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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.

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...

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.

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.

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.

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.

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.

(1) Background: During a pandemic, patients and processes in the emergency department (ED) change. These circumstances affect the length of stay (LOS) or degree of crowding in the ED. The processes for patients with acute critical illness, such as cerebrovascular disease (CVD), can be also delayed. Using the process mining (PM) method, this study aimed to evaluate LOS, ED processes for CVD, and delayed processes during the coronavirus disease 2019 (COVID-19) pandemic. (2) Methods: Data were collected from the Clinical Data Warehouse of a medical center. Phase 1 included patients who visited the ED before the COVID-19 outbreak. In Phase 2, post-COVID-19 ED patients were divided into the COVID-19 tested group (CTG) and COVID-19 not tested group (CNTG) according to whether polymerase chain reaction test was performed. We analyzed patients&rsquo, ED processes before and after COVID-19 using the PM method. We analyzed patients with acute CVD separately to determine whether the process and LOS of patients with acute critical illness were changed or delayed. (3) Results: After the COVID-19 outbreak, the overall LOS was delayed and all processes in CTG patients were delayed. Registration to triage and triage were delayed in both CTG and CNTG patients. The brain imaging process for CTG patients with acute CVD was also delayed. (4) Conclusion: After a pandemic, some processes were changed, new processes were developed, and processes for patients with acute CVD who needed proper time management were not exempted.

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.

Background and objectives: It is often challenging even for skilled rescuers to provide adequate positive pressure ventilation consistently. This study aimed to investigate the effectiveness of a newly developed real-time ventilation feedback device (RTVFD) that estimates tidal volume (TV) and ventilation interval (VI) in real time. Materials and methods: We conducted a randomised, crossover, manikin simulation study. A total of 26 medical providers were randomly assigned to the RTVFD-assisted ventilation (RAV) first group (n = 13) and the non-assisted ventilation (NV) first group (n = 13). Participants provided ventilation using adult and paediatric bag valves (BVs) for 2 min each. After a washout period, the simulation was repeated by exchanging the participants&rsquo, groups. Results: The primary outcome was optimal TV in the RAV and NV groups using adult and paediatric BVs. A secondary outcome was optimal VI in the RAV and NV groups using adult and paediatric BVs. The proportions of optimal TV values were higher for the RAVs when using both adult and paediatric BVs (adult BV: 47.29% vs. 18.46%, p &lt, 0.001, paediatric BV: 89.51% vs. 72.66%, p &lt, 0.001) than for the NVs. The proportions of optimal VI were significantly higher in RAVs when using both adult and paediatric BVs than that in NVs (adult BV: 95.64% vs. 50.20%, p &lt, paediatric BV: 95.83% vs. 57.14%, p &lt, 0.001). Additionally, we found that with paediatric BVs, the simulation had a higher OR for both optimal TV (13.26, 95% CI, 9.96&ndash, 17.65, p &lt, 0.001) and VI (1.32, 1.08&ndash, 1.62, p = 0.007), regardless of RTVFD use. Conclusion: Real-time feedback using RTVFD significantly improves the TV and VI in both adult and paediatric BVs in a manikin simulation study.

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.

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.

The effectiveness of chemotherapy and radiotherapy to treat lung cancer is limited because of highly metastatic nature. Novel strategies and drugs to attenuate metastatic activity are urgently required. In this study, red fluorescence proteins (RFP)-labeled A549 human lung cancer cells were orthotopically implantation, where they developed primary tumors. Metastasis in brain and intestines were reduced by up to 80% by treatment with 100 mpk 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) compared with that in control mice. PLAG treatment also reduced the migration of the primary tumors. Interestingly, substantial neutrophil infiltration was observed in the tumors in control mice. The neutrophil contribution to A549 cell metastatic activity was examined in in vitro co-culture system. Metastatic activity could be achieved in the A549 cells through epidermal growth factor receptor (EGFR) transactivation mediated by protease activating receptor 2 (PAR2) receptor. Neutrophil elastase secreted from tumor-infiltrating neutrophils stimulated PAR2 and induced EGFR transactivation. However, this transactivation was inhibited by inducing PAR2 degradation following PLAG treatment and metastatic activity was effectively inhibited. PLAG attenuated cancer metastatic activity via modulated PAR2/EGFR transactivation by accelerating PAR2 degradation. These results suggest PLAG as potential therapeutic agent to combat tumor metastasis via regulating the activation signal pathway of PAR2 by tumor infiltrate-neutrophils.

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.

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

5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis, in Balb/c mice injected with 5-FU (100 mg/kg, i.p.). Administration of PLAG significantly and dose-dependently reduced the duration of neutropenia and improved the nadirs of absolute neutrophil counts (ANCs). Moreover, while the ANCs of all mice in the control fell to the severely neutropenic range, none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia. Administration of PLAG significantly delayed the mean first day of monocytopenia and reduced the duration of monocytopenia. PLAG also effectively reduced extreme changes in platelet counts induced by 5-FU treatment, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. PLAG significantly decreased plasma levels of the chemokine (C&ndash, X&ndash, C motif) ligand 1 (CXCL1), CXCL2, interleukin (IL)-6, and C-reactive protein (CRP), which were elevated consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. When compared with olive oil and palmitic linoleic hydroxyl glycerol (PLH), only PLAG effectively mitigated 5-FU-induced hematological toxicity, indicating that it has a distinctive mechanism of action. In conclusion, PLAG may have therapeutic potential as a mitigator for 5-FU-induced neutropenia and other hematological disorders.

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.

// 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.

Prenatal intervention of severe fetal aortic valve stenosis by ultrasound-guided percutaneous balloon valvuloplasty has been performed to prevent the progression to hypoplastic left heart syndrome, and achieve biventricular circulation in neonates. Here we report a case of fetal aortic valvuloplasty prenatally diagnosed with aortic stenosis at 24 weeks of gestation and showed worsening features on a follow-up echocardiography. Prenatal aortic valvuloplasty was performed at 29 weeks of gestation, and was a technical success. However, fetal bradycardia sustained, and an emergency cesarean delivery was performed. To the best of our knowledge, this is the first reported case of fetal aortic valvuloplasty which was performed in Asia.

Progranulin, a protein secreted from the airway epithelium, is known to attenuate the downstream cascade of neutrophilic inflammation in particular. We hypothesized that progranulin may have a role in inflammatory regulation in asthma.To investigate the association between serum progranulin levels and various clinical features in patients with asthma.Serum samples and clinical data of 475 patients with asthma and 35 healthy controls at a tertiary referral hospital and its affiliated health promotion center were collected. Serum progranulin levels were compared between patients with asthma and healthy controls and then were compared within the patients with asthma in terms of pulmonary function and measures of inflammatory status. Univariate and multivariate analyses were performed to identify factors associated with severity of asthma.Serum progranulin levels were significantly lower in the asthma group than in healthy group and were positively correlated with prebronchodilator forced expiratory volume in 1 second predicted within patients with asthma. We found a negative correlation between serum progranulin levels and blood neutrophil counts. Multivariate analysis revealed that higher serum progranulin levels were associated with a lower risk of severe asthma (odds ratio, 0.888; 95% confidence interval, 0.846-0.932; P.001) after adjustment for other variables, such as age, sex, smoking status, blood neutrophil count, and current use of systemic corticosteroids.Although the exact mechanism of the anti-inflammatory action of progranulin remains unknown, we suggest that serum progranulin may be an indicator of severe asthma with airflow limitation. Future studies with comprehensive airway sampling strategies are warranted to clarify its role, particularly in neutrophilic asthma.

Objectives The aim of this study was to test the applicability of haptic feedback using a smartwatch to the delivery of cardiac compression (CC) by professional healthcare providers. Methods A prospective, randomized, controlled, case-crossover, standardized simulation study of 20 medical professionals was conducted. The participants were randomly assigned into haptic-first and non-haptic-first groups. The primary outcome was an adequate rate of 100-120/min of CC. The secondary outcome was a comparison of CC rate and adequate duration between the good and bad performance groups. Results The mean interval between CCs and the number of haptic and non-haptic feedback-assisted CCs with an adequate duration were insignificant. In the subgroup analysis, both the good and bad performance groups showed a significant difference in the mean CC interval between the haptic and non-haptic feedback-assisted CC groups-good: haptic feedback-assisted (0.57-0.06) vs. non-haptic feedback-assisted (0.54-0.03), p < 0.001; bad: haptic feedback-assisted (0.57-0.07) vs. non-haptic feedback-assisted (0.58-0.18), p = 0.005-and the adequate chest compression number showed significant differences- good: haptic feedback-assisted (1,597/75.1%) vs. non-haptic feedback-assisted (1,951/92.2%), p < 0.001; bad: haptic feedbackassisted (1,341/63.5%) vs. non-haptic feedback-assisted (523/25.4%), p < 0.001. Conclusions A smartwatch cardiopulmonary resuscitation feedback system could not improve rescuers' CC rate. According to our subgroup analysis, participants might be aided by the device to increase the percentage of adequate compressions after one minute.

Background: Bitter taste receptors (TAS2R) in human airway smooth muscle have recently been shown to have an important role in bronchodilation, together with β2-adrenergic receptors. Object: To evaluate the association between genetic variations in TAS2R and clinical features, including bronchodilator response and asthma control. Method: We analyzed the association between single nucleotide polymorphisms (SNPs) of TAS2R10 and TAS2R14 and variables such as demographic data, atopy, duration of disease, and asthma control status, including variables such as asthma control test (ACT) score, percent predicted value of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio, as well as bronchodilator response (BDR), in 721 asthma patients in Korea. Result: Three novel SNPs of 633G>A, 645C>A, and -79G>A in TAS2R10 and 3 known SNPs of -815T>C, -1267G>A, and -1897T>C in TAS2R14 were analyzed. Increased BDR was significantly associated with SNPs of -815T>C [OR (95% CI) = 1.88 (1.01-3.49), p = 0.04 ] [J Gen Physiol 2005;125:535-553; Am J Respir Cell Mol Biol 2010;42:373-3812], -1267A>G [OR (95% CI) = 2.07 (1.03-4.15), p = 0.04] and -1897T>C [OR (95% CI) = 3.05 (1.01-9.23), p = 0.04, in a dominant model, and OR = 1.91 (1.08−3.36), p = 0.02, in a codominant model] of the TAS2R14 gene. There was a significant association between -815T>C and a low mean ACT score [OR (95% CI) = 5.84 (1.94-17.61), p = 0.001]. In haplotype analysis, TAC, CAT, and TGT, or TG and CA haplotypes on TAS2R14 were significantly associated with increased BDR; CAT and CA haplotypes were significantly associated with a low ACT score. Conclusion: Genetic variations in TAS2Rs may be valuable genetic markers to predict therapeutic response and outcomes in asthma. Further research in an independent cohort is needed.

Background: Currently, no approved drug exist to treat oral mucositis (OM) in patients receiving chemoradiation for the treatment of head and neck cancer. To address this limitation, we examined the therapeutic effect of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), which is an immune resolution accelerator that can effectively modulate the neutrophil recruitment, against chemoradiation-induced oral mucositis (CRIOM) in a murine model. Additionally, we investigated whether necroptosis is involved in the pathogenesis of CRIOM in a murine model and the therapeutic effect of PLAG against the disease. Methods: To investigate the improved effect of PLAG on CRIOM, we established the CRIOM-bearing BALB/c mouse model using concurrent treatments of 5-fluorouracil (100 mg/kg, i.p.) and X-radiation (20 Gy) on the heads and necks of mice. Phosphate buffer saline or PLAG (100 and 250 mg/kg, p.o.) was administered daily. The body weights of mice were observed daily and on Day 9, the mice were sacrificed for extracting their tongues for further tissue analyses. The histopathological grading of OM was analyzed in the collected tongues. Human keratinocytes (HaCaT) were utilized to identify the mechanism of PLAG on regulating the necroptosis signals. 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 without the PLAG treatment. Tongue tissues of mice who received PLAG also displayed lower phosphorylation levels of necroptotic signaling proteins (RIPK1/3 and MLKL). Chemoradiation induced the release of damaged-associated molecular patterns (DAMPs), which activates the necroptosis signaling pathway if not promptly eliminated intracellularly in HaCaT cells. PLAG promoted the effective removal of DAMPs, thereby downregulating the activation of necroptosis signaling pathway. Conclusion: On day 9, the tongues of mice-treated with chemoradiotherapy activated the necroptosis signaling pathway. As a result, cells from oral mucosa released DAMPs and pro-inflammatory cytokines to induce neutrophil migration to the inflamed oral epithelium. PLAG ameliorated the degree of OM by terminating the necroptosis signaling pathway. These data suggest that PLAG may be a useful therapeutic agent for the treatment of CRIOM. Citation Format: Solji Choi, Su-Hyun Shin, Sun Young Yoon, Ji Sun Park, Ki-Young Sohn, Jae Wha Kim. 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol ameliorates chemoradiation-induced oral mucositis in a mouse model by regulating necroptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6175.

Background: The development of immune-checkpoint drugs, a fourth-generation anticancer drug, is a significant breakthrough in anticancer research. Cancer therapy using immune-checkpoint drugs are still enlarged. To improve the efficacy of immune-checkpoint drugs, modulation of the tumor microenvironment is essentially required. In this experiment, we examined the elevated anti-cancer efficacy of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG), which has been demonstrated to attenuate tumor infiltrated neutrophils (TINs) in the tumor, along with the PD-L1 immune checkpoint inhibitor treatment. Methods: The syngeneic model was used (n=6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine bladder cancer cells were implanted into the C57BL/6 mice subcutaneously and bred for 5 weeks. After a week from tumor implantation, PLAG at different dosages (25/50/100 mpk) were daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection twice a week. Tumor growth was calculated in 3-day intervals. Neutrophil chemotaxis-related chemokines and neutrophil-to-lymphocyte rate (NLR) were also evaluated with a 2-week interval. The degree of neutrophil infiltration in the tumor on the day of sacrifice and the degree of infiltration between lymphocytes and neutrophils were analyzed. Results: The PLAG treatment groups demonstrated that the tumor burden decreased in a concentration-dependent manner. In 50 and 100 mpk of PLAG treated mice, the tumor burden was decreased to a significant value compared to a positive control (p < 0.05). In the group treated with PD-L1 antibody alone, the growth rate of the tumor decreased until about 2 weeks. In the group treated simultaneously with PLAG and PD-L1 antibody, the growth of the tumor was significantly reduced compared to the group treated with PD-L1 antibody alone. As a result of calculating neutrophils and lymphocytes every two weeks, NLR level in the group treated with PLAG and PD-L1 was significantly decreased compared to that treated with PD-L1 antibody alone. Besides, the number of TINs were effectively reduced by PLAG treatment alone. The interruption of tumor growth and reduced chemokine secretion were also observed in the PLAG treated groups. In summary, our data suggest that PLAG provides an enhanced PD-L1 antibody effect on the regression of tumor burden in the syngeneic mice model via reducing the number of TINs. Conclusion: PLAG may be utilized for improving the efficacy of PD-L1 antibody on reducing the tumor burden at the devastating tumor microenvironment. Citation Format: Guen Tae Kim, Sun Young Yoon, Ji Sun Park, Ki-Young Sohn, Jae Wha Kim. The effect of PLAG on the PD-L1 immune-checkpoint drug therapy in the MB49 bladder cancer syngeneic model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5553.

Severe asthma (SA) presents in about 3%-5% of adult asthmatics and is responsible for over 60% of asthma-related medical expenses, posing a heavy socioeconomic burden. However, to date, a precise definition of or clear diagnostic criteria for SA have not been established, and therefore, it has been challenging for clinicians to diagnose and treat this disease. Currently, novel biologics targeting several molecules, such as immunoglobulin E, interleukin (IL)5, and IL4/IL13, have emerged, and many new drugs are under development. These have brought a paradigm shift in understanding the mechanism of SA and have also provided new treatment options. However, we need to agree on a precise definition of and its diagnostic criteria for SA. Additionally, it is necessary to explain the diagnostic criteria and to summarize current standard and additional treatment options. This review is an experts' opinion on SA from the Korean Academy of Asthma, Allergy, and Clinical Immunology, the Working Group on Severe Asthma, and aims to provide a definition of and diagnostic criteria for SA, and propose future direction for SA diagnosis and management in Korea.

Background: A recent study reported that tumor-infiltrating neutrophil (TIN) has potential on malignant tumor progression leading to metastasis. In our study, to control the effect of TIN, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) was used. PLAG has shown its efficacy in modulating the neutrophil counts in chemotherapy-induced neutropenia by attenuating neutrophil extravasation via down-regulation of adhesion molecules, inflammatory cytokines, and chemokines. In this study, we investigated whether PLAG has an anti-metastatic effect on A549 lung cancer orthotopic implantation model via modulating TIN. Methods: To investigate the anti-metastatic effect of PLAG on lung cancer metastasis, RFP-labeled A549 cells were implanted into the lungs of BALB/c nude mice via intratracheal injection and bred for 12 weeks. After 6 weeks from tumor implantation, PLAG with three concentrations (25/50/100 mpk) were daily administrated for another 6 weeks. Each image of the growth of the primary tumor and colonization of metastatic tumor to other sites were acquired using CT and IVIS. TIN was analyzed in the primary tumor using immunohistochemistry (IHC). To identify the mechanism of PLAG on preventing the neutrophil-associated metastasis of cancer cells, direct or non-direct co-culture methods were used. Results: In the orthotopic implantation model, metastatic tumors to GI-track and brain were detected by IVIS. It was confirmed that metastasis to GI-track was decreased by 73% in 100 mpk PLAG-treated group, while metastasis to the brain was decreased by about 92% in PLAG-diet compared with positive control. Primary lung tumor growth was retarded by PLAG in a dose-dependent manner. The size of the primary tumor was much smaller than the positive control and alveolar tissue was similar to that of normal mice in 100 mpk PLAG-diet. In contrast, massive neutrophil infiltrations in positive and delivery groups, but significantly reduced upon PLAG administration. Moreover, p-EGFR was concomitantly detected with a similar pattern of neutrophil infiltration. During the direct contact in vitro assay, the A549 lung cancer spheroid cells were scattered by neutrophils, but it was effectively hindered by PLAG treatment. Neutrophil-stimulated cancer in the non-direct contact method showed enhanced metastatic activity. However, such a phenomenon was significantly reduced with the PLAG-treated group. Moreover, neutrophil stimulated the expression of EMT markers, whereas it was effectively down-regulated by PLAG administration. Transactivation between tumor cells and neutrophil was mediated by neutrophil elastase (NE). NE binds to and activates protease-activated receptor 2 (PAR2) on cancer cells and subsequently activated EGFR for metastasis to occur by cleaving HB-EGF through the ARR2/clathrin complex. On the other hand, the suppression of metastasis by PLAG was mediated through the regulation of the NE-PAR2 pathway and acceleration of intracellular trafficking and degradation of PAR2. Conclusion: In this study, TIN was observed in the primary lung tumor and metastasis into GI-track and brain, but PLAG dramatically reduced infiltration of neutrophil. The collective results suggest that TIN educates tumor cells for enhancing metastasis by EGFR transactivation. However, PLAG effectively interfered the transactivation. Having not met the medical needs for treating metastasis, PLAG may be a promising candidate as an anti-metastatic drug by modulating the TIN. Citation Format: GUEN TAE KIM, SUN YOUNG YOON, KI-YOUNG SOHN, MYUNG-HWAN KIM, JAE WHA KIM. Anti-metastatic effect of PLAG via interference of neutrophil elastase/PAR2/EGFR signaling on A549 lung cancer orthotopic implantation model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C037. doi:10.1158/1535-7163.TARG-19-C037

Background: Tumor microenvironments (TME) promote tumor growth and induction of metastasis along with the strong presence of tumor-infiltrating neutrophil (TIN), which further contributes to abnormal tumor growth and metastasis. From this tumor-prone environment, we hypothesize that the effective destruction of TIN may enhance the therapeutic efficacy of chemotherapy for reducing the tumor. In this study, we investigated the synergistic effect of PLAG in the MDA-MB-231 breast cancer xenograft model concomitantly treated with the AC-regimen in modulating the effect of TIN. Methods: MDA-MB-231 breast cancer xenograft model was used for evaluation of the tumor growth in the AC-regimen alone and PLAG co-treated animals. AC-regimen was delivered via intraperitoneal injection twice a week with a dose of 2/20 and 5/50 mpk (Doxorubicin/Cyclophosphamide) and PLAG was daily administered with 100 and 250 mpk. Tumor growth was measured in 3-day intervals. Neutrophil chemotaxis-related chemokines, CXCL1/2/8 and circulating neutrophils were also evaluated in a 2-week interval. Expression of apoptosis-related molecular markers (Bax/Bak) and TIN in the tumor lesion was analyzed by immunohistochemistry (IHC) staining. Results: PLAG has synergistic effects on decreasing the tumor burden in the PLAG and AC-treated xenograft model. In AC-treated groups with 2/20 or 5/50 mpk, retardation of tumor growth was observed from the calculated tumor size and regulation of apoptosis-associated markers was proved by TUNEL assay and IHC. Modulated chemokine expression from tumor burden and subsequent neutrophil recruitment were also detected in proportion to the tumor mass. The measured tumor sizes in the PLAG co-treated group were consistently smaller than those from the AC-regimen alone group till the mice were sacrificed. It was confirmed that the tumor burden of the PLAG co-treated group with 5/50 AC-regimen was significantly decreased in a concentration-dependent manner compared to the AC-regimen alone group (p Citation Format: GUEN TAE KIM, SUN YOUNG YOON, KI-YOUNG SOHN, MYUNG-HWAN KIM, JAE WHA KIM. The synergistic effect of PLAG on the antitumor efficacy of AC-regimen via alleviating neutrophil tumor infiltration on breast tumor xenograft model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B054. doi:10.1158/1535-7163.TARG-19-B054

Introduction: Sleep deprivation is a major cause of motor vehicle accidents, and can impair the human brain as much as alcohol. It has been estimated that between 16% and 60% of all motor vehicle accidents are caused by sleep related problems. Adolescents and young adults frequently complain of sleep disorder symptoms and suffer from chronic sleep deprivation. There is an absence of evidence in existing literature regarding the impact of sleep disturbances on the driving function in young, novice drivers compared to that in young adults. Materials and Methods: This study is a prospective cohort study of two subject groups: young adults with driving experience of less than 36 months, and young adults with driving experience of greater than 36 months). Each subject served as its own control. The enrolled subjects are 16 – 26 years old, right-handed, with normalor corrected vision. Participants with a chronic or acute ongoing health condition which might affect the study results were excluded. Study procedures utilized were: polysomnography, multiple sleep latency test and driving simulator testing. Results: Repeated-measures MANCOVA revealed that driving experience, objective sleepiness (as measured by the Multiple Sleep Latency Test (MSLT)), interaction between driving experience and depressive symptoms (as measured by The Center for Epidemiologic Studies Depression Scale Revised (CESD-R)), and interaction between depressive symptoms and objective sleepiness had statistically significant effects on driving performance. Conclusion: Unexpectedly, more experienced drivers made more driving errors and were responsible for a greater number of accidents. Mood and ongoing sleep deprivation emerged as two key factors that impacted driving performance more than level of experience. This may represent the impact of a less-regulated post high school lifestyle, as compared to more structured high school schedule. The study findings aid in confirming that functional impairments related to sleepiness previously observed in adult study populations are also replicated in adolescents and young adults.

Complementary and alternative medicine (CAM) therapies are a group of diverse medical and health systems, practices, and products not currently considered to be part of conventional medicine. These therapies are growing in popularity, with approximately 50% of patients with depressive disorders reported to use some form of alternative treatment. Often perceived as natural and safer alternatives without many of the adverse effects commonly associated with pharmacotherapy, CAM therapies have great potential in the management of treatment-resistant depression (TRD). Many CAM therapies work via mechanisms other than those of antidepressant medications and, as such, may be viable options for patients who have failed to achieve remission with pharmacotherapy and for those who cannot adhere to medications due to intolerable adverse effects. Moreover, augmentation of pharmacotherapy with CAMs can be a practical option for partial responders for whom antidepressant medication doses cannot be increased due to issues of safety and tolerability. However, the evidence on efficacy and safety of different CAM interventions in TRD is limited. The aim of this chapter is to present the available evidence on CAM therapies for TRD, to serve as a guide for the clinician to tailor an alternate therapeutic approach for patients with treatment resistance. Based on the available data on efficacy, safety, and practicality, the most robust evidence is for exercise, mindfulness-based cognitive therapy, and omega-3 fatty acids as adjunctive treatments. There is less evidence on efficacy of yoga, light therapy, and S-adenosyl-L-methionine. Despite current limitations in the availability of studies in TRD, there is a growing body of evidence in support of specific CAMs in TRD, indicating therapeutic potential. As such, CAM therapies as add-on to evidence-based first-line interventions may be considered as part of an integrative approach to the management of treatment resistance.

The Asthma Control Test (ACT) score is widely used in asthma clinics, particularly with the recent emphasis on achievement and maintenance of optimal asthma control. However, this self-assessment score does not always correspond with lung function parameters, leading to uncertainty about each patient's control status; therefore, we investigated the clinical characteristics that are associated with discrepant correlation between the ACT score and pulmonary function. The 252 adult asthmatic subjects were divided into 5 groups according to their changes in FEV1% predicted values and ACT scores between 2 consecutive visits three months apart. The data were retrospectively reviewed and several clinical variables were compared. Elderly, non-eosinophilic, non-atopic asthma patients were more likely to show paradoxical changes of pulmonary function and ACT score. Female patients were prone to report exaggerated changes of ACT score compared with baseline lung function and changes in FEV1 levels. This group was using more medications for rhinosinusitis. Male patients seemed less sensitive to changes in lung function. From these findings, we conclude that when assessing asthma control status, physicians should carefully consider patient age, gender, atopy status, blood eosinophil levels, and comorbidities along with their ACT scores and pulmonary function test results.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but life-threatening, severe cutaneous adverse reactions most frequently caused by exposure to drugs. Several reports have associated the use of acetaminophen with the risk of SJS or TEN. A typical interval from the beginning of drug therapy to the onset of an adverse reaction is 1-3 weeks. A 43-year-old woman and a 60-year-old man developed skin lesions within 3 days after administration of acetaminophen for a 3-day period. Rapid identification of the symptoms of SJS and TEN caused by ingestion of acetaminophen enabled prompt withdrawal of the culprit drug. After administration of intravenous immunoglobulin G, both patients recovered fully and were discharged. These two cases of rapidly developed SJS/TEN after ingestion of acetaminophen highlight the possibility that these complications can develop within only a few days following ingestion of over-the-counter medications such as acetaminophen.

Chemotherapy-induced mucositis can limit the effectiveness of cancer therapy and increase the risk of infections. However, no specific therapy for protection against mucositis is currently available. In this study, we investigated the therapeutic effect of PLAG (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol, acetylated diglyceride) in 5-fluorouracil (5-FU)-induced oral mucositis animal models. Hamsters were administered 5-FU (80 mg/kg) intraperitoneally on days 0, 6, and 9. The animals’ cheek pouches were then scratched equally with the tip of an 18-gauge needle on days 1, 2, and 7. PLAG was administered daily at 250 mg/kg/day. PLAG administration significantly reduced 5-FU/scratching–induced mucositis. Dramatic reversal of weight loss in PLAG-treated hamsters with mucositis was observed. Histochemical staining data also revealed newly differentiated epidermis and blood vessels in the cheek pouches of PLAG-treated hamsters, indicative of recovery. Whole blood analyses indicated that PLAG prevents 5-FU–induced excessive neutrophil transmigration to the infection site and eventually stabilizes the number of circulating neutrophils. In a mouse mucositis model, mice with 5-FU–induced disease treated with PLAG exhibited resistance to body-weight loss compared with mice that received 5-FU or 5-FU/scratching alone. PLAG also dramatically reversed mucositis-associated weight loss and inhibited mucositis-induced inflammatory responses in the tongue and serum. These data suggest that PLAG enhances recovery from 5-FU–induced oral mucositis and may therefore be a useful therapeutic agent for treating side effects of chemotherapy, such as mucositis and cachexia.

Background Unbiased cluster analysis has identified several asthma phenotypes. However, these phenotypes did not consistently predict disease prognosis and reflect temporal variability in airway inflammation. Objective We aimed to identify longitudinal trajectories in terms of pulmonary function parameters and investigated whether the trajectories are associated with prognosis. Methods Data were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA). Three-year pulmonary function test results were used to apply finite mixture models for group-based trajectory in 486 patients with eligible data set. Results Two main sets of longitudinal trajectories were identified in terms of FEV1% predicted, and FEV1 variability. In the 4 trajectories determined with FEV1% predicted, the pulmonary function showed a consistent course in 4 stratified levels during 3 years of follow-up, which was associated with unexpected hospital visits and the use of steroid bursts due to exacerbation. The variability in pulmonary function showed 3 different patterns, and we found that higher blood and sputum eosinophil levels were associated with the higher variability in pulmonary function and more exacerbations. Conclusions Trajectory analysis is a novel method that provides longitudinal asthma phenotypes and aids in prediction of future risk of exacerbation. Further analysis is needed to validate the usefulness of these trajectories in an independent population.

Chemotherapy-induced neutropenia (CIN) is a complication that arises during cancer treatment and necessitates dose reduction. Preventing CIN and maintaining absolute neutrophil counts (ANC) is critical for successful chemotherapy because a rapid decline of neutrophils increases susceptibility to infection. Here, we investigated whether administration of EC-18 has therapeutic effects on the treatment of CIN in 5-fluorouracil (5-FU)-induced neutropenia mouse model. A single injection of 5-FU 100mg/kg reduced the ANC in the control, EC-18 125 and EC-18 250mg/kg-treated cohort from pre-injection values to 1000 cells/μL. EC-18 125 or 250mg/kg significantly reduced the duration of neutropenia from 7.4±1.14 days to 2.6±0.55 or 3.0±0.71 days, respectively. Moreover, the ANC of all individuals in the control cohort fell to severely neutropenic range (ANC Citation Format: Yong-Jae Kim, Jinseon Jeong, Ki-Young Sohn, Do Young Lee, Sun Young Yoon, Jae Wha Kim. Therapeutic potential of EC-18 as a chemotherapy adjuvant for 5-fluorouracil-induced neutropenia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 360.

Background Cephalosporin is a major offending agent in terms of drug hypersensitivity along with penicillin. Cephalosporin intradermal skin tests (IDTs) have been widely used; however, their validity for predicting immediate hypersensitivity has not been studied. This study aimed to determine the predictive value of cephalosporin intradermal skin testing before administration of the drug. Methods We prospectively conducted IDTs with four cephalosporins, one each of selected first-, second-, third-, or fourth-generation cephalosporins: ceftezol; cefotetan or cefamandole; ceftriaxone or cefotaxime; and flomoxef, respectively, as well as with penicillin G. After the skin test, whatever the result, one of the tested cephalosporins was administered intravenously and the patient was carefully observed. Results We recruited 1421 patients who required preoperative cephalosporins. Seventy-four patients (74/1421, 5.2%) were positive to at least one cephalosporin. However, none of responders had immediate hypersensitivity reactions after a challenge dose of the same or different cephalosporin, which were positive in the skin test. Four patients who suffered generalized urticaria and itching after challenge gave negative skin tests for the corresponding drug. The IDT for cephalosporin had a sensitivity of 0%, a specificity of 97.5%, a negative predictive value of 99.7%, and a positive predictive value (PPV) of 0%, when challenged with the same drugs that were positive in the skin test. Conclusion Routine skin testing with a cephalosporin before its administration is not useful for predicting immediate hypersensitivity because of the extremely low sensitivity and PPV of the skin test (CRIS registration no. KCT0000455).

The purpose of this study is to investigate mediatiing effects of perceived organization support and supervisor support that impact on dual commitment. Data were gathered from 188 employees who were working in Airlines. In the result of the hypothesis verification, First, perceived organization support and supervisor support have positive effects on dual commitment. Second, organiational identification turns out to have the mediating role in the relationship between perceived organization support and supervisor support and dual commitment. Finally, implication of results and future tasks were discussed with limitations.

The efficient synthesis of an 80-member library of unique benzoxathiazocine 1,1-dioxides by a microwave-assisted, intermolecular nucleophilic aromatic substitution (SNAr) diversification pathway is reported. Eight benzofused sultam cores were generated by means of a sulfonylation/SNAr/Mitsunobu reaction pairing protocol, and subsequently diversified by intermolecular SNAr with ten chiral, non-racemic amine/amino alcohol building blocks. Computational analyses were employed to explore and evaluate the chemical diversity of the library.

Supplemental Digital Content is available in the text, Blood eosinophilia is a common clinical finding. Helminthic infections, including toxocariasis, are a common cause of eosinophilia; however, the clinical course of toxocariasis associated with eosinophilia is not fully understood. Thus, controversies exist regarding treatment indications. To evaluate the clinical features and natural course of various types of eosinophilia, with a particular focus on toxocariasis, we retrospectively reviewed the medical records of 1000 patients with peripheral blood eosinophilia who were referred to the allergy clinic at Asan Medical Center between 2007 and 2012. Clinical parameters and imaging study findings were evaluated. The treatment response to albendazole and resulting changes in eosinophilia and imaging studies were analyzed in patients diagnosed with toxocariasis. Among the 1000 subjects, toxocariasis was the most common cause of eosinophilia (n = 534; 53.4%), followed by allergic disease and adverse drug reactions. The majority of patients with toxocariasis were men, and they were mostly asymptomatic. More than one-third of patients (n = 215; 40.3%) with toxocariasis exhibited organ involvement, particularly hepatic involvement. In most cases of eosinophilia and organ involvement due to toxocariasis, the symptoms normalized regardless of treatment. Most cases of eosinophilia related to toxocariasis displayed a self-remitting course regardless of treatment. With the exception of several clinical situations, including ocular involvement, the clinical need for anti-helminthic therapy in toxocariasis is not that significant.

Oral mucositis is a common complication of chemoradiation therapy and is often accompanied by erythema, ulceration, pain, weight loss. It could delay remission and limit the effectiveness of cancer therapy and increase the risk of infections. However, no specific therapy for protection against mucositis is currently available. In previous study, PLAG (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol, acetylated diglyceride) was shown to exert a therapeutic effect with pegfilgrastim to treat chemotherapy-induced neutropenia by modulating neutrophil transmigration and chemotherapy-induced megakaryocyte/erythrocyte progenitor decrese was significantly alleviated following PLAG administration. In this study, we investigated the therapeutic effect of PLAG in 5-fluorouracil (5-FU) and radiation-induced oral mucositis mouse model. Following 5-FU (100 mg/kg) injection on Day 0, mice were exposed to whole-body irradiation with 1 Gy gamma-ray radiation on Day 2. In order to facilitate the risk of infection, tongue was scratched 0.2 cm wound at using the tip of an 18-gauge needle at an equal force and depth on Day 4. PLAG was orally administered at 250 mg/kg/day. 5-FU, Radiation and scratching-induced oral mucositis mice exhibited ulceration, fibrosis, and festering wounds. PLAG treatment group decreased ulcer formation and diminished the degree of wound festering form on Day 5. Although CCRT-induce mice declined 16% of body-weight, PLAG only suppressed 2% of body-weight compare to control mice on Day 8. PLAG supported to mouse survival and inhibited mucositis-induced inflammatory responses in the tongue and serum. For head only radiation, custom-made lead shield was used for mice to limit the radiation to the head. After 5-FU (100 mg/kg) injection, mouse's head were received 20 Gy x-ray radiation and PLAG was administrated with 250 mg/kg daily. In toluidine blue (TB) staining, PLAG suppressed concurrent chemoradiotherapy (CCRT)-induced oral mucositis and inflammatory responses. At Day 10, CCRT-induced oral mucositis mice were shown the weight loss and tongue wound festered, and had still not fully recovered and resulted in death. PLAG administration significantly reduced CCRT-induced mucositis and recovered scar better quicker. PLAG also decreased body-weight loss and increased mice survival rate. In histological analysis, CCRT-induced inflammation was recovered in PLAG-treated mice. These data suggest that PLAG enhances recovery from 5-FU/radiation-induced oral mucositis and cachexia. From these data, PLAG could be therapeutically useful in reducing the complications associated with chemotherapy and radiation, and thus may be an excellent supplementary agent for anti-cancer therapy. Citation Format: Ha-Reum Lee, Solji Choi, Kwang Hoon Yang, Do Young Lee, Byoung-Gon Moon, Ki-Young Sohn, Sun Young Yoon, Jae Wha Kim. 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) exhibits the therapeutic effect in chemoradiation-induced oral mucositis mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4154.

Controlling balance between T-helper type 1 (Th1) and T-helper type 2 (Th2) plays a pivotal role in maintaining the biological rhythm of Th1/Th2 and circumventing diseases caused by Th1/Th2 imbalance. Interleukin 4 (IL-4) is a Th2-type cytokine and often associated with hypersensitivity-related diseases such as atopic dermatitis and allergies when overexpressed. In this study, we have tried to elucidate the function of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (EC-18) as an essential modulator of Th1/Th2 balance. EC-18 has showed an inhibitory effect on the production of IL-4 in a dose-dependent manner. RT-PCR analysis has proved EC-18 affect the transcription of IL-4. By analyzing the phosphorylation status of Signal transducer and activator of transcription 6 (STAT6), which is a transcriptional activator of IL-4 expression, we discovered that EC-18 induced the decrease of STAT6 activity in several stimulated cell lines, which was also showed in STAT6 reporter analysis. Co-treatment of EC-18 significantly weakened atopy-like phenotypes in mice treated with an allergen. Collectively, our results suggest that EC-18 is a potent Th2 modulating factor by regulating the transcription of IL-4 via STAT6 modulation, and could be developed for immune-modulatory therapeutics.

To the Editor, Anti-phospholipid syndrome (APS) is a prothrombotic disorder characterized by anti-phospholipid antibodies in the serum [1]. Anti-phospholipid antibodies recognize phospholipid-bindi...