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In our previous study, we found that lymphatic vessels stimulate hair follicle growth through paracrine effects on dermal papilla cells. However, the paracrine factors secreted from cutaneous lymphatic vessels that can activate dermal papilla cells are still unknown. In this study, we investigated whether lymphatic endothelial cells might secrete paracrine factors that activate dermal papilla cells in vitro. We found that Sostdc1 was more expressed in lymphatic endothelial cells compared with blood vascular endothelial cells. In addition, Sostdc1 expression levels were significantly increased during the anagen phase in the back skin of C57BL/6J mice, as compared to the telogen phase. We also observed that incubation of dermal papilla cells with 200 ng/mL Sostdc1 for 72 h induced the expression levels of Lef-1, a downstream target of Wnt signaling. Taken together, our results reveal that Sostdc1, a BMP antagonist, secreted from cutaneous lymphatic vessels, may act as a paracrine factor for hair follicle growth., Current Issues in Molecular Biology, 44 (5)

Triage in an emergency department (ED) can help identify the urgency of patients’ treatment and allocate the appropriate resources. Interpretable machine learning methods could be a helpful tool for facilitating the triage process. However, existing related research used only conventional logistic regression methods. This study aims to develop and externally validate an interpretable machine learning model using a partial dependent plot (PDP). This retrospective cohort study included all adult ED patients of the Samsung Medical Center for development and Tan Tock Seng Hospital, from 2016–2020. The outcome of interest was in-hospital mortality after patients’ ED visit. We used the area under the receiver operating characteristic curve (AUROC) to assess the performance of the PDP score and other conventional scores, including the Korea Triage Acuity Scale (KTAS). Of the included 285,523 ED visits, 1.60% ended in in-hospital mortality. The PDP score achieved an AUROC of 0.821 in temporal validation and 0.833 in external validation, outperforming the KTAS score of 0.729. The PDP triage score was therefore superior to other scores for in-hospital mortality prediction. PDP is a generic, intuitive, and effective triage tool to stratify general patients who present to the ED.

Chemotherapy-induced cachexia has been a significant challenge to the successful treatment of cancer patients. Chemotherapy leads to loss of muscle, loss of appetite, and excessive weight loss, which makes these necessary treatments intolerable for most patients. Therefore, it is necessary to alleviate cachexia to successfully treat cancer patients. In this study, tumor-implanted mouse models administered cisplatin showed rapid weight loss and reduced feeding rate by the second week of treatment, and 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) effectively alleviated cisplatin-induced cachexia. In mice treated with cisplatin on a sacrificial day after 6 weeks, the weight of the two major leg muscles (quadriceps femoris and gastrocnemius) were reduced by up to 70%, but this muscle reduction was successfully prevented in the PLAG co-treatment group. The distribution and size of muscle fibers that appear in small units in cisplatin-treated mice were restored to normal levels by PLAG co-treatment. Furthermore, myostatin expression levels were upregulated by cisplatin, whereas myostatin decreased to normal levels with muscle recovery in the PLAG co-treated group. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), which are commonly expressed in cachexia, were significantly increased in cisplatin-treated mice but were reduced to normal levels in PLAG co-treated mice. Glucose absorption, an indicator of muscle tissue activity, decreased with cisplatin treatment and recovered to normal levels with PLAG co-treatment. Overall, PLAG effectively alleviated cisplatin-induced cachexia symptoms and reduced tumor growth in tumor-implanted mice. These findings suggest PLAG may be a promising drug to alleviate cachexia in cancer patients receiving chemotherapy.

Background/aims New direct-acting antivirals have shown surprising success in the treatment of hepatitis C, not only in the general population, but also in difficult-to-treat cohorts. However, there is still limited data regarding direct-acting antivirals, including sofosbuvir (SOF), in the context of hemodialysis. The aim of this study was to investigate the safety and outcome of administering full-dose SOF (400 mg/day) plus low-dose ribavirin (RBV, 100 to 200 mg/day) in hemodialysis patients with hepatitis C virus (HCV) genotype 2 (GT2) infection. Methods Patients with chronic HCV GT2 infection and end-stage renal disease on maintenance hemodialysis treated with full-dose SOF plus low-dose RBV were retrospectively identified from a database of patients with HCV GT2 who were treated in Konkuk University Chungju Hospital between February 2017 and February 2018. Medical records were reviewed for demographics, medical history, laboratory data, and radiologic and electrocardiographic findings. Results All nine patients completed a full course of 12 weeks of treatment with a full-dose SOF plus low-dose RBV regimen. Two had compensated cirrhosis. Seven patients were treatment-naive, and two had a relapse following previous interferon-based therapy. All patients had a sustained viral response at 12 weeks post-treatment. There was no discontinuation of treatment because of side effects. Conclusion In hemodialysis patients with HCV GT2 infection, the full-dose SOF plus low-dose RBV regimen appears to be safe and well tolerated, and yields high rates of sustained virologic response.

Activated epidermal growth factor receptors (EGFRs) are crucial for inducing metastasis in cancer cells by promoting matrix metalloproteinase (MMP) expression. The present study was designed to investigate the effects of 1‑palmitoyl‑2‑linoleoyl‑3‑acetyl‑rac‑glycerol (PLAG) on MMP expression in epidermal growth factor (EGF)‑stimulated breast cancer cells in vitro. EGF stimulation induced internalization of its cognate receptor, EGFR, for stimulus‑desensitization. These internalized receptors, complexed with the ubiquitin ligase c‑Cbl and EGFR pathway substrate 15 (EPS15) (for degradation), were evaluated by confocal microscopy at 5‑90 min time intervals. During intracellular trafficking of EGFRs, EGF‑induced signaling cascades were analyzed by examining EGFR and SHC phosphorylation. Modulation of MMP expression was assessed by evaluating the activity of transcription factor AP‑1 using a luciferase assay. PLAG accelerated the assembly of EGFRs with c‑Cbl and EPS15 and promoted receptor degradation. This faster intracellular EGFR degradation reduced AP‑1‑mediated MMP expression. PLAG stimulation upregulated thioredoxin‑interacting protein (TXNIP) expression, and this mediated the accelerated receptor internalization. This PLAG‑induced increase in EGFR trafficking was blocked in TXNIP‑silenced cells. By downregulating MMP expression, PLAG effectively attenuated EGF‑induced mobility and invasiveness in these cancer cells. These data suggest that PLAG may be a potential therapeutic agent for blocking metastasis.

Tourism gentrification, or the transformation of residential areas into tourist destinations, is an important issue worldwide. It generally affects only the original residents, who often ch...

Platelet-derived growth factor receptor (PDGFR) plays an essential role in the proliferation and invasion of malignant cancer cells. However, the functional role of PDGFR alpha (PDGFRA) in HER2-positive (HER2+) breast cancer has not been fully clarified yet. Thus, the objective of this study was to investigate the clinical significance of PDGFRA and the therapeutic potential of PDGFR inhibitors as part of an effort to overcome trastuzumab (TRZ) resistance. Aberrant PDGFRA expression is closely associated with decreased survival in HER2+ breast cancers. Therefore, we established BT474 trastuzumab-sensitive (TRZ_S) and trastuzumab-resistant (TRZ_R) cells to investigate the association between PDGFR signaling and TRZ resistance. We found that PDGFRA was significantly upregulated in the BT474 TRZ_R cells. In addition, IL-6 expression, which was also found to be upregulated in the TRZ_R cells, was induced by PDGFC, a ligand of PDGFR. Next, we investigated the effects of ponatinib and sunitinib, PDGFR inhibitors, on the BT474 TRZ_R and HCC1954 (TRZ-resistant cell line) cells. These inhibitors decreased cell viability and migration in a dose-dependent manner. Additionally, IL-6 expression was decreased by ponatinib in both the BT474 TRZ_R and HCC1954 cells. In contrast, IL-6 was not suppressed by TRZ, implying that the PDGFRA/STAT3/IL-6 axis is associated with resistance to TRZ. In addition, we found that STAT3 and ERK phosphorylation were increased in the BT474 TRZ_R cells. IL-6 expression was suppressed by a STAT3 inhibitor, indicating that IL-6 expression is modulated downstream of STAT3. Taken together, these results suggest that PDGFRA could serve as a therapeutic target to overcome TRZ resistance.

Basal-like breast cancer (BLBC) has a clinically aggressive nature. It is prevalent in young women and is known to often relapse rapidly. To date, the molecular mechanisms regarding the aggressiveness of BLBC have not been fully understood. In the present study, mechanisms of aggressiveness of BLBC involving EGFR and/or HER2 expression and interactions between tumor and tumor-associated macrophages (TAMs) were explored. The prognosis of breast cancer patients who underwent surgery at Samsung Medical Center was analyzed. It was found that the co-expression of EGFR and HER2 was associated with a worse prognosis. Therefore, we generated EGFR-positive BLBC cells with stable HER2 overexpression and analyzed the profile of secretory cytokines. Chemokine (C-C motif) ligand 2 (CCL2) expression was increased in HER2-overexpressed BLBC cells. Recombinant human CCL2 treatment augmented the motility of TAMs. In addition, the conditioned culture media of HER2-overexpressed BLBC cells increased the motility of TAMs. Furthermore, activation of TAMs by CCL2 or the conditioned culture media of HER2-overexpressed cells resulted in the production of pro-inflammatory cytokines, such as IL-8 and IL-1β. These observations reveal that CCL2 derived from EGFR and HER2 co-expressed BLBC cells can lead to increased TAM recruitment and the induction of IL-8 and IL-1β from recruited TAMs, triggering the tumorigenesis of breast cancer with the expression of both EGFR and HER2. Our findings demonstrate that EGFR+ and HER2+ BLBC aggressiveness is partially mediated through the interaction between BLBC and TAMs recruited by CCL2.

Purpose Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism.Materials and Methods To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib.Results Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway.Conclusion These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.

Asthma and nonalcoholic fatty liver disease (NAFLD) are chronic diseases and are known to be associated with metabolic abnormalities. We aimed to clarify the association between NAFLD and the incidence of asthma in a large population-based cohort. We selected 160,603 healthy individuals without comorbidities from the National Health Insurance Service-National Sample cohort during 2009–2014. . NAFLD was defined by a surrogate marker, the fatty liver index (FLI). During a median of 5.08 years’ follow-up, 16,377 subjects (10.2%) were newly diagnosed with asthma and categorized into three groups according to FLI. The cumulative incidence of asthma was higher in subjects with higher vs. lower FLIs (FLI < 30 10.1%, 30 ≤ FLI < 60 10.8%, FLI ≥ 60 10.5% ). Higher FLI associated with an increased incidence of asthma (Harzard ratios (HR)highest vs. lowest FLI, 1.25; 95% CI, 1.15-1.36). The results using another definition of NAFLD as measured by hepatic steatosis index (HIS) are similar to the primary results. This association was more pronounced in women than in men (HR 1.46; 95% CI, 1.13-1.64 vs. HR 1.07; 95% CI, 0.94-1.20). This study demonstrated that NAFLD as measured by FLI and HIS may influence the incidence rates of asthma in adults, especially in women.

Neutrophil activity, including trapping of damage-associated molecular patterns by neutrophil extracellular traps (NETs), is an important response to microbial infection. Most activated neutrophils commit to apoptosis and are removed by activated macrophages in the process of efferocytosis. Improper clearance of apoptotic neutrophils often causes an unnecessary and exaggerated immune response and subsequent chronic inflammation. Effective macrophage mobility toward activated neutrophils, which is triggered by binding of 'find-me' signals to receptors such as P2Y2, is a crucial step for the timely clearance of apoptotic neutrophils. In this paper, we investigated the effect of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on efferocytosis and the underlying molecular mechanisms. In a coculture of apoptotic neutrophils with macrophages, PLAG treatment increased levels of efferocytosis of apoptotic neutrophils. PLAG induced faster translocation of P2Y2 from lipid rafts to nonlipid raft plasma membrane domains in macrophages. This repositioning of P2Y2 enables the polarization of the cytoskeleton by association of the receptor with cytoskeletal proteins such as α-tubulin and actin to improve the mobility of macrophages. The formation of vesicular, chylomicron-like structures by PLAG was a prerequisite for the induction of this macrophage activity, as none of these effects was seen when the vesicle receptor GPIHBP1 was absent. Taken together, these data showed that PLAG is a powerful immune resolvent that triggers the prompt clearance of apoptotic neutrophils by enhanced efferocytosis activity. PLAG could therefore be an effective lipid-based efferocytosis enhancer for use as a therapeutic drug to prevent inflammatory disease caused by uncontrolled immune responses.

Objective This study was designed to investigate whether necroptosis is involved in the pathogenesis of chemoradiation-induced oral mucositis in a murine model and whether 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) ameliorates this disorder. Materials and methods A chemoradiation-induced oral mucositis model was established by treating mice with concurrent 5-fluorouracil (100 mg/kg, i.p.) and head and neck X-irradiation (20 Gy). Phosphate-buffered saline or PLAG (100 mg/kg or 250 mg/kg, p.o.) was administered daily. Body weights were recorded daily, and mice were sacrificed on Day 9 for tongue tissue analysis. Results On Day 9, chemoradiotherapy-treated (ChemoRT) mice had tongue ulcerations and experienced significant weight loss (Day 0:26.18 ± 1.41 g; Day 9:19.44 ± 3.26 g). They also had elevated serum macrophage inhibitory protein 2 (MIP-2) (control: 5.57 ± 3.49 pg/ml; ChemoRT: 130.14 ± 114.54 pg/ml) and interleukin (IL)-6 (control: 198.25 ± 16.91 pg/ml; ChemoRT: 467.25 ± 108.12 pg/ml) levels. ChemoRT-treated mice who received PLAG exhibited no weight loss (Day 0:25.78 ± 1.04 g; Day 9:26.46 ± 1.68 g) and had lower serum MIP-2 (4.42 ± 4.04 pg/ml) and IL-6 (205.75 ± 30.41 pg/ml) levels than ChemoRT-treated mice who did not receive PLAG. Tongue tissues of mice who received PLAG also displayed lower phosphorylation levels of necroptotic signalling proteins. Conclusion 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol mitigated chemoradiation-induced oral mucositis by modulating necroptosis.

Doxorubicin (DOX), a widely used chemotherapeutic agent, has been linked to an increased risk of bone damage in human patients and induces bone loss in mice. DOX induces autophagy, which contributes to bone homeostasis and excess autophagy in osteoclasts (OCs), resulting in bone loss. We hypothesized that DOX-induced bone loss is caused by the induction of autophagy in OCs. In vitro, DOX significantly increased the area of OCs and bone resorption activity, whereas it decreased OC number through apoptosis. DOX enhanced the level of LC3II and acidic vesicular organelles-containing cells in OCs, whereas an autophagy inhibitor, 3-methyladenine (3-MA), reversed these, indicating that enhanced autophagy was responsible for the effects of DOX. Increased mitochondrial reactive oxygen species (mROS) by DOX oxidized transient receptor potential mucolipin 1 (TRPML1) on the lysosomal membrane, which led to nuclear localization of transcription factor EB (TFEB), an autophagy-inducing transcription factor. In vivo, micro-computerized tomography analysis revealed that the injection of 3-MA reversed DOX-induced bone loss, and tartrate-resistant acid phosphatase staining showed that 3-MA reduced the area of OCs on the bone surface, which was enhanced upon DOX administration. Collectively, DOX-induced bone loss is at least partly attributable to autophagy upregulation in OCs via an mROS/TRPML1/TFEB axis.

Introduction: Head and neck squamous cell carcinomas (HNSCC) are very unfavorable carcinoma that lowers the quality of life. In addition, side effects associated with treatment such as oral mucositis also deteriorate enough to be classified as a disease. This study verified the synergistic antitumor effect of EC-18 (PLAG, 1-Palmitoyl-2-linoleoyl-3-acetyl-roc-glycerol) with or without cisplatin as a chemotherapy and side effects alleviation effects in the metastatic mouse oral squamous carcinoma (MOSCC) orthotopic model. Method: After inserting mouse-derived squamous oral carcinoma into the right side of the tongue (n=12), it was treated with EC-18 alone or with cisplatin for three weeks. The changes in feed rate and body weight were quantitatively verified on a 2-day interval. Changes in tumor size and oral mucositis symptoms (toluidine-blue positive) were analyzed on the sacrifice day. In addition, changes in the amount of damage-associated molecular pattern (DAMP) increased by tumor and cisplatin, and changes in related active factors were quantitatively analyzed. Result: Compared to the positive control group, the tumor size was reduced by 42% in the group treated with EC-18 alone (P Conclusion: EC-18 can effectively inhibit the growth of HNSCC and alleviate the side effects caused by existing anticancer drugs at the same time. Therefore, it can be a desirable therapy for HNSCC patients. Citation Format: Guentae KIM, Eun Young Kim, Su-Hyun Shin, Hyowon Lee, Sun Young Yoon, Kaapjoo Park, Ki-young Sohn, Jae Wha Kim. EC-18 suppressed tumor growth and alleviated side effects caused by cisplatin in the HNSCC implantation model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5478.

12106 Background: Oral mucositis (OM) is a debilitating side effect of concomitant chemoradiotherapy (CRT) for head and neck cancer (HNC). EC-18 may effectively mitigate OM by minimizing the CRT-induced innate immune response. This Phase II, 2-stage trial evaluated safety, tolerability, and efficacy of EC-18 in reducing the duration, incidence, and trajectory of severe OM (SOM) in HNC patients. Methods: Patients (n = 105) with pathologically confirmed oral cavity, oropharynx, hypopharynx, or nasopharynx squamous cell cancers who received intensity-modulated radiation therapy (IMRT; with ≥ 55 Gy on ≥ 2 oral sites) and weekly or tri-weekly cisplatin were studied. In Stage 1, 24 patients were randomized (n = 6 per arm) to receive 500, 1000, or 2000 mg of EC-18, or placebo. Following independent Data Safety Monitoring Board review, 81 patients in Stage 2 received EC-18 2000 mg (n = 41) or placebo (n = 40) throughout CRT. WHO OM grade was assessed twice weekly during IMRT and then once weekly for up to 6 weeks post-IMRT. The primary efficacy endpoint was duration of SOM during the active and short-term follow-up (STFU) periods in the compliant per-protocol population (PP). Much of Stage 2 was conducted during peak periods of the COVID-19 pandemic which measurably impacted patient compliance relative to test medication dosing and planned radiation. Consequently, to assess efficacy most accurately, the PP population was analyzed (with at least 4 weeks of study drug dosing, minimum cumulative radiation of 55 Gy, 80% study drug compliance in the first 28 days of dosing, and without using not-allowed-therapy). Results: Patient demographics and baseline characteristics were balanced between groups. Adverse events (AEs) were comparable amongst cohorts without drug-related severe AEs. In the PP, the median duration of SOM from baseline through STFU was 0 day in the EC-18 group (n = 22) v 13.5 days in the placebo group (n = 20). SOM incidence through STFU (45.5% v 70%) and opioid use (time to onset: 32.3 v 26.0 days; and duration: 32.8 v 37.5 days) favored EC-18 v placebo. Results of the covariates analyses suggested that EC-18 favorably impacted SOM incidence in patients who experienced SOM treated with weekly low-dose cisplatin (n = 26; 37.5% v placebo 70.0%) and HPV+ tumors (n = 29; 35.3% v placebo 66.7%; Table). One-year long-term follow-up for tumor outcomes is ongoing. Conclusions: EC-18 safely mitigated the development and the time course of SOM in CRT-treated HNC patients. In addition, EC-18 may provide substantial benefits to subpopulations of HPV+ HNC patients treated with low dose cisplatin. Clinical trial information: NCT03200340. [Table: see text]

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.

IL‑1 promotes cancer cell proliferation and invasiveness in various malignancies, such as breast and colorectal cancer. In the present study, the functional roles of IL‑1β (IL1B) and the inhibitory effect of celastrol on IL1B expression were investigated in triple‑negative breast cancer (TNBC) cells. The data revealed that celastrol markedly decreased IL1B expression and suppressed TNBC cell proliferation in a dose‑dependent manner. The levels of IL1B and IL8 mRNA were significantly increased in TNBC cells compared with non‑TNBC cells. In addition, IL1B augmented the expression levels of IL8 as well as matrix metalloproteinases (MMPs), including MMP‑1 and MMP‑9, in TNBC cells. Furthermore, IL1B expression was decreased by a specific MEK1/2 inhibitor, MEK162. Celastrol also promoted IL1B downregulation through the suppression of the MEK/ERK‑dependent pathway. Furthermore, the results also revealed a decrease in IL1B‑induced IL8, MMP‑1, and MMP‑9 expression in response to celastrol treatment. The induction of cellular invasion by IL1B was also markedly decreased by celastrol. Collectively, the present study results suggested celastrol as an effective drug for the treatment of TNBC, involving a reduction in IL1B expression, activity or signaling pathways.

Background and objectives: As in adults, the survival rates and neurological outcomes after infant Cardiopulmonary resuscitation (CPR) are closely related to the quality of resuscitation. This study aimed to demonstrate that using a smartwatch as a haptic feedback device increases the quality of infant CPR performed by medical professionals. Materials and methods: We designed a prospective, randomized, case-crossover simulation study. The participants (n = 36) were randomly allocated to two groups: control first group and smartwatch first group. Each CPR session consisted of 2 min of chest compressions (CCs) using the two-finger technique (TFT), 2 min of rest, and 2 min of CCs using the two-thumb encircling hands technique (TTHT). Results: The primary outcome was the variation in the “proportion of optimal chest compression duration” and “compression rate” between the smartwatch-assisted and non-smartwatch-assisted groups. The secondary outcome was the variation in the “compression depth” between two groups. The proportion of optimal CC duration was significantly higher in the smartwatch-assisted group than in the non-smartwatch-assisted group. The absolute difference from 220 was much smaller in the smartwatch-assisted group (218.02) than in the non-smartwatch-assisted group (226.59) (p-Value = 0.018). Conclusion: This study demonstrated the haptic feedback system using a smartwatch improves the quality of infant CPR by maintaining proper speed and depth regardless of the compression method used.

Qualitative analysis of cucurbitane-type triterpenoids of bitter melon (fruit of

The growing risk of accidental radiation exposure due to increased usage of ionizing radiation, such as in nuclear power, industries and medicine, has increased the necessity for the development of radiation countermeasures. Previously, we demonstrated the therapeutic potential of the acetylated diacylglycerol, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), as a radiation countermeasure by mitigating radiation-associated mortality and hematopoietic acute radiation syndrome (H-ARS) in BALB/c mice after a lethal dose (LD70/30) of gamma-ray total-body irradiation (TBI). In this study, we show that PLAG mitigates symptoms of H-ARS, as characterized by mature blood cell recovery and restoration of bone marrow cellularity, by regulating systemic inflammation. Log-rank test demonstrated that high levels of WBCs, lymphocytes and neutrophils on day 10 post-TBI resulted in significantly improved survival rate. PLAG significantly enhanced the nadir values of all major blood cell types as well as bone marrow cellularity. A single TBI at LD70/30 induced an immediate increase in the blood levels of CXCL1 (12.5 fold), CXCL2 (1.5 fold), IL-6 (86.9 fold), C-reactive protein (CRP; 1.3 fold) and G-CSF (15.7 fold) at 6 h post-TBI, but the cytokine levels returned to baseline level afterward. When the irradiated mice started to die around 15 days post-TBI, they exhibited a second surge in blood levels of CXCL1 (49.3 fold), CXCL2 (87.1 fold), IL-6 (208 fold), CRP (3.6 fold) and G-CSF (265.7 fold). However, PLAG-treated groups showed a significant decrease in these same blood levels (P < 0.001). Considering the inverse correlation between inflammatory cytokine levels and hematological nadirs, PLAG exerts its therapeutic effects on H-ARS by regulating inflammatory cytokine production. These data suggest that PLAG has high potential as a radiation countermeasure to mitigate H-ARS after accidental exposure to radiation.

Morin is a naturally occurring flavonoid with anti-inflammatory and antioxidative properties. Therefore, we hypothesized that morin may prevent inflammatory bone loss by reducing oxidative stress. To investigate the effect of morin on inflammatory bone loss, mice were injected with lipopolysaccharide (LPS). Osteoclasts (OCs) were analyzed by tartrate-resistant acid phosphatase (TRAP) staining and actin ring formation. Micro-computerized tomography analysis indicated that morin prevented LPS-induced bone loss in mice. In vivo TRAP staining indicated that morin decreased the number and surface of the OCs that were increased in LPS-treated mice. Furthermore, in vitro experiments indicated that morin decreased the number and activity of OCs upon LPS stimulation. Morin decreased actin ring-containing OCs with decreased activation of c-Src (Y416)/vav guanine nucleotide exchange factor 3/Ras-related C3 botulinum toxin substrate 1 compared with LPS alone. Morin decreased cytosolic reactive oxygen species (ROS), thus preventing the oxidation of Src homology region 2 domain-containing phosphatase 1 (SHP-1), followed by the inactivation of c-Src via direct interaction with SHP1. Conversely, SHP1 knockdown abolished the inhibitory effect of morin on OCs. Therefore, our findings suggest that morin disrupted cytoskeletal reorganization via an ROS/SHP1/c-Src axis in OCs, thereby granting protection from LPS-induced bone loss, which demonstrates its therapeutic potential against inflammatory bone loss.

The abalone aquaculture industry in South Korea has grown rapidly since the 2000s. In this study, we investigated the sedimentary pollution at four major abalone farms responsible for ~60% of all South Korean abalone produced. We also surveyed the current statuses of cage facilities, abalone mass mortality, and current velocities within and outside farm cages. The concentrations of total organic carbon in the study area were 7.92 ± 2.09 mg g−1, indicating a mild level of sedimentary pollution. We observed higher mortality rates in rectangular-shaped shelter cages than in triangular shelters. With increases in the number and size of abalone farming facilities, current velocities inside the cages declined by an average of 45% relative to those outside the cages, leading to poor habitat conditions for farmed abalone. Our results provide insights into the current status of the benthic environments and major causes of mass mortality in the abalone farms of South Korea.

The platelet-derived growth factor (PDGF) family, a complex and imperative group of proangiogenic factors, acts as strong cell growth chemokines and is essential for the progression of malignancy in humans. In the present study, it was observed that aberrant PDGFB expression is associated with survival rates in patients with estrogen receptor-positive (ER+) breast cancer unlike other subtypes, including PDGFA, PDGFC and PDGFD. Accordingly, the effect of specific PDGF receptor (PDGFR) inhibitors on ER-α+ breast cancer cells was investigated. To block the PDGF-BB signaling pathway, PDGFR inhibitors (sunitinib or ponatinib) were employed. Sunitinib and ponatinib were found to arrest the cell cycle at the G0-G1 phase. In addition, the two PDGFR inhibitors were revealed to significantly inhibit cell growth and decrease the expression of matrix metalloproteinase-1, which is one of the metastasis-related genes. Finally, the combined effects of the two PDGFR inhibitors with tamoxifen were investigated. The results demonstrated that the combination of two PDGFR inhibitors with tamoxifen inhibited the growth of cells more consistently, compared with the effect mediated by tamoxifen alone. Therefore, it is proposed that PDGFR inhibitors, including sunitinib and ponatinib, should be applied effectively to treat ER-α+ breast cancer.

Background Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators. Objective To clarify which therapeutic effect is better between the ICS + long-acting β2 agonist (LABA) and ICS + LABA + long-acting muscarinic antagonist (LAMA) treatment in patients with ACO. Methods We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS + LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS + LABA + LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV1, forced vital capacity, FEV1/forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide. Results In the ICS + LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS + LABA + LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV1 and forced vital capacity (P Conclusions Although this study was unable to conclude that ICS + LABA treatment is not inferior to ICS + LABA + LAMA in terms of exacerbation, it is obvious that the ICS + LABA + LAMA treatment group had improved lung function in ACO.

Acute gouty arthritis is an auto-inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints or tissues. Excessive neutrophil recruitment into gouty lesions is a general clinical sign and induces a pain phenotype. Attenuation of successive periods of neutrophil infiltration might be a beneficial approach to achieve therapeutic efficacy. In this study, the activity of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) in attenuation of excess neutrophil infiltration was assessed in gout-induced lesions of BALB/c mice. Neutrophil infiltration in MSU-induced gouty lesions was analyzed using immunohistochemical staining. ELISA and RT-PCR were used to measure attenuation of expression of the major neutrophil chemoattractant, CXC motif chemokine ligand 8 (CXCL8), in a PLAG-treated animal model and in cells in vitro. The animal model revealed massive increased neutrophil infiltration in the MSU-induced gouty lesions, but the PLAG-treated mice had significantly reduced neutrophil numbers in these lesions. The results also indicated that the MSU crystals stimulated a damage-associated molecular pattern that was recognized by the P2Y6 purinergic receptor. This MSU-stimulated P2Y6 receptor was destined to intracellular trafficking. During intracellular endosomal trafficking of the receptor, endosome-dependent signaling provided expression of CXCL8 chemokines for neutrophil recruitment. PLAG accelerated initiation of the intracellular trafficking of the P2Y6 receptor and returning the receptor to the membrane. This process shortened the intracellular retention time of the receptor anchoring endosome and subsequently attenuated endosome-dependent signaling for CXCL8 expression. These study results suggested that PLAG could be used for resolution of acute inflammation induced in gout lesions.

WNT5A is abnormally increased in a variety of cancers including breast cancer and has an adverse effect on the prognosis. However, the biological function of WNT5A is not fully known in HER2-positive (HER2+) breast cancer. Using public clinical data, we analyzed disease-free survival (DFS) and distant metastasis-free survival (DMFS). Here, we found that abnormal WNT5A induction is a correlation with the poor prognosis of HER2+ breast cancer. WNT5A expression was also decreased by pan-HER inhibitor neratinib but not by trastuzumab. In addition, WNT5A augmented cell invasiveness of HER2+ breast-cancer cells. To find WNT5A-induced metastatic-related factors, we did a human cytokine array. The levels of GM-CSF and CXCL8 were significantly increased by WNT5A. CXCL8 also accelerated cell invasiveness in HCC1954 breast-cancer cells. The expression of CXCL8 induced by WNT5A has been significantly reduced by MEK inhibitor, binimetinib. Finally, we studied the effect of CXCR2 antagonist, SB225002, to verify the relevance of CXCL8 in WNT5A-induced cell invasion. As expected, we found that WNT5A-induced cell invasion is completely inhibited by SB225002. Taken together, we have demonstrated that WNT5A directly mediates cell invasion through the induction of CXCL8 and ultimately affects the survival rate of HER2+ breast cancer.

Background The chronic obstructive pulmonary disease (COPD) assessment test (CAT) is a validated, eight-item questionnaire used to quantify the health status of patients. The aim of this study was to evaluate the usefulness of the CAT questionnaire as a tool to assess the response to treatment in acute exacerbations of COPD in an outpatient setting. Methods A multicenter, phase 3 randomized controlled trial was conducted previously to examine the efficacy and safety of oral zabofloxacin for the treatment of COPD exacerbations. In the present post hoc analysis of the original study, patients with COPD exacerbation were categorized as responders or non-responders according to the respiratory symptoms persisting on day 10 (visit 3) of treatment. The CAT questionnaire was completed daily by patients at home from the initial visit to the second visit on day 5. Subsequently, the questionnaire was completed in the presence of a physician on days 10 (visit 3) and 36 (visit 4). Multivariate regression analysis was performed to determine the association between CAT scores and the therapeutic response. Results The CAT scores decreased more rapidly in responders compared to non-responders during the first 5 days (23.3–20.4 vs. 23.5–22). Among responders, patients with higher severity of illness also revealed higher CAT scores on the first day of an exacerbation (mild, 19.8; moderate, 21.4; severe, 23.8; very severe, 28.6). Multivariate analysis revealed that a change in the CAT score during the first 3 days influenced the therapeutic response. A significant decrease in scores in the domains of sputum production, chest tightness, and activities of daily living was seen among responders. Conclusion Early improvement in CAT scores may be associated with a more favorable response to the treatment of COPD exacerbations. Trial Registration ClinicalTrials.gov Identifier: NCT01658020 Trial Registration Clinical Research Information Service Identifier: KCT0000532, Graphical Abstract

Background Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. Methods We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. Results TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. Conclusion TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC., Graphical Abstract

Protein tyrosine phosphatases (PTPs), along with protein tyrosine kinases, control signaling pathways involved in cell growth, metabolism, differentiation, proliferation, and survival. Several PTPs, such as PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, and DUSP9, disrupt insulin signaling and trigger type 2 diabetes, indicating that PTPs are promising drug targets for the treatment or prevention of type 2 diabetes. As part of an ongoing study on the discovery of pharmacologically active bioactive natural products, we conducted a phytochemical investigation of African mango (Irvingia gabonensis) using liquid chromatography–mass spectrometry (LC/MS)-based analysis, which led to the isolation of terminalin as a major component from the extract of the seeds of I. gabonensis. The structure of terminalin was characterized by spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high-resolution (HR) electrospray ionization (ESI) mass spectroscopy. Moreover, terminalin was evaluated for its antidiabetic property; terminalin inhibited the catalytic activity of PTPN1, PTPN9, PTPN11, and PTPRS in vitro and led to a significant increase in glucose uptake in differentiated C2C12 muscle cells, indicating that terminalin exhibits antidiabetic effect through the PTP inhibitory mechanism. These findings suggest that terminalin derived from African mango could be used as a functional food ingredient or pharmaceutical supplement for the prevention of type 2 diabetes.

Background Current asthma guidelines recommend stepping down controller treatment when the condition is well-controlled for a certain time. However, the optimal step-down strategy for well-controlled patients receiving a low-dose inhaled corticosteroid (ICS) with a long-acting β2-agonist (LABA) remains unclear. Objective This study was a randomized, open-label, three-arm, parallel pragmatic trial comparing two kinds of step-down approaches for maintaining treatment. Methods Adults with asthma who were aged 18 years or older, and who had been stable with low-dose ICS/LABA for at least 3 months, were enrolled. Subjects (n = 225) were randomly allocated into one of three groups (maintaining low-dose ICS/LABA [G1], discontinuing LABA [G2], and reducing ICS/LABA to once daily [G3]), and were observed for 6 months. The primary end point was a change in Asthma Control Test (ACT) scores between randomization and the final 6-month follow-up. Results The change in ACT was analyzed in the per-protocol population; noninferiority was not demonstrated in either step-down group compared with the maintenance group (95% confidence interval of the difference, G2 vs G1 = –1.40-0.55; G3 vs G1 = –1.19-0.77). Although over 90% of patients were fine, higher rates of treatment failure were observed in step-down groups (G1: 0%; G2: 9.46%; and G3: 9.09%; P = .027). There were no significant differences between step-down approaches in terms of ACT change or treatment failure. Conclusions Both step-down methods were not noninferior to maintenance of treatment. Step-down therapy can be attempted when patients are stable, but appropriate monitoring and supervision are necessary with precautions regarding loss of disease control.

Background: There are limited side effects with ICI therapy such as not responding or reduced therapeutic effect caused by its tolerance. In particular, adenosine-induced tumor progression and drug adaptability are the obstacles in use of ICI therapy. Removing adenosine around the tumor is a prerequisite factor of improving the effect of ICI therapy along with suppression of tumor progression. Methods: To investigate the anti-tumor effect of PLAG with the PD-1 antibody (aPD-1), the syngeneic model was used (n=6/group). LLC-1 lung carcinoma cells were implanted into the C57BL/6 mice via subcutaneous. PLAG was daily administrated for 4 weeks with or without 5 mpk of aPD-1 (RMP1-14). it was delivered via IP injection biweekly. The adenosine levels and infiltrated immune cell populations in the tumor and blood were analyzed weekly until the sacrifice day. Results: The tumor size decreased by 23%/65%/81% in a dose-dependently compared to the positive control. Especially, the tumor completely disappeared in 1 animal in treated with aPD-1 and 50 mpk of PLAG, and the 2 animals in treated with 100 mpk. The adenosine levels of blood and tumor burden in the PLAG-treated group decreased by more than 50% compared to the positive control group. It was also confirmed that the adenosine level was about 25% lower in the PLAG-treated group compared to the aPD-1 alone. We found that the expression of A2B receptor in the tumor was significantly reduced in PLAG-treated group. Interestingly, the tumor growth inhibitory effect of PLAG was about 23% better than MRS1754, an A2B receptor antagonist. MRS1754-treated group showed significantly high adenosine level in the blood and tumor, whereas, in the PLAG-treated group, similar adenosine level in blood was continuously maintained as the negative control and its level in the tumor was decreased compared to the positive control. Increasing cancer cell growth and adenosine secretion were shown at 8 h post-treatment of adenosine. PLAG co-treatment decreased the adenosine level by half rapidly and then reduced continuously. In particular, degradation of the A2B receptor was observed after 4 h in PLAG-treated cells. Also intracellular ROS generated during the trafficking of the receptor was elevated within a short period by PLAG and then rapidly decreased at the same time as the signal protein change. PLAG may induce intracellular ROS regulation and A2B receptor degradation through overexpression of αARR. The effect of PLAG disappeared when αARR was knock-down. Conclusion: Extracellular adenosine level of tumor in ICI therapy could be the critical factor to be a successful anticancer treatment. To attenuate adenosine levels, a number of targeted therapies are being developed. Unlike these targeted therapeutics, PLAG fundamentally blocks cancer growth by adenosine clearance. Therefore, PLAG has its own anti-cancer effect and can maximize the effect of ICI therapy. Citation Format: Guen Tae Kim, Sun Young Yoon, Kaapjoo Park, Heesoo Kim, Ki-Young Sohn, Jae Wha Kim. Suppressive effect of PLAG on tumor progression and its synergistic therapeutic effect with ICI therapy through adenosine clearance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1447.

A Gram-stain-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, designated OITF-22T, was isolated from a tidal flat of Oido, an island of South Korea, and subjected to a polyphasic taxonomic study. Strain OITF-22T grew optimally at 25 °C, at pH 7.0–8.0 and in the presence of 2.0–3.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences showed that strain OITF-22T fell within the clade comprising the type strains of Polaribacter species. Strain OITF-22T exhibited 16S rRNA gene sequence similarity values of 97.2–99.4 % to the type strains of Polaribacter vadi , P. haliotis , P. atrinae , P. dokdonensis , P. litorisediminis, P. reichenbachii , P. irgensii and P. marinaquae , and of 93.0–96.9 % to the type strains of the other Polaribacter species. Strain OITF-22T contained MK-6 as the predominant menaquinone and iso-C15 : 0 and iso-C15 : 0 3-OH as the major fatty acids. The major polar lipids detected in strain OITF-22T were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain OITF-22T was 32.3 mol% and its DNA–DNA relatedness values with the type strains of the eight phylogenetically most closely related Polaribacter species were 9–32 %. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, revealed that strain OITF-22T is separated from recognized species of the genus Polaribacter . On the basis of the data presented, strain OITF-22T is considered to represent a novel species of the genus Polaribacter , for which the name Polaribacter insulae sp. nov. is proposed. The type strain is OITF-22T (=KCTC 52658T=NBRC 112706T).

// Young-Jun Kim 1,* , Jae Min Shin 1,* , Su-Hyun Shin 1 , Joo Heon Kim 2 , Ki-Young Sohn 3 , Heung-Jae Kim 3 , Jong-Koo Kang 4 , Sun Young Yoon 3 and Jae Wha Kim 1 1 Cell Factory Research Center, Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 2 Department of Pathology, EulJi University School of Medicine, Daejeon, Republic of Korea 3 Enzychem Lifesciences, Daejeon, Republic of Korea 4 Department of Laboratory Animal medicine, College of Veterinary medicine, Chungbuk National University, Cheongju, Republic of Korea * These authors have contributed equally to this work Correspondence to: Jae Wha Kim, email: // Sun Young Yoon, email: // Keywords : PLAG, collagen-induced arthritis, IL-6, STAT3, neutrophil, Immunology and Microbiology Section, Immune response, Immunity Received : December 05, 2016 Accepted : July 06, 2017 Published : July 19, 2017 Abstract The pathogenesis of rheumatoid arthritis (RA) has been implicated neutrophil extracellular traps (NETs) formation which could generate autoantigen. Neutrophil contributes to initiate and maintain the inflammatory process in the joint. In this study, we show that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) decreases neutrophil migration by regulating the activity of STAT3, a regulator of IL-6 and MIP-2 expression. PLAG caused a decrease in IL-6 production in the RAW264.7 macrophage cell line and in rheumatoid arthritis–fibroblast-like synoviocytes via the regulation of STAT3 signaling without affecting NF-κB signaling. In a mouse model of collagen-induced arthritis (CIA), arthritic symptoms were recapitulated, with increased IL-6 level in the synovium, and PLAG treatment restored IL-6 to a level comparable to that achieved with commercial therapeutics (such as Remicade or methotrexate). Staining of joint tissue with neutrophil-specific antibody showed that PLAG significantly reduced the infiltration of neutrophils into the joint synovium of CIA mice. The inhibitory effect of PLAG on IL-6/STAT3 or MIP-2 signaling also reduced the migration of differentiated neutrophils in vitro . Therefore, PLAG inhibits the infiltration of destructive neutrophils into inflammatory sites, and can be utilized as a potent therapeutic agent for the treatment of sustained inflammation and joint destruction.