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Abstract Background Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. Methods We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. Results We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Conclusions Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.

Background Thyroid-associated ophthalmopathy (TAO) involves tissue expansion and inflammation, potentially causing a hypoxic microenvironment. Hypoxia-inducible factor (HIF)-1α is crucial in fibrosis and adipogenesis, which are observed in TAO progression. We investigated the effects of hypoxia on orbital fibroblasts (OFs) in TAO, focusing on the role of HIF-1α in TAO progression. Methods OFs were isolated from TAO and non-TAO patients (as controls). In addition to HIF-1α, adipogenic differentiation markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (CEBP) were measured by Western blot, and phenotype changes were evaluated by Oil Red O staining under both normoxia and hypoxia. To elucidate the effect of HIF-1α inhibition, protein expression changes after HIF-1α inhibitor treatment were evaluated under normoxia and hypoxia. Results TAO OFs exhibited significantly higher HIF-1α expression than non-TAO OFs, and the difference was more distinct under hypoxia than under normoxia. Oil Red O staining showed that adipogenic differentiation of TAO OFs was prominent under hypoxia. Hypoxic conditions increased the expression of adipogenic markers, namely PPARγ and CEBP, as well as HIF-1α in TAO OFs. Interleukin 6 levels also increased in response to hypoxia. The effect of hypoxia on adipogenesis was reduced at the protein level after HIF-1α inhibitor treatment, and this inhibitory effect was sustained even with IGF-1 stimulation in addition to hypoxia. Conclusion Hypoxia induces tissue remodeling in TAO by stimulating adipogenesis through HIF-1α activation. These data could provide insights into new treatment strategies and the mechanisms of adipose tissue remodeling in TAO.

Abstract We investigated the association of CA125 response with prognosis and RECIST response/progressive disease (PD) criteria in recurrent high grade serous ovarian cancer (HGSOC) patients treated with a cell cycle checkpoint kinase 1 inhibitor (CHK1i), prexasertib. 81 patients had measurable disease per RECISTv1.1, of which 72 and 70 were measurable by Gynecologic Cancer InterGroup (GCIG) CA125 response and PD criteria, respectively. Univariate and multivariate analyses showed that GCIG CA125 response (n = 32) is associated with improved progression-free survival (PFS) and overall survival (OS) compared to no GCIG CA125 response (n = 40) (median PFS 8.0 vs. 3.5 months [HR: 0.30, 95% CI: 0.18–0.51, p

Abstract Dengue virus (DENV) infection is a public health concern in several countries and is associated with severe diseases, such as dengue hemorrhagic fever and dengue shock syndrome. DENVs are transmitted to humans via the bites of infected Aedes mosquitoes, and no antiviral therapeutics are currently available. In this work, we aimed to identify antiviral drugs against DENV type 2 (DENV2) infections and selected pimecrolimus as a potential antiviral drug candidate. Pimecrolimus significantly inhibited DENV2-mediated cell death and replication in vitro. We also confirmed a decrease in the number of plaques formed as well as in the envelope protein levels of DENV2. The time-of-addition and course experiments revealed that pimecrolimus inhibited DENV2 infection during the early stages of the virus replication cycle. In an experimental mouse model, orally administered pimecrolimus alleviated body weight loss and lethality caused by DENV2 infection, which we used as readouts of the drug’s antiviral potency. Furthermore, pimecrolimus significantly inhibited the DENV2 load and ameliorated focal necrosis in the liver and spleen. Taken together, our in vitro and in vivo findings suggest that pimecrolimus is a promising antiviral drug candidate for the treatment of DENV2 infection.

Truffles, belonging to the genus Tuber, are ectomycorrhizal (ECM) fungi that form underground ascocarps and primarily establish symbiosis with oaks and hazels. The cultivation of Tuber spp. involves transplanting inoculated seedlings that have formed ectomycorrhiza with Tuber species, with mulching being effective for truffle cultivation. In this study, we investigated the effects of mulching on the mycelial growth of four Tuber species (T. himalayense, T. koreanum, T. melanosporum, and T. borchii) in the Korean natural environment, highlighting the potential for Korea as a truffle cultivation site. We developed and tested species-specific primers for quantifying the soil mycelial biomass of Tuber spp. by qRT-PCR, determined the superior mulch color for mycelial growth, and identified the Tuber species exhibiting the highest growth rate in the Korean field environment. Our results demonstrated that white mulch significantly enhanced mycelial growth in Tuber species than black mulch, likely owing to its ability to maintain low soil temperatures, control weeds, and improve host plant growth. Among the Tuber species, T. himalayense showed the greatest growth potential in the Korean natural environment. Additionally, a significant and positive correlation was observed between the mycelial biomass of Tuber species and the growth of inoculated seedlings, as measured by the total stem length and the number of leaves, thereby indicating the importance of symbiosis between ECM fungi and host plants. This study provides valuable insights into truffle cultivation in Korea and highlights the potential of using white mulch to promote mycelial growth, thereby contributing essential data for understanding the appropriate environmental conditions for Tuber spp. cultivation in Korea. Further study is needed to assess the long-term impact of mulching and to explore the effectiveness of other mulching materials.

Abstract The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS

Background: To effectively understand and evaluate plant diversity in a specific area and make meaningful comparisons between regions, standardized methods that measure diversity irrespective of survey plot size are crucial. This study proposes a model equation for comparing plant species diversity using the modified Whittaker plots. Plant species diversity was measured in two Gotjawal areas on Jeju Island, where the coexistence of northern and southern limit species significantly impacts diversity. By analyzing the relationship between plant species diversity and environmental factors, the study clarified the characteristics of plant and habitat diversity in the Gotjawal ecosystem. Results: The species richness of vascular plants, herbaceous plants, and woody plants increased with area and was higher in Jeoji Gotjawal than in Seonheul Gotjawal. Similarly, the species turnover rate (slope value) was higher in Jeoji Gotjawal (4.37) than in Seonheul Gotjawal (3.85). This indicates that the species richness in Jeoji Gotjawal increases more with the expansion of the survey area (1-1,000 m2), reflecting a faster species turnover rate. Additionally, in Gotjawal areas, species richness increased with greater leaf litter depth, elevation, slope, and rock ratio. These results indicate that differences in plant species diversity were attributed to soil environmental factors. Conclusions: The plant species diversity of Gotjawal, surveyed using standardized methods, was lower than that of forested areas in the central region of South Korea where the same method was applied. Most previous studies on species diversity likely compared diversity without considering a consistent survey area. Therefore, when comparing plant species diversity domestically and globally, it emphasizes the need for the use of standardized survey methods.

In this study, we analyzed the environmental factors influencing the restoration process of the degraded ecosystem in the Inner Mongolian steppe, the largest steppe ecosystem in Asia, which is experiencing rapid desertification, and evaluated the effects of restoration on the damaged ecosystem in China. For this purpose, we selected degraded steppe areas left to desertification in the Hulunbuir region, four restored sites where vegetation was artificially introduced for restoration, and reference ecosystems, including a non-desertified area with the dominant Pinus sylvestris var. mongolica community and a meadow steppe area. We conducted analyses and monitoring of plant community characteristics and soil environmental factors to assess the progress of restoration. The results showed that the introduction of indigenous woody plants in the degraded areas led to a proportional increase in vegetation cover, plant biodiversity, and species abundance over time. The primary external forces driving the succession of vegetation in the restored sites were soil factors including organic matter content, temperature and total nitrogen levels, which were associated with an increase in vegetation cover. These results can be interpreted as an increase in vegetation cover leading to an increase in litter production. This in turn reduces soil temperature and evaporation, subsequently enhancing the activity of soil microorganisms. Over time, the species composition, structural diversity of communities, and ecosystem functions in the restored sites gradually became more similar to those of the reference ecosystems. This indicates that vegetation restoration in this area has been very successful. In particular, the positive change in local residents’ awareness regarding the necessity of restoration has been considered a crucial contribution to the success of restoration in the degraded areas. It has led to a decrease in perceived anthropogenic threats to the restored sites. These results indicate that the introduction of native woody plants is crucial and can increase vegetation cover and species composition complexity and local residents’ positive perception of restoration for the successful restoration of desertified drylands.

Objectives: This study aims to investigate the influence of socioeconomic status (SES) on variations in physical activity (PA) levels and diabetes-related cognitive dysfunction and impairment amidst disruptions caused by the COVID-19 pandemic. Methods: With the sample of old population, comprising about 20 thousand from the Fact-Finding Survey on the Status of Senior Citizens (FSSSC) released by Ministry of Health and Welfare of South Korea in 2017 and 2020, we empirically tested the direct and indirect effects of SES on cognitive dysfunction using structural equation modeling (SEM). Two SEMs provided the comparison on the effects of COVID-19. Results: Household income had a negative impact on the likelihood of dementia diagnosis via PA related diabetes during the pandemic (p

Background This study investigates the association between thyroid function and frailty in the old patients using representative data. Methods The study was conducted using data from the Korea National Health and Nutrition Examination Survey conducted from 2013 to 2015. The study population included 2,416 participants aged 50 years and older with available thyroid function test data. Frailty assessment was performed using the Fried frailty phenotype. The prevalence of frailty was analyzed across different thyroid diseases and thyroid function parameters. Results The significant association between thyroid dysfunction and frailty was observed in overt hyperthyroidism and subclinical hyperthyroidism. After adjusting for various factors, the association between thyroid dysfunction and frailty remained significant. On the other hand, overt hypothyroidism did not show a significant association with frailty in the adjusted analysis. For individuals with overt hyperthyroidism and subclinical hyperthyroidism, higher levels of free thyroxine (FT4) were significantly associated with an increased risk of frailty (aOR >999; 95% CI, >999 to 999). Among individuals with overt hypothyroidism, lower level of FT4 levels and high thyrotropin (TSH) levels showed a significant association with frailty risk (FT4: aOR,

Background and Objective: Obesity is associated with difficult or failed intubation attempts, making general anesthesia challenging for anesthesiologists to perform. The purpose of this study was to evaluate and compare the efficacy of a McCoy laryngoscope and a C-MAC D-blade video laryngoscope for intubation in obese patients with a body mass index (BMI) ≥ 35 kg/m2. Methods: In total, 104 patients were randomly assigned to be intubated with a McCoy (McCoy group) or C-MAC D-blade video laryngoscope (C-MAC group). The primary outcome was intubation time. The secondary outcomes were vocal cord exposure time, vocal cord passage time, proportion of successful intubation, mask ventilation scale, intubation difficulty scale (IDS), percentage of glottis opening (POGO) score, and hemodynamic variables. Results: Although the intubation time did not significantly differ, the C-MAC group showed shorter vocal cord exposure times and a higher rate of successful vocal cord exposure within 5 s. The IDS value was significantly lower in the C-MAC group than in the McCoy group. The proportion of patients who required an increase in lifting force during laryngoscopy was higher in the McCoy group than in the C-MAC group, which may explain the difference in MAP between the groups. Conclusions: Both the McCoy laryngoscope and the C-MAC D-blade video laryngoscope were useful during the intubation of obese patients. The C-MAC D-blade video laryngoscope might be more useful for obese patients in terms of hemodynamic stability.

The purpose of this study was to examine the validity of two wearable smartwatches (the Apple Watch 6 (AW) and the Galaxy Watch 4 (GW)) and smartphone applications (Apple Health for iPhone mobiles and Samsung Health for Android mobiles) for estimating step counts in daily life. A total of 104 healthy adults (36 AW, 25 GW, and 43 smartphone application users) were engaged in daily activities for 24 h while wearing an ActivPAL accelerometer on the thigh and a smartwatch on the wrist. The validities of the smartwatch and smartphone estimates of step counts were evaluated relative to criterion values obtained from an ActivPAL accelerometer. The strongest relationship between the ActivPAL accelerometer and the devices was found for the AW (r = 0.99, p < 0.001), followed by the GW (r = 0.82, p < 0.001), and the smartphone applications (r = 0.93, p < 0.001). For overall group comparisons, the MAPE (Mean Absolute Percentage Error) values (computed as the average absolute value of the group-level errors) were 6.4%, 10.5%, and 29.6% for the AW, GW, and smartphone applications, respectively. The results of the present study indicate that the AW and GW showed strong validity in measuring steps, while the smartphone applications did not provide reliable step counts in free-living conditions.

The PI3K signaling pathway plays an essential role in cancer cell proliferation and survival. PI3K pathway inhibitors are now FDA-approved as a single agent treatment or in combination for solid tumors such as renal cell carcinoma or breast cancer. However, despite the high prevalence of PI3K pathway alterations in gynecological cancers and promising preclinical activity in endometrial and ovarian cancer models, PI3K pathway inhibitors showed limited clinical activity in gynecological cancers. In this review, we provide an overview on resistance mechanisms against PI3K pathway inhibitors that limit their use in gynecological malignancies, including genetic alterations that reactivate the PI3K pathway such as PIK3CA mutations and PTEN loss, compensatory signaling pathway activation, and feedback loops causing the reactivation of the PI3K signaling pathway. We also discuss the successes and limitations of recent clinical trials aiming to address such resistance mechanisms through combination therapies.

AbstractThe aim of this study was to characterize a new fungal species, Acremonium conglutinatum, isolated from air samples collected in Wando, South Korea. Phylogenetic analysis based on the internal transcribed spacer and large subunit regions revealed its unique position within the genus Acremonium. The isolated strain displayed distinct morphological characteristics, including ellipsoid or bent-ellipsoid conidia formed in clusters on the phialides. These features differentiate the new species from closely related species within the genus. This study describes the morphological and molecular characteristics of A. conglutinatum and emphasizes its phylogenetic relationships with other Acremonium spp. The identification of this novel species contributes to our understanding of the diversity and ecological role of Acremonium.

We report the first discovery of Penicillium mexicanum in Korea. Fungal strains were isolated from air samples collected in Taean-gun, Chungcheongnam-do, Korea. The strain was identified based on its morphological characteristics, as well as molecular phylogenetic analysis of the internal transcribed spacer (ITS), β-tubulin (BenA), and calmodulin (CaM) regions. This strain exhibited a high sequence similarity to the reference sequences of P. mexicanum. These findings enhance our understanding of fungal biodiversity in Korea and underscore the importance of continuous monitoring of fungal species.

ABSTRACTThe highdose quadrivalent influenza vaccine (QIVHD) has shown improved protection against influenza and its complications in older adults. We aimed to evaluate the costeffectiveness of QIVHD compared with QIVSD among Korean adults aged ≥ 65 years in reducing influenzarelated disease burden. We evaluated the 2016/2017 and 2017/2018 seasons and their average values using a static decision tree model. The difference in efficacy between standard-dose (SD) and high-dose (HD) was calculated based on the results of a clinical trial comparing Fluzone® High-Dose Vaccine and Fluzone® Vaccine in older adults. Incremental cost-effectiveness ratios (ICERs) were assessed from the healthcare system perspective. A discount rate of 4.5% was applied to life-year-gained (LYG) values and utilities. We performed deterministic and probabilistic sensitivity analyses to account for both epidemiological and economic sources of uncertainty. In the analysis of the 2017/2018 season, the QIV-HD strategy generated an excess of 0.00182 life-years (Lys)/person and 0.003953 quality-adjusted life-years (QALYs)/person compared with QIV-SD. The ICER was 6,467.56 United States Dollars (USD)/QALY. In the analysis from the 2016/2017 season, QIV-HD caused a surplus of 0.00117 Lys/person and 0.003272 QALYs/person compared with QIV-SD. ICER was 7,902.46 USD /QALY. From the average data of the 2016/2017 and 2017/2018 seasons, an excess of 0.00147 Lys/person and 0.003561 QALYs/person were generated using QIV-HD compared with QIV-SD, while the ICER was 7,190.44 USD /QALY. From the healthcare system perspective, QIV-HD was a more cost-effective vaccination option in reducing influenza-related disease burden and healthcare costs in Koreans aged ≥ 65 years compared with QIV-SD.

Abstract Background NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. Methods This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. Results Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1–15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. Conclusions NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. Trial registration NCT03476681 . Registered 03/26/2018. Graphical Abstract

PurposeThis research seeks to evaluate the repercussions of socioeconomic status (SES) on physical activity (PA) among the older population, both pre and intra-COVID-19 pandemic. The study aims to scrutinize whether alteration in PA behaviors based on SES impacts cardiovascular diseases (CVDs). It is well established that PA has a significant association with CVDs and the pandemic has restricted PA in the older population. We endeavor to discern whether SES modulates PA levels and whether these levels of PA behavior subsequently influence the incidence of CVDs among older adults.MethodsThe analytical framework of this study relies on the data procured from the Fact-Finding on the Status of Senior Citizens (FSSSC) survey conducted in 2017 and 2020, involving 10,299 (75 ± 6 years) and 10,097 (74 ± 6 years) participants, respectively. We employ Structural Equation Modeling (SEM) to elucidate the ramification of the COVID-19 pandemic on CVDs while accommodating potential mediating and confounding variables, including socioeconomic status, PA levels, body mass index (BMI), and gender, in the context of the pandemic and CVDs.ResultsOur empirical models indicated a tendency for older adults of lower socioeconomic status (SES) to exhibit diminished levels of physical activity (PA) compared to their counterparts of higher SES, particularly considering the influence of the COVID-19 pandemic. Furthermore, prolonged engagement in PA is associated with a reduced risk of hypertension (p = 0.010), and congestive heart failure & arrhythmia (p

Endophytic fungal strains were isolated from the leaves of two conifer species (Juniperus rigida and Pinus densiflora) in Korea and identified on the basis of their morphological and molecular characteristics. Internal transcribed spacer and large subunit regions of rDNA were used for the phylogenetic analysis, and the translation elongation factor 1-alpha (TEF) and RNA polymerase II second largest subunit (RPB2) genes were analyzed depending on the species. Two fungal species that were previously unrecorded in Korea were identified: Acrodontium burrowsianum and Pestalotiopsis humicola. Their morphological and phylogenetic characteristics are described herein.

Truffles are ectomycorrhizal fungi that belong to the genus Tuber. They exhibit symbiotic relationships, particularly with oak (Quercus spp.) and hazel (Corylus spp.) trees. We performed an inoculation using a spore suspension to synthesize mycorrhizae between European truffles, Tuber borchii and Tuber melanosporum, and an indigenous oak species, Quercus acutissima. This resulted in the formation of mycorrhizae within 2 months after inoculation. Despite having the same host plant, differences in features were observed between Tuber species, including color and mantle type. These results indicate that Q. acutissima is a suitable host plant for truffle cultivation in Korea and provide a better understanding of the mycorrhization of T. borchii and T. melanosporum.

PURPOSE This study aimed to examine the associations between accelerometer-measured physical activity and both cardiometabolic disease risk factors and metabolic syndrome in Korean adults. METHODS We performed a retrospective cohort study with age-sex matched case-control using data from the 2014-2016 Korea National Health and Nutrition Examination Survey, which was administered to South Korean adults (n=320). Individuals were categorized into quartiles based on accelerometer-measured moderate-to-vigorous physical activity (MVPA). Demographic and physical characteristics, waist circumference, visceral adiposity index, blood pressure, lipid profiles, and TG/HDL-C were observed. The associations between MVPA status and cardiometabolic disease risk factors as well as metabolic syndrome were determined using multiple logistic regression. RESULTS For the waist circumference, SBP, DBP, MBP, visceral adiposity, triglyceride, and a surrogate estimate of insulin resistance, the Q1 and Q2 groups had higher means compared with the Q3 and Q4 groups. HDL-C was higher in the Q3 and Q4 groups compared to the Q1 and Q2 groups. Odds ratios for cardiometabolic disease risk factors and metabolic syndrome decreased in a curvilinear manner with the increasing quartile of MVPA. CONCLUSIONS Adults with higher MVPA participation were strongly associated with cardiometabolic disease risk factors and metabolic syndrome.

AbstractThis study was conducted to investigate the effect of changes in soil moisture content under climate change conditions on the growth response of Quercus dentata, a representative species of the genus Quercus on the Korean peninsula. The results showed that Q. dentata germination increased by 9.4 days under climate change conditions (RCP 4.5 scenario), whereas the below-ground biomass and plant biomass increased by 1.3 and 1.2 times, respectively. However, the soil moisture treatment condition solely affected the leaf area, below-ground biomass, and plant biomass but not the germination percentage, germination speed, above-ground length, and above-ground biomass. The variance across the measured growth variables was considerably higher in the control group than in the climate change treatment group, whereas the variance was lower for lower soil moisture content. The findings suggested that under climate change conditions, Q. dentata germinated rapidly and exhibited broader leaf area and increased development below ground, which may be advantageous for the early establishment of seedlings. However, the plants may face difficulties in conditions with low soil moisture content. In conclusion, with continuous climate changes, Q. dentata seedlings are predicted to efficiently adapt to the altered soil moisture content to exhibit even more reliable growth than with the current condition. However, the growth of Q. dentata seedlings would be more difficult with severely low soil moisture content than with abundant soil moisture content, which is predicted to be detrimental to population maintenance in the long term.

The tumour microenvironment has been shown to change the phenotypes and functionality of immune cells to enable tumour propagation. Here authors show that cancers can derail B cell development to give rise to macrophage-like cells, contributing to cancer progression and metastasis via disabling local T cell response.

Whey protein (WP) in milk shows physiologically active functions such as cholesterol control and immune system strengthening. In this study, we performed hydrolysis and peptide polarity fractionation to enhance the efficacy and diversity of its physiological activities, using the digesting enzyme, pancreatin. Our results indicate that hydrolysis significantly increased the cell proliferation of the WP fractions, with the lower-polarity fractions showing greater efficacy in this regard. Our results indicate that hydrolysis significantly increases cell proliferation of the WP fractions. Additionally, we confirmed differences in the antioxidant activity of the WP fractions as a function of polarity was confirmed via scavenging 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay in vitro. WP itself did not show anti-inflammatory efficacy. However, all the hydrolyzed fractions downregulated the mRNA expression levels of inflammatory cytokines in all treated cell lines and, based on a senescence-associated (SA)-β-galactosidase assay, the fraction with the lowest polarity (F6) inhibited cellular senescence to the greatest extent. Furthermore, we identified the peptide sequences with various physiological activities from whey protein hydrolysates through mass spectrometry. Taken together, our results indicate that the fractionation of WP via hydrolysis generates novel functions including promoting cellular cell proliferation, anti-inflammatory effects, and enhancing antioxidant and anti-cellular senescence.

Smart cities have been introduced globally. It involves technical development and economic, social, and environmental objectives. In response to the Fourth Industrial Revolution (Industry 4.0) and global trends, Korea has prepared legal and institutional measures for smart city composition. This study reviewed the importance of key documents and agreements in Daegu Metropolitan City to reduce disaster risk for the vulnerable in the context of smart cities. 25 research studies were critically and systematically reviewed from the perspective of disaster risk reduction in smart cities. In its disaster safety areas, Daegu Metropolitan City aims to reduce property damage and casualties that may occur because of physical events such as collapse, water-related disasters, and heatwaves by up to 20%. Smart disaster mitigation involves data collection, sharing, and propagation. The entire process is handled on a safety platform called Data hub. According to the Daegu Metropolitan City government, solving social problems and managing disasters is key to a smart city, and it is striving to improve the efficiency of other cities. However, Daegu has limitations because it is a service-oriented smart city, and it is necessary to engage citizens to participate, raise awareness of the smart city, and educate them on the platform. The study results recommend future research that focus on disaster risk reduction and resilience in smart cities worldwide.

PurposeThis study aims to investigate the association between factors affecting decreased physical activity (PA) during the COVID-19 pandemic by matching groups based on age, gender, and BMI variables using public Community Health Survey (CHS) data.MethodsData from the CHS was selected and used to investigate health-related factors related to PA, including demographic, psychological, behavioral characteristics, sociocultural, and chronic disease. Exact group matching was conducted based on age, gender, and BMI variables. Frequency analysis, Chi-square test (χ2 test), and multinominal logistic regression analysis were performed to analyze the data, and odds ratio (OR) and 95% confidence interval (95% CI) were presented. The study also examined the impact of COVID-19 on PA, the fear of PA infection.ResultsThe logistic regression analysis by gender showed that PA decreased in all age groups, males, and females during the COVID-19 pandemic. The decrease in PA was lower in age groups other than those aged 60 or older. Stress experience, residence area, housing type, drinking, smoking, education level, and fear of infection were found to affect decreased PA due to COVID-19. Specifically, experiencing stress (Odds Ratio [OR] = 1.178; 95% Confidence Interval [CI] = 1.054 ~ 1.317) and increased smoking (OR = 1.332; 95% CI = 1.073 ~ 1.653) had a slightly higher impact on decreased PA. Conversely, living in a suburban area (OR = 0.653; CI = 0.585 ~ 0.728), having public housing (OR = 0.836; CI = 0.754 ~ 0.928), having less than a high school education (OR = 0.813; CI = 0.729 ~ 0.907), staying the same with alcohol (OR = 0.567; CI = 0.507 ~ 0.633) and smoking (OR = 0.836; CI = 0.728 ~ 0.959), and having low fear of infection (OR = 0.817; CI = 0.737 ~ 0.905) had a slightly lower impact on decreased PA.ConclusionPA should be maintained or increased, particularly in the context of social distancing measures during the pandemic. To ensure that PA can be sustained, a program should be developed that considers the individual’s geographical location, economic status, lifestyle, and environment.

Background Whether the early use of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors have cardioprotective effects following acute myocardial infarction is unknown. Thus, we aimed to evaluate the association between the early initiation of SGLT2 inhibitors and cardiac event rates in patients with diabetes with acute myocardial infarction undergoing percutaneous coronary intervention. Methods and Results Based on the National Health Insurance claims data in South Korea, patients who received percutaneous coronary intervention for acute myocardial infarction between 2014 and 2018 were analyzed. Patients given SGLT2 inhibitors or other glucose‐lowering drugs were matched based on a propensity score. The primary end point was a composite of all‐cause mortality and hospitalizations for heart failure. Major adverse cardiac events (a composite of all‐cause death, nonfatal myocardial infarction, and ischemic stroke) were compared as the secondary end point. After 1:2 propensity score matching, the SGLT2 inhibitors group (938 patients) and the no use of SGLT2 inhibitors group (1876 patients) were compared. During a median follow‐up of 2.1 years, the early use of SGLT2 inhibitors was associated with lower risks of both the primary end point (9.8% versus 13.9%; adjusted hazard ratio [HR], 0.68 [95% CI, 0.54–0.87]; P=0.002) and secondary end point (9.1% versus 11.6%; adjusted HR, 0.77 [95% CI, 0.60–0.99]; P=0.04). All‐cause mortality and hospitalizations for heart failure were also significantly lower in early users of SGLT2 inhibitors. Conclusions The early use of SGLT2 inhibitors in patients with diabetes treated with percutaneous coronary intervention for acute myocardial infarction was associated with a significantly lower risk of cardiovascular events, including all‐cause mortality, hospitalizations for heart failure, and major adverse cardiac events.

Background Patients with thyroid cancer undergo less extensive surgery and additional therapies compared to those with other cancers. We aimed to compare the quality of life (QoL) between patients with thyroid cancer and healthy subjects using representative data from Korea. Differences in QoL of thyroid cancer survivors according to the duration after cancer diagnosis was also evaluated. Methods This population-based cohort study included 50,278 subjects who participated in the Korea National Health and Nutrition Examination Survey between 2007 and 2017. QoL was compared between patients with thyroid cancer and healthy subjects using self-reported data from the EuroQoL (EQ)-5 dimension (5D) and EQ-visual analog scale (VAS). Propensity score matching was used to match thyroid cancer survivors to healthy subjects (1:5 matching). Results Linear regression with univariate analysis showed that the presence of thyroid cancer was positively correlated with better EQ-5D index scores (β-coefficient=0.010, P=0.046). After adjusting for multiple covariables, statistical significance was maintained. EQ-VAS fails to demonstrate any significant correlation. Among the EQ-5D categories, patients with thyroid cancer showed better self-care than healthy subjects. Thyroid cancer duration did not correlate with the EQ-5D index score. In subgroup analyses, compared to patients with thyroid cancer duration of

Melittin is a major component of bee venom; it is widely used in traditional medicine because of its therapeutic effects, such as anti-inflammatory effects. However, melittin has limited medical applications owing to its adverse effects, such as high cytotoxicity. In this study, we investigated the physiological activities of various hydrolyzed melittin-derived peptides to eliminate the cytotoxicity of melittin and enhance its efficacy. The 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assay confirmed that melittin-derived peptides showed antioxidant activity comparable to that of melittin. Moreover, unlike melittin, which showed high cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)−5-(3-carboxymethoxyphenyl)−2-(4-sulfophenyl)−2H-tetrazolium inner salt (MTS) assay, the melittin-derived peptides showed negligible cytotoxicity. Among the melittin-derived peptides, the peptide composed of sequence TTGLPALISWIKRKRQQ (P1) showed inhibitory effects on the mRNA expression of inflammatory cytokines and phosphorylation of IκBα, similar to the effects of melittin in RAW 264.7 cells. Degranulation of RBL-2H3 cells was analyzed using a β-hexosaminidase release assay to confirm the allergenic activity of melittin and P1, which showed remarkably reduced allergenicity of P1 compared to that of melittin. These results indicate that P1 maintained the anti-inflammatory effects of melittin while reducing its cytotoxicity and allergic reactions. In conclusion, the melittin-derived peptide P1 efficiently decreased the adverse effects while maintaining the beneficial effects of melittin, making it suitable for therapeutic applications.

ObjectivesAmong US firefighters, sudden cardiac arrest and psychological stress (i.e., PTSD) are the leading cause of on-duty death. Metabolic syndrome (MetSyn) may influence both cardiometabolic and cognitive health. Here, we examined differences in cardiometabolic disease risk factors, cognitive function, and physical fitness in US firefighters with vs. without MetSyn.Materials and methodsOne hundred fourteen male firefighters, aged 20 to 60 years, participated in the study. US firefighters with MetSyn vs. non-MetSyn were divided by AHA/NHLBI criteria. Of them, we performed a paired-match analysis with respect to the age and BMI of firefighters with (n = 18) vs. without MetSyn (n = 18). The cardiometabolic disease risk factors included blood pressure, fasting glucose, blood lipid profiles [HDL-C, triglyceride (TG)], and surrogate markers of insulin resistance [TG/HDL-C, TG glucose index (TyG)]. The cognitive test included a psychomotor vigilance task as a measure of reaction time and a delayed-match-to-sample task (DMS) as a measure of memory, using the computer-based Psychological Experiment Building Language Version 2.0 program. The differences between MetSyn and non-MetSyn groups in US firefighters were analyzed using an independent t-test adjusted for age and BMI. In addition, Spearman correlation and stepwise multiple regression were conducted.ResultsUS firefighters with MetSyn exhibited severe insulin resistance estimated by TG/HDL-C and TyG (Cohen’s d > 0.8, all p 0.8, all p

The current study is to examine the disparities in physical activity (PA), sedentary behavior (SB), and stress levels in Korean adolescents concerning changes in their perception of family economic status (ES) during COVID-19. Among a total of 6144 Korean adolescents aged 12 to 18, the participants were categorized into two groups based on their responses regarding changes in their family ES due to COVID-19: Declined ES (n = 3072) and Non-changed ES (n = 3072), with matching in terms of age, gender, and BMI. All variables were assessed using the 16th year (2020) of the Korean Youth Risk Behavior Survey. Statistical analyses were conducted using the SPSS 26.0 version, employing independent t-tests to examine anthropometrics' differences and multinominal logistic regression to predict the impact of perception of family ES on PA, SB, and stress while comparing the two groups. The significance level was set at α = 0.05. Adolescents in the Declined ES group were 1.2 times more likely to engage in MVPA for less than 420 mins/wk (OR = 1.16, p = 0.039), 1.7 times more likely to meet recommended muscular strength activities (i.e., ≥ 3 days/wk) (OR = 1.70, p < 0.001), 37% less likely to not meet recommended recreational sitting time (i.e., ≥ 840 mins/wk) (OR = 0.63, p < 0.01), and were 2.1 times more likely to experience very severe stress level than the Non-changed ES group (p < 0.001). These results shed light on the importance of promoting mental health care in adolescents, regardless of PA levels, for their well-being during potential future pandemics. Understanding the impact of perceived ES changes on health behaviors can inform targeted interventions and support strategies to improve the mental health outcomes of adolescents during challenging times.

PurposeThis study aimed to examine the relationship between smartphone dependency (SD) and mental health (MH) in adolescents in order to develop and implement plans pertaining to SD control.MethodsRaw data from the 16th Online Adolescent Health Behavior Survey in 2020 were analyzed. A total of 482 respondents were selected as study subjects based on their experience of smartphone overdependence (SO), specifically, 241 participants whose score for SO was 37 or higher (Group 2) and age- and gender-matched 241 participants whose score was lower than 10 (Group 1).ResultsFrequency analysis, cross-tab analysis (χ2 test), and multinomial logistic regression were performed Analysis shows that the MH affecting the increase in SO is the subjective perception of happiness, subjective perception of stress, sadness and despair, and experience of Loneliness. But, the variable affecting the reduction is the subjective evaluation of sleep quality. The likelihood of SO increased as adolescents felt unhappier [Exp (β) = 2.408] and more stressed [Exp (β) = 4.453] and more often felt lonely [Exp (β) = 8.149], but the likelihood decreased as they had neither sufficient nor insufficient sleep duration [Exp (β) = 0.344]. The findings suggest that it is necessary to develop aggressive measures for the prevention and management of MH in adolescents showing SO because mental health is closely linked to SD. In developing the measures, realistic approaches to widely pervasive SO among adolescents should be explored by taking into account MH factors, that is, predictors of SO, and the characteristics of youths, such that they can self-control smartphone use and form desirable life habits.

BackgroundThe impact of nirmatrelvir/ritonavir treatment on shedding of viable virus in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear.MethodsA prospective cohort study evaluating mildly ill COVID-19 patients was conducted. Virologic responses were compared between nirmatrelvir/ritonavir-treatment and supportive care groups. Risk factors and relevant clinical factors for shedding of viable virus were investigated.ResultsA total of 80 COVID-19 patients were enrolled and 222 sputum specimens were collected. Ten patients were dropped during follow-up, and 33 patients in the nirmatrelvir/ritonavir and 37 in the supportive care groups were compared. The median age was 67 years, and 67% were male. Clinical characteristics were similar between groups. Viral loads decreased significantly faster in the nirmatrelvir/ritonavir group compared with the supportive care group (P < 0.001), and the slope was significantly steeper (–2.99 ± 1.54 vs. –1.44 ± 1.52; P < 0.001). The duration of viable virus shedding was not statistically different between groups. In the multivariable analyses evaluating all collected specimens, male gender (OR 2.51, 95% CI 1.25–5.03, P = 0.010), symptom score (OR 1.41, 95% CI 1.07–1.87, P = 0.015), days from symptom onset (OR 0.72, 95% CI 0.59–0.88, P = 0.002), complete vaccination (OR 0.09, 95% CI 0.01–0.87, P = 0.038), and BA.2 subtype (OR 0.49, 95% CI 0.26–0.91, P = 0.025) were independently associated with viable viral shedding, while nirmatrelvir/ritonavir treatment was not.ConclusionNirmatrelvir/ritonavir treatment effectively reduced viral loads of SARS-CoV-2 Omicron variants but did not decrease the duration of viable virus shedding.

To identify effective light spectra for increasing the productivity of Panax ginseng, we conducted experiments in a controlled environment using a hydroponic cultivation system in a plant factory. We investigated the effect of single LEDs (red, blue, and yellow) and mixed LEDs (red + blue and red + blue + white). The relationships between four light spectra (red, blue, yellow, and white) and physiological responses (net photosynthetic rate, stomata conductance, transpiration rate, and intercellular CO2 partial pressure), as well as growth responses (shoot and root biomass), were analyzed using multivariate statistical analysis. Among the four physiological response variables, shoot biomass was not increased by any pathway, and root biomass was increased only by the intercellular CO2 partial pressure. Red and yellow light increased shoot biomass, whereas white light promoted an increase in the net photosynthetic rate and enhanced root biomass. In contrast, blue light was less effective than the other light spectra in increasing both shoot and root biomass. Therefore, red and yellow light are the most effective light spectra for increasing shoot biomass and white light is effective for increasing root biomass in a plant factory that uses artificial LED lighting. Furthermore, the intercellular CO2 partial pressure is an important physiological variable for increasing the root biomass of P. ginseng.

Chloroplast development and brassinosteroid (BR) signaling both regulate plant photomorphogenesis. Here the authors show that DAY, a DnaJ-like domain-containing membrane protein, regulates both processes by binding and stabilizing both BRI1, the BR receptor, and POR, a key enzyme in chlorophyll biosynthesis.

Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC) and the mechanisms driving benefit are poorly understood. Here, the authors show that elevated Notch signaling predicts clinical benefit in ICB in relapsed SCLC.

In South Korea, the ready-to-use hexavalent vaccine (against diphtheria, tetanus, pertussis, poliovirus, Haemophilus influenzae type b, and hepatitis B) is not listed despite its facility of no need to reconstitute. It, therefore, has the potential to augment the efficiency of prevention against the six infectious diseases, and it may reduce vaccine-related errors of reconstitution when compared with the currently used vaccination scheme of the pentavalent vaccine with the additional shots against hepatitis B. Given the assumed clinical equivalence between the two vaccination schemes, a cost-minimization analysis has been performed from a societal perspective including all the medical and non-medical direct and indirect costs when vaccinating one birth cohort. The results indicate that the ready-to-use hexavalent vaccine induces a cost reduction of KRW 47,155 (USD36.22) per infant or 12,026 million Korean Won ($9,236,417) in total for the whole birth cohort with 260,500 children. Using the ready-to-use hexavalent vaccine causes a lower infection rate, has fewer vaccination sessions, and may save much time as compared with the current vaccination scheme in place. The ready-to-use hexavalent vaccine may, therefore, benefit the National Immunization Program by reducing the total societal costs of vaccination while improving convenience of infants, parents, and medical care professionals.

For the study on the relationships between the seed dispersal of exotic plants and bird population, flora, avifauna, vegetation patches, and the dynamics of seed banks were investigated in and around the exposed floodplains of the large rivers, and the causes of exotic vegetation development were determined with respect to plant life form, bird population characteristics, and landscape using multivariate analysis. The number of dominant exotic plant species observed in exposed areas was higher than that observed in an abandoned field and paddy field undergoing secondary succession. Additionally, the area occupied by exotic vegetation in exposed areas increased with the increase in number of vine plants and small terrestrial birds, whereas the relationship between vine and runner plants was inversely proportional. Therefore, to control exotic plants in exposed floodplains surrounding large rivers, it is necessary to remove vines and shrubs along the waterfront where small resident birds carrying plant seeds live and to maintain and manage runner plant populations. Furthermore, implementing an ecological landscape management strategy, such as afforestation through the planting of trees, may also be effective.

Oxidative stress and cellular senescence in dermal papilla cells (DPCs) are major etiological factors causing hair loss. In this study, the effect of the Allium hookeri extract (AHE) on hair-inductive and anti-oxidative properties was investigated in human DPCs. As a result, it was found that a non-cytotoxic concentration of the extracts increased the viability and size of the human DPC spheroid, which was associated with the increased expression of hair-growth-related genes in cells. To determine whether or not these effects could be attributed to intracellular anti-oxidative effects, liquid chromatography-mass spectrometry alongside various biochemical analyses are conducted herein. An ingredient called alliin was identified as one of the main components. Furthermore, AHE treatment induced a significant decrease in H2O2-mediated cytotoxicities, cell death, and cellular senescence in human DPCs. Upon analyzing these results with a molecular mechanism approach, it was shown that AHE treatment increased β-Catenin and NRF2 translocation into the nucleus while inhibiting the translocation of NF-κB (p50) through p38 and PKA-mediated phosphorylations of GSK3β, an upstream regulator of those proteins. These results overall indicate the possibility that AHE can regulate GSK3β-mediated β-Catenin, NRF2, and NF-κB signaling to enhance hair-inductive properties and ultimately protect against oxidative stress-induced cellular damage in human DPCs.

Purple corn extract (PCE) is a nutraceutical, an activator of AMPK, and it has antioxidants and anticancer properties. Therefore, PCE could be a candidate for alleviating cigarette smoke (CS)-induced oxidative DNA damage. This study examined whether PCE can have a protective effect on blood cells in an animal model of cigarette smoke (CS)-induced DNA damage. PCE was orally administered to CS-inhaled Spraque-Dawley (SD) rats, followed by the target cells being examined for markers of DNA damage. The study also sought to elucidate the mechanism of PCE action in the PCE treated animals. SD rat inhalation of CS was for once a day for 30 min, repeated for 7 days. PCE was administered orally before CS inhalation. Pretreatment of the animals with oral PCE kept the numbers of white blood cells (WBC) as well as neutrophils (NE), lymphocytes (LY), monocytes (Mo), eosinophils (EO), abd jasophils (BA) from increasing as those were increased in the CS-inhaling SD rats. The amount of phosphorylated γ-H2AX, a DNA damage marker, was assayed in the circulating blood cells collected from the animals and western blot analysis with anti-Foxo3a, p-Foxo3a, p-AMPK, MnSOD antibodies were performed on those cells. PCE protected the circulating blood cells from CS inhalation-induced DNA damage by 44% as assayed by increases in γ-H2AX. PCE also increased the nuclear localization of Foxo3a by 52% over control cells. Mechanistically, PCE appears to efficiently protect various blood cell types from CS-induced DNA damage through removal of ROS via activation of the AMPK/Foxo3a/MnSOD pathway.

In this study, we examined the feasibility of Myzus persicae proliferation through interrelationships with host plants in a smart farm facility during winter. We investigated aphid proliferation under an LED artificial light source and attempted to interpret aphid proliferation in relation to the net photosynthetic rate of the host plant, Eutrema japonicum. We observed that aphids continuously proliferated in the smart farm facility in winter without dormancy. The average number of aphids was greater under the 1:1 red:blue light irradiation time ratio, where the photosynthetic rate of the host plant was lower than under the 5:1 and 10:1 red:blue light irradiation time ratios. These results show that it is important to maintain a low net photosynthetic rate of the host plant, E. japonicum, in order to effectively proliferate aphids under artificial light such as in the case of smart farm facilities.

Gas turbine failure diagnosis is performed in this work based on seven types of tag data consisting of a total of 7976 data. The data consist of about 7000 normal data and less than 500 abnormal data. While normal data are easy to extract, failure data are difficult to extract. So, this study mainly is composed of normal data and a one-class support vector machine (OC-SVM) is used here, which has an advantage in classification accuracy performance. To advance the classification performance, four hyperparameter tuning (manual search, grid search, random search, Bayesian optimization) methods are applied. To analyze the performance of each technique, four evaluation indicators (accuracy, precision, recall, and F-1 score) are used. As a result, about 54.3% of the initial failure diagnosis performance is improved up to 64.88% through the advanced process in terms of accuracy.

Recent literature has highlighted altered spinal-reflex excitability following acute lateral ankle sprain (ALAS), yet there is little information on the conduction velocity of spinal reflex pathways (CV-SRP) in these patients. Therefore, we aimed to investigate the effects of ALAS on the CV-SRP. We employed a cross-sectional study with two groups: ALAS (n = 30) and healthy controls (n = 30). The CV-SRP of the soleus, fibularis longus, and tibialis anterior was assessed using the H-index method. As secondary outcomes, H-reflex and M-wave latencies were assessed as well as acute symptoms including ankle swelling, pain, and self-reported ankle function. Separate group-by-limb ANOVA with repeated measures revealed a significant interaction for soleus CV-SRP (p < 0.001) and H-reflex latency (p < 0.001), showing significant slower CV-SRP and longer H-reflex latency in the involved limb of the ALAS group compared with both limbs in the control group. However, there was no significant interaction or main effect in any other ankle muscles (p > 0.05). A further correlation analysis showed a significant relationship between CV-SRP and acute symptoms, including ankle swelling (r = −0.37, p = 0.048) and self-reported ankle function (r = 0.44, p = 0.017) in ALAS patients. These results suggest a disrupted functionality of the afferent pathway and/or synaptic transmission following ALAS. Level of Evidence: 4.

Abstract Background Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1–3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable. Methods This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints. Results Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2–6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not. Conclusions The RP2D is tolerable and has preliminary activity in recurrent women’s cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients. Trial registration ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.

Neural changes in the ankle stabilizing muscles following ankle sprains are thought to be one contributing factor to persistent ankle dysfunction. However, empirical evidence is limited. Therefore, we aimed to examine spinal reflex excitability of lower leg muscles following acute ankle sprains (AAS). We performed a case-control study with 2 groups consisting of 30 young adults with AAS and 30 aged-matched uninjured controls. Hoffmann reflex (H-reflex) testing was performed to estimate spinal reflex excitability of lower leg muscles: soleus, fibularis longus (FL), tibialis anterior (TA). Maximal H-reflex (Hmax) and motor responses (Mmax) were determined by delivering a series of electrical stimuli at the sciatic nerve. Hmax/Mmax ratios were calculated to represent normalized spinal reflex excitability. Separate group-by-limb analyses of variance (ANOVA) with repeated measures found there were no significant interactions for any of the muscles (SL: F1,56 = 0.95, p = 0.33, FL: F1,51 = 0.65, p = 0.42, TA: F1,51 = 1.87, p = 0.18), but there was a significant main effect of group in the soleus (F1,56 = 6.56, p = 0.013), indicating the Hmax/Mmax ratio of soleus in the AAS group was significantly lower bilaterally (AAS = 0.56 ± 0.19, control = 0.68 ± 0.17, p = 0.013), with no significant group differences in the other muscles (FL: F1,51 = 0.26, p = 0.61, TA: F1,51 = 0.93, p = 0.34). The bilateral inhibition of the soleus spinal reflex excitability following AAS may be significant in that it may explain bilateral sensorimotor deficits (postural control deficits) following unilateral injury, and provide insights into additional therapies aimed at the neural change.

Abstract Background Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. Methods Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. Results Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. Conclusions Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. Trial registration ClinicalTrials.gov identifier: NCT02484404.

Background/Aims Thyroid hormones are involved in wide range of glucose metabolism functions. Overt thyroid dysfunctions are related to altered glucose homeostasis. However, it is not conclusive as to whether subtle changes in thyroid hormones within normal ranges can induce alterations in glucose homeostasis. The aim of this study was to evaluate the association between thyroid hormone and glucose homeostasis parameters in subjects without overt thyroid dysfunction based on nationwide population data. Methods In the Sixth Korea National Health and Nutrition Examination Survey 2015 (n = 7,380), data were collected from subjects with insulin and thyroid function measurements who were older than 19-years-old. After the exclusion of 5,837 subjects, a total of 1,543 patients were included in the analysis. Subjects were categorized into the quartiles of the free thyroxine (FT4). Fasting glucose, insulin, homeostatic model assessment of insulin resistance and hemoglobin A1c (HbA1c) levels were considered to be glucose homeostasis parameters. Results Subjects with the highest FT4 quartile showed significantly lower fasting insulin and HbA1c levels. A significant inverse correlation FT4 and HbA1c levels was observed (β = –0.261, p = 0.025). In the logistic regression analysis, the highest quartile of FT4 was demonstrated to lower the risk of HbA1c to a greater degree than the median by approximately 40%, after adjusting for confounders, compared to the lowest quartile (p = 0.028). Conclusions We demonstrated subjects with a lower FT4 quartile exhibited high risk of HbA1c levels above the median value in a representative Korean population. Subjects with the lowest FT4 quartile should be cautiously managed in terms of altered glucose homeostasis.