Huanghe and the western Korean rivers. Although the northwestern part of CYSM is proximate to the Huanghe, the contents of smectite and CaO were extremely low. It could be evidence that the Huanghe materials do not enter directly into the CYSM due to the Shandong Peninsula Front. Considering the oceanic circulation in the Yellow Sea, the Changjiang sediments could be transported eastward with the Changjiang Diluted Water and then mixed in CYSM via the Yellow Sea Warm Current (YSWC). Huanghe sediments could be provided by coastal currents (Shandong Coastal Current and Yellow Sea Coastal Current) and the YSWC. In addition, sediments from western Korean rivers might be supplied into the CYSM deposit via the Korean Coastal Current, Transversal Current, and YSWC.

Chalcone, (2E)-1,3-Diphenylprop-2-en-1-one, and its synthetic derivatives are known to possess anti-oxidative and anti-inflammatory properties. In the present study, we prepared a novel synthetic chalcone compound, (E)-1-(4-hydroxyphenyl)-3-(2-(trifluoromethoxy)phenyl)prop-2-en-1-one name (YJI-7), and investigated its inhibitory effects on endotoxin-stimulated production of reactive oxygen species (ROS) and expression of inflammatory mediators in macrophages. We demonstrated that treatment of RAW 264.7 macrophages with YJI-7 significantly suppressed lipopolysaccharide (LPS)-stimulated ROS production. We also found that YJI-7 substantially decreased NADPH oxidase activity stimulated by LPS, indicating that YJI-7 regulates ROS production via modulation of NADPH oxidase in macrophages. Furthermore, YJI-7 strongly inhibited the expression of a number of inflammatory mediators in a gene-selective manner, suggesting that YJI-7 possesses potent anti-inflammatory properties, as well as anti-oxidative activity. In continuing experiments to investigate the mechanisms that could underlie such biological effects, we revealed that YJI-7 suppressed phosphorylation of p38MAPK and JNK stimulated by LPS, whereas no significant effect on ERK was observed. Furthermore, LPS-stimulated production of ROS, activation of NADPH oxidase and expression of inflammatory mediators were markedly suppressed by treatment with selective inhibitor of p38MAPK (SB203580) and JNK (SP600125). Taken together, these results demonstrated that YJI-7, a novel synthetic chalcone derivative, suppressed LPS-stimulated ROS production via modulation of NADPH oxidase and diminished expression of inflammatory mediators, at least in part, via down-regulation of p38MAPK and JNK signaling in macrophages.

Background: This study aimed to investigate the effect of harvest time on the growth, yield characteristics and loganin content in Dipsacus asperoides Wall. Methods and Results: Dipsacus asperoides seedlings were planted within a nursery environment in early May 2015 and harvested in early, middle and late October 2015, and early November 2015. Harvest time did not result significant differences in the plant height, stem diameter, branch length, leaf width and aboveground dry weight moreover, no significant differences were observed in root length, number of roots and root diameter. However, the diameter of lateral roots was greater in the harvests from the late October and period thereafter. The highest values of root dry weight and yield were recorded in early November. Specifically, the yield significantly increased from 205 kg/10 a (index: 100) in early October to 358 kg/10 a (index: 175) in early November, in terms of root part weight. Loganin contents of D. asperoides differed significantly among harvest times raging from 0.0766% in early October to 0.1704% in late November, thereby showing an increasing trend in later harvest times. Conclusions: These results suggest that the optimum harvest time for D. asperoides is early November, when the yield is the highest. Harvest time significantly affected loganin contents, which constantly increased from early October until early November.

It is well known that performance on a trial is flexibly modulated by preceding trial congruency in tasks that require cognitive control, such as the Stroop task, referred to as the conflict adaptation effect (CAE). The CAE indicates that conflict on the preceding trial leads to enhanced cognitive control, leading to more efficient regulation of current conflict. The present study aimed to identify neural mechanisms implicated in individual differences in CAEs. The participants performed a version of the color-word Stroop task during a functional magnetic resonance imaging (fMRI) experiment and were divided into two groups according to the magnitude of behavioral CAE: one exhibiting the CAE only in congruent trials and the other in both congruent and incongruent trials. The imaging results showed different activations in the pre-supplementary motor area for the Stroop effect between groups. Importantly, group differences in activation for the preceding trials were observed in several prefrontal regions including the bilateral frontopolar, dorsolateral prefrontal, and rostro-dorsal cingulate cortices. More interestingly, analyses of the preceding trials suggest that the frontopolar cortex is involved in conflict resolution through higher-order cognitive control strategies that are closely associated with subsequent conflict. The current study provides new evidence of the role of the frontopolar cortex in conflict adaptation.

Gene expression signature-based inference of functional connectivity within and between genetic perturbations, chemical perturbations, and disease status can lead to the development of actionable hypotheses for gene function, chemical modes of action, and disease treatment strategies. Here, we report a FuSiOn-based genome-wide integration of hypomorphic cellular phenotypes that enables functional annotation of gene network topology, assignment of mechanistic hypotheses to genes of unknown function, and detection of cooperativity among cell regulatory systems. Dovetailing genetic perturbation data with chemical perturbation phenotypes allowed simultaneous generation of mechanism of action hypotheses for thousands of uncharacterized natural products fractions (NPFs). The predicted mechanism of actions span a broad spectrum of cellular mechanisms, many of which are not currently recognized as "druggable." To enable use of FuSiOn as a hypothesis generation resource, all associations and analyses are available within an open source web-based GUI (http://fusion.yuhs.ac).

본 연구에서는 섬쑥부쟁이 (Aster glehni)와 쑥부쟁이(Aster yomena)의 항산화 효과 및 항비만 효과를 검정하기 하여 물 (-W)과 에탄올 (-E)추출물을 이용하여 실험을 실히 하였다. 각 추출물을 총 페놀 및 총 플라보노이드를 함량을 분석하고 DPPH와 $ABTS^+$ 를 이용하여 항산화 활성을 비교 분석하였다. 또한 총 페놀 ...

The secreted immunoglobulin footprint of single hybridoma cells, containing ~10 fg of antibody purified in situ, has been probed for 9 properties concurrently by use of detection labels comprising 280 nm combinatorially colored fluorescent latex beads functionalized with proteins. Specificity of each individual hybridoma cell’s product has thereby been assessed in a primary screen. Varying the density of antigen on beads to modulate the avidity of the interaction between bead and secreted antibody footprint allowed rank ordering by affinity in the same primary screen. As more criteria were added to the selection process, the frequency of positive cells went down; in some cases, the favorable cell was present at

The purpose of this literature review is to discuss infectious diseases found in children adopted from South Korea but not commonly seen in pediatric primary care settings in the United States, as well as summarize screening tests and guidelines for early management of these medical conditions. The diseases were selected based on statistics from the Korea Center for Disease Control and Prevention and discussed in terms of pathophysiology, clinical manifestations, screening tests, management regimens, and implications on pre and post-adoptions. Additionally, current recommendations for the immunization of internationally adopted children and the immunization schedule in South Korea were reviewed. Pediatric primary care providers play a critical role in assessing newly arrived children from South Korea, providing age-appropriate immunizations, and educating the adoptive families about screening tests and management regimens when there are positive screening or diagnostic results and clinical symptoms.