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Anthrax is caused by Bacillus anthracis and can result in nearly 100% mortality due in part to anthrax toxin. Antimalarial amodiaquine (AQ) acts as a host-oriented inhibitor of anthrax toxin endocytosis. Here, we determined the pharmacokinetics and safety of AQ in mice, rabbits, and humans as well as the efficacy in the fly, mouse, and rabbit models of anthrax infection. In the therapeutic-intervention studies, AQ nearly doubled the survival of mice infected subcutaneously with a B. anthracis dose lethal to 60% of the animals (LD 60 ). In rabbits challenged with 200 LD 50 of aerosolized B. anthracis , AQ as a monotherapy delayed death, doubled the survival rate of infected animals that received a suboptimal amount of antibacterial levofloxacin, and reduced bacteremia and toxemia in tissues. Surprisingly, the anthrax efficacy of AQ relies on an additional host macrophage-directed antibacterial mechanism, which was validated in the toxin-independent Drosophila model of Bacillus infection. Lastly, a systematic literature review of the safety and pharmacokinetics of AQ in humans from over 2 000 published articles revealed that AQ is likely safe when taken as prescribed, and its pharmacokinetics predicts anthrax efficacy in humans. Our results support the future examination of AQ as adjunctive therapy for the prophylactic anthrax treatment.

The aim of the present study was to clarify the relationship between regular LTPA (i.e., 150-300 min of moderate-intensity or 75-150 min of high-intensity physical activity) and happiness among middle-aged and older adults in Taiwan. The cross-sectional study data were obtained from the Taiwan National Physical Activity Survey, a nationally representative survey of the Taiwanese population. A total of 12,687 middle-aged and older adults (45-108 years) were ultimately enrolled in this study. The questionnaire data obtained through this national telephone survey included sociodemographic characteristics, self-reported health status, self-evaluations (comprising height, body weight, and happiness), and zip code of residence. The results suggest a significant positive relationship between regular LTPA and happiness scores; that is, the middle-aged adults who engaged in more LTPA may report higher happiness occurrence than others. This study suggests that regular LTPA is an essential factor influencing happiness. LTPA is an essential form of physical activity that helps middle-aged and older people to relax.

The effects of exposure to atmospheric pollution on the incidence and mortality due to COVID-19 have been studied but not for sulfur dioxide (SO 2 ) in most studies. However, most studies failed to consider important cofounding factors in the estimation of health effects of air pollution. The objective of the study was to assess the short- and long-term effects of air pollution on the COVID-19 risk and fatality in Lombardy and Veneto. Air pollutants were studied based on monitoring station information in Lombardy and Veneto from January 2013 to May 2020. The daily number of cases and deaths of COVID-19 were collected from the reports of the Italian Ministry of Health in Italy. A generalized linear model with the generalized estimating equation method was used to evaluate the effects of short- and long-term exposure to air pollution on the COVID-19 outbreak in Lombardy and Veneto. After adjusting for other covariates, we found that short-term exposure to PM 2.5 and PM 10 had a tendency to increase the incidence and mortality of COVID-19 than long-term exposure, while for other air pollutants, including SO 2 and NO 2 , long-term exposure was more significant than short-term exposure. Both short- and long-term exposure of SO 2 resulted in increased health effects on COVID-19 pandemic. Our findings suggest that exposure to atmospheric pollution has a significant impact on COVID-19 pandemic and call for further researches to deeply investigate this topic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Population aging is creating critical issues in Taiwan, and adults are being forced to maintain productivity at work; in other words, they need to work longer. Therefore, their fitness and health warrant immediate attention. Although the association between health and anthropometric characteristics has been reported, few profiles on Taiwanese adults can be found. The purpose of this study was to provide a suitable reference on the anthropometric data of Taiwanese adults. We recruited 60,056 anthropometric measurements from a representative database. Significant differences were found in every measurement for each gender and age group. Statistically, our results indicated anthropometric differences in different ages. However, CVs showed that the dispersions are minor. This study presents a sufficient profile on Taiwanese adults from a representative database to practitioners and other potential users.

Assessment of T-cell receptor γ gene (TRG) rearrangements is an importants consideration in the diagnostic workup of lymphoproliferative diseases. Although fragment analysis by PCR and capillary electrophoresis (CE) is the current standard of such assessment in clinical molecular diagnostic laboratories, it does not provide sequence information and is only semi-quantitative. Next-generation sequencing (NGS)-based assays are an attractive alternative to the conventional fragment size-based methods, given that they generate results with specific clonotype sequence information and allow for more accurate quantitation. The present study evaluated various test parameters and performance characteristics of a commercially available NGS-based TRG gene-rearrangement assay by testing 101 clinical samples previously characterized by fragment analysis. The NGS TRG assay showed an overall accuracy of 83% and an analytical specificity of 100%. The concordance rates were 88% to 95% in the V γ 1-8, V γ 10, and V γ 11 gene families, but lower in the V γ 9 gene family. This difference was mostly attributed to the incomplete polyclonal symmetry resulting from the two-tube CE assay versus the one-tube design of the NGS assay. The NGS assay also demonstrated strengths in distinguishing clonotypes of the same fragment size. This clinical validation demonstrated robust performance of the NGS-based TRG assay and identified potential pitfalls associated with CE assay design that are important for understanding the observed discrepancies with the CE-based assay., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The development of a new generation of tyrosine kinase inhibitors (TKIs) has improved the treatment response in lung adenocarcinomas. However, acquired resistance often occurs due to new epidermal growth factor receptor (EGFR) mutations. In particular, the C797S mutation confers drug resistance to T790M-targeting EGFR TKIs. To address C797S resistance, a promising therapeutic avenue is combination therapy that targets both total EGFR and acquired mutations to increase drug efficacy. We showed that combining vorinostat, a histone deacetylase inhibitor (HDACi), with brigatinib, a TKI, enhanced antitumor effects in primary culture and cell lines of lung adenocarcinomas harboring EGFR L858R/T790M/C797S mutations (EGFR-3M). While EGFR phosphorylation was decreased by brigatinib, vorinostat reduced total EGFR-3M (L858R/T790M/C797S) proteins through STUB1-mediated ubiquitination and degradation. STUB1 preferably ubiquitinated other EGFR mutants and facilitated protein turnover compared to EGFR-WT. The association between EGFR and STUB1 required the functional chaperone-binding domain of STUB1 and was further enhanced by vorinostat. Finally, STUB1 levels modulated EGFR downstream functions. Low STUB1 expression was associated with significantly poorer overall survival than high STUB1 expression in patients harboring mutant EGFR. Vorinostat combined with brigatinib significantly improved EGFR-TKI sensitivity to EGFR C797S by inducing EGFR-dependent cell death and may be a promising therapy in treating C797S-resistant lung adenocarcinomas., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Palladium(II) boronates are recognized as fundamental pre-transmetalation intermediates in Suzuki-Miyaura cross-couplings. While these typically transient species have been detected and studied spectroscopically, it is conspicuous that they have never been isolated since this important reaction was discovered over forty years ago. This study reports the synthesis of a family of unprecedented arylpalladium(II) boronates that are, by design, kinetically stable at ambient temperature, both in solution and in the solid state. These properties enabled unambiguous crystallographic confirmation of their structure for the first time and their chemical competence in a Suzuki-Miyaura reaction was demonstrated., (© 2021 Wiley-VCH GmbH.)

Current clinical trials of combined EGFR-tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) therapies show no additional effect. This raises questions regarding whether EGFR-TKIs attenuate ICB-enhanced CD8 + T lymphocyte function. Here we show that the EGFR-TKI afatinib suppresses CD8 + T lymphocyte proliferation, and we identify CAD, a key enzyme of de novo pyrimidine biosynthesis, to be a novel afatinib target. Afatinib reduced tumor-infiltrating lymphocyte numbers in Lewis lung carcinoma (LLC)-bearing mice. Early afatinib treatment inhibited CD8 + T lymphocyte proliferation in patients with non-small cell lung cancer, but their proliferation unexpectedly rebounded following long-term treatment. This suggests a transient immunomodulatory effect of afatinib on CD8 + T lymphocytes. Sequential treatment of afatinib with anti-PD1 immunotherapy substantially enhanced therapeutic efficacy in MC38 and LLC-bearing mice, while simultaneous combination therapy showed only marginal improvement over each single treatment. These results suggest that afatinib can suppress CD8 + T lymphocyte proliferation by targeting CAD, proposing a timing window for combined therapy that may prevent the dampening of ICB efficacy by EGFR-TKIs. SIGNIFICANCE: This study elucidates a mechanism of afatinib-mediated immunosuppression and provides new insights into treatment timing for combined targeted therapy and immunotherapy. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3270/F1.large.jpg., (©2021 American Association for Cancer Research.)

Magnetic nanoparticles (MNPs) subjected to external alternating magnetic field can induce heat in MNPs due to hysteresis, which is usually employed for tumor hyperthermia. An effective hyperthermia treatment should selectively kill the tumor cells without damaging the ambient healthy tissue. Hence, it is important for hyperthermia to correctly control the alternating magnetic field-induced temperature of MNPs in the tumor. This work develops a thermal model to analyze various forms of temperature-rise with time in magnetic nanoparticles for tumor hyperthermia. Results show that there are horizontal, linear rise, square root, exponential decay and abrupt temperature-rise lines with time in MNPs. The horizontal, linear rise, and square root temperature lines with time are consistent with the available experimental data. It is worthily noted that the form of abrupt temperaturerise with time can result in harm to the normal cells or tissue. If the abrupt temperature-rise does not be controlled and predicted well.

Background: Giardia lamblia differentiates into resistant cysts as an established model for dormancy. Myeloid leukemia factor (MLF) proteins are important regulators of cell differentiation. Giardia possesses a MLF homolog which was up-regulated during encystation and localized to unknown cytosolic vesicles named MLF vesicles (MLFVs)., Methods: We used double staining for visualization of potential factors with role in protein metabolism pathway and a strategy that employed a deletion mutant, CDK2m3, to test the protein degradation pathway. We also explored whether autophagy or proteasomal degradation are regulators of Giardia encystation by treatment with MG132, rapamycin, or chloroquine., Results: Double staining of MLF and ISCU or CWP1 revealed no overlap between their vesicles. The aberrant CDK2m3 colocalized with MLFVs and formed complexes with MLF. MG132 increased the number of CDK2m3-localized vesicles and its protein level. We further found that MLF colocalized and interacted with a FYVE protein and an ATG8-like (ATG8L) protein, which were up-regulated during encystation and their expression induced Giardia encystation. The addition of MG132, rapamycin, or chloroquine, increased their levels and the number of their vesicles, and inhibited the cyst formation. MLF and FYVE were detected in exosomes released from culture., Conclusions: The MLFVs are not mitosomes or encystation-specific vesicles, but are related with degradative pathway for CDK2m3. MLF, FYVE, and ATG8L play a positive role in encystation and function in protein clearance pathway, which is important for encystation and coordinated with Exosomes., General Significance: MLF, FYVE, and ATG8L may be involved an encystation-induced protein metabolism during Giardia differentiation., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Circulating tumor cells (CTCs) are associated with tumor spread, whereas cancer stem cells may be related to drug resistance. However, few studies have analyzed the levels of circulating cancer stem cells (CCSCs) and CTCs in patients with advanced non-small cell lung cancer (NSCLC)., Materials and Methods: Treatment-naïve patients with EGFR-mutated NSCLC who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy were recruited prospectively. The cell surface vimentin antibody was used for CTC detection and CD133 antibody for CCSC detection. CCSC and CTC levels were measured as cell count per 4 mL of blood, before treatment, after 2 and 12 weeks of treatment, and at disease progression. Data on clinical characteristics and outcomes were also collected., Results: At diagnosis (n = 29), the median CCSC and CTC levels were 0 (interquartile range, 0-2) and 3 (2-9), respectively. After 12 weeks, the CCSC and CTC levels were lower than those at diagnosis (CCSC: 0 (0-0), p = 0.14; CTC: 1 (0-4), p = 0.048). At disease progression, the median CCSC and CTC levels were 0 (0-1) and 1 (0-2), respectively. Patients with higher CCSC and CTC levels at diagnosis had a numerically shorter progression-free survival., Conclusion: In patients with EGFR-mutated NSCLC, CCSC and CTC levels became lower after 12 weeks of EGFR-TKI therapy and remained low at disease progression. High pre-treatment CCSC and CTC levels may be associated with a trend towards poor treatment outcomes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Alcohol consumption is one of the modifiable risk factors for intracerebral hemorrhage, which accounts for approximately 10-20% of all strokes worldwide. We evaluated the association of stroke with genetic polymorphisms in the alcohol metabolizing genes, alcohol dehydrogenase 1B (ADH1B, rs1229984) and aldehyde dehydrogenase 2 (ALDH2, rs671) genes based on alcohol consumption., Methods: Data were available for 19,500 Taiwan Biobank (TWB) participants. We used logistic regression models to test for associations between genetic variants and stroke. Overall, there were 890 individuals with ischemic stroke, 70 with hemorrhagic stroke, and 16,837 control individuals. Participants with ischemic but not hemorrhagic stroke were older than their control individuals (mean  ±  SE, 58.47 ± 8.17 vs. 48.33 ± 10.90 years, p  <  0.0001). ALDH2 rs671 was not associated with either hemorrhagic or ischemic stroke among alcohol drinkers. However, the risk of developing hemorrhagic stroke was significantly higher among ADH1B rs1229984 TC  +  CC individuals who drank alcohol (odds ratio (OR), 4.85; 95% confidence interval (CI) 1.92-12.21). We found that the test for interaction was significant for alcohol exposure and rs1229984 genotypes (p for interaction  =  0.016). Stratification by alcohol exposure and ADH1B rs1229984 genotypes showed that the risk of developing hemorrhagic stroke remained significantly higher among alcohol drinkers with TC  +  CC genotype relative to those with the TT genotype (OR, 4.43, 95% CI 1.19-16.52)., Conclusions: Our study suggests that the ADH1B rs1229984 TC  +  CC genotype and alcohol exposure of at least 150 ml/week may increase the risk of developing hemorrhagic stroke among Taiwanese adults.

Background: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear., Materials and Methods: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for <5 Y. Plasma cell-free DNA (cfDNA) samples were collected from patient subsets, pre- and post-TKI, in the >5 Y group., Results: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and <5 Y groups, respectively. Significant factors in the multivariate analysis of patients' characteristics including Eastern Cooperative Oncology Group performance status 0-1, postoperative recurrence, without brain metastasis, oligometastasis (each score of 2), female sex, erlotinib use, and without bone metastasis (each score of 1), were incorporated into a risk scoring system. The area under the receiver operating characteristic curve was 0.82 [95% confidence interval (CI): 0.78-0.86]. Of the plasma cfDNA samples from 33 patients in the ⩾5 Y group, only 1 had a T790M in 25 patients without progressive disease. In 27 patients with single agent use for ⩾96 months, 22 (81.5%) received local treatment (surgery or radiotherapy) for the primary lung tumor before and during TKI treatment., Conclusion: For NSCLC patients with single first-generation EGFR-TKI use for ⩾5 Y, factors with different relative importance exist and the risk-scoring model is feasible with modest accuracy. The role of local treatment for primary tumors in patients with long-term TKI use requires further investigation., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Epidemiological studies have demonstrated an association between ambient particulate matter (PM) exposure and vascular diseases. Here, we observed that treatment with ambient PM increased cell migration ability in vascular smooth muscle cells (VSMCs) and pulmonary arterial SMCs (PASMCs). These results suggest that VSMCs and PASMCs transitioned from a differentiated to a synthetic phenotype after PM exposure. Furthermore, treatment with PM increased intracellular reactive oxygen species (ROS), activated the NF-κB signaling pathway, and increased the expression of proinflammatory cytokines in VSMCs. Using specific inhibitors, we demonstrated that PM increased the migration ability of VSMCs via the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1)/ROS-dependent NF-κB signaling pathway, which also partially involved in the induction of proinflammatory cytokines. Finally, we investigated whether nature polyphenolic compounds prevent PM-induced migration and proinflammatory cytokines secretion in VSMCs. Curcumin, resveratrol, and gallic acid prevented PM 2.5 -induced migration via the ROS-dependent NF-κB signaling pathway. However, honokiol did not prevent PM 2.5 -induced migration or activation of the ROS-dependent NF-κB signaling pathway. On the other hand, all polyphenols prevented PM 2.5 -induced cytokines secretion. These data indicated that polyphenols prevented PM-induced migration and cytokine secretion via blocking the ROS-dependent NF-κB signaling pathway in VSMCs. However, other mechanisms may also contribute to PM-induced cytokine secretion.

Biological control commonly involves the commercialization and introduction of natural enemies. Phytoseiulus persimilis Athias-Henriot, a mite species widely used in the control of spider mites, was imported to Taiwan in the 1990s and was mass-reared and released into the field. However, none have been observed in comprehensive surveys of phytoseiid mites for over 30 years. In this study, the distribution of P. persimilis in Taiwan was predicted, and environmental variables that affect its distribution were analyzed. The mountainous region of southcentral Taiwan was determined to be suitable for the establishment of this species, whereas the four sites at which it was released in the 1990s, particularly those in southwestern Taiwan, exhibited low suitability. Notably, the minimum temperature of the coldest month was identified as a crucial limiting factor affecting the distribution of P. persimilis , indicating that a Mediterranean climate is more suitable for this species. To the best of our knowledge, this study is the first to predict the suitable distribution of exotic predatory mites in a biological control program. The present findings serve as a pivotal assessment framework for the commercialization and foreign introduction of natural enemies.

Background: Malignant pleural effusion (MPE)-macrophage (Mφ) of lung cancer patients within unique M1/M2 spectrum showed plasticity in M1-M2 transition. The M1/M2 features of MPE-Mφ and their significance to patient outcomes need to be clarified; furthermore, whether M1-repolarization could benefit treatment remains unclear., Methods: Total 147 stage-IV lung adenocarcinoma patients undergoing MPE drainage were enrolled for profiling and validation of their M1/M2 spectrum. In addition, the MPE-Mφ signature on overall patient survival was analyzed. The impact of the M1-polarization strategy of patient-derived MPE-Mφ on anti-cancer activity was examined., Results: We found that MPE-Mφ expressed both traditional M1 (HLA-DRA) and M2 (CD163) markers and showed a wide range of M1/M2 spectrum. Most of the MPE-Mφ displayed diverse PD-L1 expression patterns, while the low PD-L1 expression group was correlated with higher levels of IL-10. Among these markers, we identified a novel two-gene MPE-Mφ signature, IL-1β and TGF-β1, representing the M1/M2 tendency, which showed a strong predictive power in patient outcomes in our MPE-Mφ patient cohort (N = 60, p = 0.013) and The Cancer Genome Atlas Lung Adenocarcinoma dataset (N = 478, p < 0.0001). Significantly, β-glucan worked synergistically with IFN-γ to reverse the risk signature by repolarizing the MPE-Mφ toward the M1 pattern, enhancing anti-cancer activity., Conclusions: We identified MPE-Mφ on the M1/M2 spectrum and plasticity and described a two-gene M1/M2 signature that could predict the outcome of late-stage lung cancer patients. In addition, we found that "re-education" of these MPE-Mφ toward anti-cancer M1 macrophages using clinically applicable strategies may overcome tumor immune escape and benefit anti-cancer therapies.

Purpose . This study aims to evaluate the performance of a commercial 1.5 T MR-Linac by analyzing its patient-specific quality assurance (QA) data collected during one full year of clinical operation. Methods and Materials . The patient-specific QA system consisted of offline delivery QA (DQA) and online calculation-based QA. Offline DQA was based on ArcCHECK-MR combined with an ionization chamber. Online QA was performed using RadCalc that calculated and compared the point dose calculation with the treatment planning system (TPS). A total of 24 patients with 189 treatment fractions were enrolled in this study. Gamma analysis was performed and the threshold that encompassed 95% of QA results (T95) was reported. The plan complexity metric was calculated for each plan and compared with the dose measurements to determine whether any correlation existed. Results . All point dose measurements were within 5% deviation. The mean gamma passing rates of the group data were found to be 96.8 ± 4.0% and 99.6 ± 0.7% with criteria of 2%/2mm and 3%/3mm, respectively. T95 of 87.4% and 98.2% was reported for the overall group with the two passing criteria, respectively. No statistically significant difference was found between adaptive treatments with adapt-to-position (ATP) and adapt-to-shape (ATS), whilst the category of pelvis data showed a better passing rate than other sites. Online QA gave a mean deviation of 0.2 ± 2.2%. The plan complexity metric was positively correlated with the mean dose difference whilst the complexity of the ATS cohort had larger variations than the ATP cohort. Conclusions . A patient-specific QA system based on ArcCHECK-MR, solid phantom and ionization chamber has been well established and implemented for validation of treatment delivery of a 1.5 T MR-Linac. Our QA data obtained over one year confirms that good agreement between TPS calculation and treatment delivery was achieved., (© 2021 IOP Publishing Ltd.)

Objective: Osteopontin (OPN) is involved in vascular calcification and atherosclerosis. We evaluated the association between serum OPN levels and the first postoperative hospitalization and all-cause mortality in patients who received kidney transplantation (KT)., Materials and Methods: Seventy KT recipients were enrolled in this study from January to April 2012. The primary end point was first postoperative hospitalization or death. All patients were monitored in the outpatient clinics until June 30, 2017. Serum OPN level was measured by enzyme-linked immunosorbent assay., Results: During follow-up (median length, 65 months), 47 first postoperative hospitalizations and 8 deaths occurred. In comparison with serum median OPN levels, serum OPN level was positively associated with KT duration ( P = 0.048), serum blood urea nitrogen (BUN; P = 0.043), and serum creatinine levels ( P = 0.045) but negatively associated with estimated glomerular filtration rate (eGFR; P = 0.049). Hospitalized KT recipients had a higher prevalence of diabetes mellitus (DM) ( P = 0.032), BUN ( P = 0.002), and serum OPN level ( P = 0.001) but lower eGFR ( P = 0.030) than did patients not hospitalized. KT recipients who died had higher serum level of creatinine ( P = 0.009) and OPN ( P = 0.001) but lower eGFR ( P = 0.036) than did surviving patients. Multivariate Cox analysis adjusted for age, gender, DM, hypertension, eGFR, KT duration, and steroid used showed that serum OPN level was associated with both first postoperative hospitalization ( P = 0.049) and all-cause mortality ( P = 0.017)., Conclusions: Serum OPN level is a potential biomarker for first postoperative hospitalization and all-cause mortality in KT recipients., Competing Interests: Dr. Bang-Gee Hsu and Dr. Ming-Che Lee, the editorial board members at Tzu Chi Medical Journal, had no roles in the peer review process of or decision to publish this article. The other authors declared that they have no conflicts of interest., (Copyright: © 2021 Tzu Chi Medical Journal.)

Skin pigmentation is resulted from several processes, such as melanin synthesis transportation and abnormal melanin accumulation in keratinocytes. Various studies have suggested that seven traditional Chinese herbal extracts from Atractylodes macrocephala, Paeonia lactiflora, Bletilla striata, Poria cocos, Dictamnus dasycarpus, Ampelopsis japonica and Tribulus terrestris (which we collectively named ChiBai), show several protective effects toward skin-related diseases. Lactobacillus rhamnosus, a lactic acid bacterium, has been reported to treat skin inflammation and atopic dermatitis. In this study, the broth produced by the cofermentation of ChiBai with Lactobacillus rhamnosus was studied for its effects on skin pigmentation through in vitro and in vitro experiments. In the in vitro experiments, we found that the fermented broth of ChiBai (FB-ChiBai) suppressed alpha-melanocyte stimulating hormone (α-MSH)-induced melanogenesis in B16F0 murine melanoma cells without any cytotoxicity at a concentration of 0.5%. FB-ChiBai significantly attenuated melanin production, tyrosinase activities and melanogenesis-related signaling pathways. Treatment with FB-ChiBai also reduced the nuclear translocation and promoter binding activities of MITF. In the in vivo experiments, FB-ChiBai was topically applied to the dorsal skin of C57BL/6J nude mice and concurrently irradiated with UVB, three times a week for 8 weeks. The results indicated that FB-ChiBai alleviated UVB-induced hyperpigmentation by reducing epidermal hyperplasia and inhibiting the CREB/MITF/tyrosinase pathway. In conclusion, our data indicated that the anti-melanogenic effects of FB-ChiBai are mediated by the inhibition of CREB/MITF/tyrosinase signaling pathway. The findings suggest that FB-ChiBai can protect against UV-B irradiation and that it might be used as an agent in cosmetic products to protect against UVB-induced hyperpigmentation., (© 2020 Wiley Periodicals LLC.)

The present study tested the hypothesis that 30 low-intensity (10%) eccentric contractions (10%EC) or two maximal voluntary isometric contractions at a long muscle length (2MVIC) that were performed at two days before maximal eccentric exercise of the elbow flexors consisting of five sets of six maximal eccentric contractions (MaxEC) would reduce increases in biceps brachii distal myotendinous junction displacement (MTJd) over the eccentric contractions during MaxEC. Sedentary young men were randomly placed (n = 12/group) to a control group that performed two bouts of MaxEC (CONT-1st, CONT-2nd) separated by two weeks, or one of two preconditioning groups that performed 10%EC or 2MVIC at 20° elbow flexion at two days prior to MaxEC. All exercises were performed by the non-dominant arm. MTJd of each contraction was assessed by B-mode ultrasound, and its changes over sets were compared among the groups. The average MTJd from the start to the end of six eccentric contractions in the first set was similar among the groups (6.4 ± 0.7 mm). The MTJd increased from the first to fifth set, but the increase was smaller (P < .05) for the 10%EC (13 ± 6%) and 2MVIC (16 ± 9%) groups, and CONT-2nd (3 ± 6%) when compared with CONT-1st (60 ± 12%). Both 10%EC and 2MVIC groups showed smaller (P < .05) changes in all muscle damage markers after MaxEC similarly when compared with CONT-1st, but the changes were greater than those after CONT-2nd. These results supported the hypothesis that protective effect was associated with less MTJd changes, suggesting that this is associated with the mechanisms underpinning the preconditioning effect on muscle damage., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Ultraviolet (UV) irradiation is a crucial factor that leads to skin photoaging and results in increased DNA damage, oxidative stress, and collagen degradation. Jasmine flowers have been utilized as a traditional medicine in Asia to treat various diseases, including dermatitis, diarrhea, and fever. Furthermore, the fermented broth of Lactobacillus rhamnosus has been reported to exert protective effects on the skin. In the present study, jasmine flower extract was fermented with L. rhamnosus. We investigated the antioxidant and collagen-promoting effects on UVB/H 2 O 2 -induced HS68 dermal fibroblast cell damage. The results indicated that treatment with the fermented flower extracts of Jasminum sambac (F-FEJS) could enhance the viability of HS68 cells. Furthermore, the UVB/H 2 O 2 -induced excessive production of reactive oxygen species, degradation of collagen, activation of MAPKs, including P38, ERK, and JNK, and premature senescence were remarkably attenuated by F-FEJS in dermal fibroblast cells. The nuclear accumulation of p-c-jun, which is downstream of MAPK, and the inactivation of p-smad2/3, which is one of the crucial transcription factors that enhance collagen synthesis, were reversed in response to F-FEJS treatment in UVB/H 2 O 2 -exposed cells. Notably, the expression of antioxidant genes, such as HO-1, and the nuclear translocation of Nrf2 were further enhanced by F-FEJS in UVB/H 2 O 2 -treated cells. Interestingly, the F-FEJS-induced increase in ARE luciferase activity indicated the activation of Nrf2/ARE signaling. In conclusion, our findings demonstrated that F-FEJS can effectively ameliorate UVB/H 2 O 2 -induced dermal cell aging and may be considered a promising ingredient in skin aging therapy., (© 2020 Wiley Periodicals LLC.)

Objectives: Myostatin is a myokine predominantly expressed and secreted in skeletal muscle in response to stimulations, including oxidative stress or inflammation. We investigated a potential association between myostatin levels and endothelial function among kidney transplantation (KT) patients., Materials and Methods: Fasting blood samples were collected from 64 KT patients. The endothelial function that indicated by vascular reactivity index (VRI) was measured by digital thermal monitoring test. Serum myostatin levels were measured using a commercial enzyme-linked immunosorbent assay kit. All patients were categorized into three groups according to their VRI values: poor vascular reactivity was considered if VRI <1.0; 1.0 ≤VRI <2.0 indicated intermediate vascular reactivity, and VRI ≥2.0 was grouped as good vascular reactivity., Results: Seven KT patients (10.9%) were categorized as poor vascular reactivity, 24 KT patients (37.5%) were grouped as intermediate vascular reactivity, and 33 KT patients had good vascular reactivity. Advanced age ( r = -0.372, P = 0.002) and serum alkaline phosphate (ALP) level ( r = -0.341, P = 0.006) were negatively correlated with VRI. However, serum myostatin level ( r = 0.430, P < 0.001) was positively correlated with VRI. In multivariable forward stepwise linear regression analysis, high serum level of myostatin (β = 0.441, adjusted R 2 change = 0.171; P < 0.001), advanced age (β = -0.317, adjusted R 2 change = 0.138; P = 0.003), and serum ALP level (β = -0.270, adjusted R 2 change = 0.060; P = 0.011) were significantly associated with VRI in KT patients., Conclusion: Our study showed that fasting myostatin level was positively associated with VRI and endothelial function among KT patients., Competing Interests: Dr. Bang-Gee Hsu and Dr. Ming-Che Lee, the editorial board members at Tzu Chi Medical Journal, had no roles in the peer review process of or decision to publish this article. The other authors declared that they have no conflicts of interest., (Copyright: © 2021 Tzu Chi Medical Journal.)

Background: The relationship between sleep duration and physical fitness is one aspect of sleep health. Potential factors associated with sleep duration interfere with physical fitness performance, but the impact trends on physical fitness indicators remain unclear., Methods: This study examined associations between sleep duration and physical fitness among young to middle-aged adults in Taiwan. A total of 42,781 Taiwanese adults aged 23-45 participated in the National Physical Fitness Examination Survey 2013 (NPFES-2013) in Taiwan between October 2013 and March 2014. A standardized structural questionnaire was used to record participants' sleep duration, which was stratified as short (< 6 h/day (h/d)), moderate (6-7 h/d; 7-8 h/d; 8-9 h), and long (≥ 9 h/d) sleep duration groups. Physical fitness was assessed based on four components: body composition (body mass index [BMI], waist-to-height ratio [WHtR], and waist-to-hip ratio [WHR]), muscle strength and endurance (1-min bent-leg sit-up test [BS]), flexibility (sit-and-reach test [SR]), and cardiorespiratory endurance index (3-min step test [CEI])., Results: By using analysis of covariance (ANCOVA), after sex grouping and age adjustment, we observed that sleep duration was significantly associated with obesity, functional fitness, and self-perception of health. The sleep duration for low obesity-related values (BMI, WHtR, and WHR) for men was 7-9 h/d, and that for women was 7-8 h/d. Sleeping more than 8 h/d showed poor functional fitness performances (BS and SR). For both sexes, sleep duration of 8-9 h/d was the optimal sleep duration for self-perceptions of health., Conclusions: Our research found that there were wide and different associations of sleep duration with physical fitness and self-perception of health among Taiwanese adults aged 23-45, and there were differences in these associated manifestations between men and women. This study could be of great importance in regional public health management in Taiwan, and provide inspirations for clinical research on physical fitness.

This study investigated the risk of insomnia and hypnotics use among emergency physicians. This cross-sectional study recruited physicians working in Taiwanese hospitals in 2015 and the general population as the participants. Data from 1,097 emergency physicians obtained from the National Health Insurance Research Database were grouped into the case group, whereas 14,112 nonemergency physicians and 4,388 people from the general population were categorized into the control groups. This study used logistic regression and conditional logistic regression to compare the risks of insomnia between emergency and nonemergency physicians and between emergency physicians and the general population, respectively. The prevalence of insomnia among emergency physicians, nonemergency physicians and general population was 5.56%, 4.08%, and 1.73%, respectively. Compared with nonemergency physicians and the general population, emergency physicians had a significantly higher risk of insomnia. The proportions of emergency physicians, nonemergency physicians, and general population using hypnotics were 19.96%, 18.24%, and 13.26%, respectively. Among emergency physicians who used hypnotics, 49.77%, 25.57%, and 24.66% used only benzodiazepines, only nonbenzodiazepines, and both benzodiazepines and nonbenzodiazepines, respectively. Nonpharmacological interventions to improve insomnia and reminder of safe use of hypnotics to emergency physicians can serve as references for hospitals in developing health-promoting activities.

Background: The purpose of the present study was to investigate the associations between health-related physical fitness performance and overweight/obesity risk among Taiwanese healthy older adults., Methods: A secondary dataset from the nationwide survey was applied in this study. Data from a total of 21,630 respondents aged 65-96 years were collected in this study. Demographic characteristics, life habits, perceived health status, anthropometric assessments, and health-related physical fitness measurements from this dataset were analyzed using the chi-square test, one-way analysis of variance, and logistic regression analysis., Results: The results indicated that overweight and obesity significantly associated with health-related physical fitness performance in the Taiwanese older adult population. In particular, the upper extremity muscular endurance scores of older adults with poor activity and physical fitness scores revealed obesity as a critical indicator of health-related physical fitness performance., Conclusions: Future studies can use muscle quality or body fat classification to predict obesity in older adults, which could more precisely portray the relationship between obesity and health-related physical fitness performance.

Purpose: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) show efficacy in treating patients with lung adenocarcinoma with EGFR -activating mutations. However, a significant subset of targeted patients fail to respond. Unlike acquired resistance (AR), intrinsic resistance (IR) remains poorly understood. We investigated whether epigenomic factors contribute to patient-to-patient heterogeneity in the EGFR-TKI response and aimed to characterize the IR subpopulation that obtains no benefit from EGFR-TKIs., Patients and Methods: We conducted genome-wide DNA methylation profiling of 79 tumors sampled from patients with advanced lung adenocarcinoma before they received EGFR-TKI treatment and analyzed the patient responses. Pyrosequencing was performed in a validation cohort of 163 patients with EGFR -activating mutations., Results: A DNA methylation landscape of 216 CpG sites with differential methylation was established to elucidate the association of DNA methylation with the characteristics and EGFR-TKI response status of the patients. Functional analysis of 37 transcription-repressive sites identified the enrichment of transcription factors, notably homeobox ( HOX ) genes. DNA methylation of HOXB9 (cg13643585) in the enhancer region yielded 88% sensitivity for predicting drug response (odds ratio [OR], 6.64; 95% CI, 1.98 to 25.23; P = .0009). Pyrosequencing validated that HOXB9 gained methylation in patients with a poor EGFR-TKI response (OR, 3.06; 95% CI, 1.13 to 8.19; P = .019)., Conclusion: Our data suggest that homeobox DNA methylation could be a novel tumor cellular state that can aid the precise categorization of tumor heterogeneity in the study of IR to EGFR-TKIs. We identified, for the first time, an epigenomic factor that can potentially complement DNA mutation status in discriminating patients with lung adenocarcinoma who are less likely to benefit from EGFR-TKI treatment, thereby leading to improved patient management in precision medicine., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Chao-Chi HoConsulting or Advisory Role: Boehringer Ingelheim, Eli Lilly, Roche/Genentech/Chugai, BMS, Ono Speakers' Bureau: Boehringer Ingelheim, Eli Lilly, Roche/Genentech/Chugai, MSD, Pfizer, Novartis, BMS, Ono Research Funding: AstraZeneca No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Global trade has increased the invasion risk of exotic organisms and damaged agricultural and natural ecosystems. The Bureau of Animal and Plant Health Inspection and Quarantine (BAPHIQ) handles quarantine services of animal- and plant-associated pests and diseases in Taiwan. The predatory mite family Phytoseiidae (Acari: Mesostigmata) is a well-known group due to the potential use of certain species as biocontrol agents for small phytophagous pests. Some species are available in commercial markets and frequently used in biological control in many agricultural systems, especially in greenhouse crops. However, exotic biological control agents may interfere with natural or naturalised populations of predatory mites and they may threaten indigenous populations via intraguild predation. The present study aims to provide a checklist of phytoseiid mite species found in plant quarantine from 2006-2013. Twenty-five species belonging to two subfamilies and eight genera were found in samples imported to Taiwan from twelve countries, including one new species Typhlodromus (Anthoseius) ueckermanni sp. nov. from South Africa. The checklist provides distribution, remarks, and also an identification key for all species.

Background: Quality of life and functional improvement have emerged as important goals for patients with oncologic disease. For patients with head and neck cancer, free anterolateral thigh (ALT) flaps serve as reliable reconstruction and provide functional restoration. Nevertheless, factors affecting the resumption of oral feeding are rarely described. This study aimed to evaluate and compare the functional outcomes of oral feeding for patients with different oncologic defect patterns and reconstructive ALT flap designs., Methods: We retrospectively reviewed patients with head and neck cancer undergoing oncologic ablation and free ALT reconstruction between January 2016 and April 2018 at National Taiwan University Hospital. Patients were categorized into 2 groups as through-and-through (T&T) and non-through-and-through (non-T&T) according to the defect pattern. We further subgrouped T&T patients into lip resection/lip sparing according to lip involvement. Reconstructive ALT flaps were of 2 designs, folded (F-ALT) and chimeric (C-ALT). Outcomes of oral feeding were analyzed using descriptive statistics, and differences between groups were compared using the Student t test., Results: We identified 233 patients who received oncologic ablation and free ALT flap reconstruction. There was no significant difference in functional recovery between the T&T and non-T&T groups (81.2% vs 73%, P = 0.137). However, among patients who succeeded in resuming oral feeding, lip-sparing patients had better functional recovery in terms of early oral feeding within 6 months and nasogastric tube removal compared with lip-resection patients (100% vs 83.3%, P = 0.001). Moreover, the F-ALT design resulted in a higher success rate in resuming oral feeding compared with the C-ALT design (90.5% vs 54.6%, P = 0.032)., Conclusions: Patients with head and neck cancer with T&T defects were associated with higher rates of secondary flap revision and a trend of delayed oral feeding. In the long term, improved oral feeding outcome with the F-ALT design was observed compared with the C-ALT design in the specific group with T&T defect., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The capacity to synthesize a protective cyst wall is critical for infectivity of Giardia lamblia . It is of interest to know the mechanism of coordinated synthesis of three cyst wall proteins (CWPs) during encystation, a differentiation process. Multiprotein bridging factor 1 (MBF1) gene family is a group of transcription coactivators that bridge various transcription factors. They are involved in cell growth and differentiation in yeast and animals, or in stress response in fungi and plants. We asked whether Giardia has MBF1-like genes and whether their products influence gene expression. BLAST searches of the Giardia genome database identified one gene encoding a putative MBF1 protein with a helix-turn-helix domain. We found that it can specifically bind to the AT-rich initiator promoters of the encystation-induced cwp1-3 and myb2 genes. MBF1 localized to cell nuclei and cytoplasm with higher expression during encystation. In addition, overexpression of MBF1 induced cwp1-3 and myb2 gene expression and cyst generation. Mutation of the helixes in the helix-turn-helix domain reduced cwp1-3 and myb2 gene expression and cyst generation. Chromatin immunoprecipitation assays confirmed the binding of MBF1 to the promoters with its binding sites in vivo. We also found that MBF1 can interact with E2F1, Pax2, WRKY, and Myb2 transcription factors that coordinately up-regulate the cwp genes during encystation. Using a CRISPR/Cas9 system for targeted disruption of mbf1 gene, we found a downregulation of cwp1-3 and myb2 genes and decrease of cyst generation. Our results suggest that MBF1 is functionally conserved and positively regulates Giardia cyst differentiation.

In this study, laser processing equipment was used to drill aluminum alloy materials and with different auxiliary mechanisms, the deformation around the holes after processing was observed. The experimental results show that, due to the high temperature generated during laser processing, a large thermal gradient causes thermal stress to be introduced into the test piece and outward expansion deformation occurs. In this study, the digital image correlation and residual stress detection methods were applied. Based on the correlation between the drilled hole depth and the hole deformation, the hole depth of the laser processing was estimated. The average coefficient of determination for all auxiliary mechanisms is 0.82. The experimental results confirm that the digital image correlation method can be used to estimate the hole depth of laser processing.

We have identified and extensively investigated the photochemical activation and reaction of a hydroxyquinone-derived phenyliodonium ylide in the presence of visible light using experiment and theory. These studies revealed that in its photoexcited state this iodonium is capable of facilitating a range of single-electron transfer (SET) processes, including hydrogen atom transfer (HAT), a Povarov-type reaction, and atom-transfer radical addition chemistry. Where possible, we have employed density functional theory (DFT) to develop a more complete understanding of these photoinduced synthetic transformations.

Background and objectives: Respiratory muscle fatigue is one of the important factors limiting sports performance due to the metaboreflex. This reflex will cause a decrease in blood flow to the extremities and accelerate exercising limb fatigue. Previous studies found that inspiratory muscle training (IMT) can effectively enhance the respiratory muscle endurance and reduce fatigue during long-duration exercise or aerobic exercise, thereby enhancing athletic performance. However, the mechanism between inspiratory muscle strength, change of limb blood flow and sports performance still requires investigation, especially in short-duration exercise, anaerobic or both aerobic and anaerobic exercise. The purpose of this study was to investigate the effects of 4-week inspiratory muscle training on respiratory muscle strength, limb blood flow change rate and sports performance in recreational 800-m college runners. Materials and Methods: Twenty healthy 800-m college runners randomized into the IMT group (11 subjects) and control group (9 subjects). IMT consisted of 30 inspiratory efforts twice daily, 5 days a week, with intensity at 50%, 60%, 70% and 80% of maximum inspiratory pressure (MIP) for 4 weeks, while a control group kept 50% of MIP for 4 weeks. An 800-m trial test, limb blood flow change rate by using Impedance Plethysmography, and MIP were as the outcome measured variables and be evaluated. All measured variables were assessed before and after 4-week IMT training. Two-way ANOVA was conducted for statistical analysis. Results: The results showed significantly interaction between groups and pre-posttest. IMT group significantly decreased limb blood flow change rate from 19.91 ± 11.65% to 9.63 ± 7.62% after received the IMT training program ( p < 0.05). The MIP significantly improved from 112.95 ± 27.13 cmH 2 O to 131.09 ± 28.20 cm H 2 O in IMT group, and the 800-m trial test also shorted the running time from 162.97 ± 24.96 s to 156.75 ± 20.73 s. But the control group no significantly changed in MIP and 800-m trial test. Conclusions: Our results indicated that the 4-week IMT training (twice a day, 5 days a week) significantly improves participants' inspiratory muscle strength, 800-m running performance and decreases the limb blood flow change rate.

Abstract: We investigated the association between high-density lipoprotein cholesterol (HDL-C) and rs2014355 variant in the gene, short-chain acyl-coenzyme A dehydrogenase (ACADS) based on exercise habits.Data collected between 2008 and 2015 for individuals aged 30 to 70 years were available in the Taiwan Biobank (TWB) database. Backward stepwise linear regression was used to evaluate the associations of rs2014355 and exercise with HDL-C levels.We analyzed data of 5515 physically active and 4169 inactive biobank participants. The HDL-C concentrations were higher in the exercise compared to no exercise group (beta value, β = 1.79856; P < .0001). We observed that the test for interaction was significant for the ACADS rs2014355 variant and exercise (P for interaction =.0412). Multivariate analyses showed significant association between TC+CC genotype and HDL-C in the exercise (β = 1.09785; P value = .0146) compared to the no-exercise group (β = -0.03754, P = .9154).In summary, the association between HDL-C and exercise differed significantly with respect to ACADS rs2014355 genotypes. Compared to the TT genotype, the TC+CC genotype together with exercise was associated with higher levels of HDL-C., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Sirtuin 3 (SIRT3) is a protein deacetylase regulating β-cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of β-cell-specific SIRT3 on metabolic homeostasis, and its potential effect on other metabolic organs, are unknown. We found that glucose tolerance and glucose-stimulated insulin secretion were impaired in high-fat diet (HFD)-fed β-cell-selective Sirt3 knockout ( Sirt3 f/f;Cre/+ ) mice. In addition, Sirt3 f/f;Cre/+ mice had more severe hepatic steatosis than Sirt3 f/f mice upon HFD feeding. RNA sequencing of islets suggested that Sirt3 deficiency overactivated 5-hydroxytryptamine (5-HT) synthesis as evidenced by upregulation of tryptophan hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum of Sirt3 f/f;Cre/+ mice. 5-HT also facilitated the effect of palmitate to increase lipid deposition. Treatment with TPH1 inhibitor ameliorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3 f/f;Cre/+ mice. These data suggested that under HFD feeding, SIRT3 deficiency in β-cells not only regulates insulin secretion but also modulates hepatic lipid metabolism via the release of 5-HT., (© 2020 by the American Diabetes Association.)

Objectives: Using a prospective longitudinal design, this paper examines a serial mediation model of the associations between self-compassion, trait mindfulness, caregiver stress, and depressive symptoms among the family caregivers of patients with lung cancer., Methods: A four-wave design was used, with initial assessment (T1) and three follow-ups, at the 2 nd month (T2), the 5 th month (T3), and the 8 th month (T4). A total of 123 family caregivers completed the baseline measurements, including caregiver stress, self-compassion, trait mindfulness, and depressive symptoms. Data were analyzed by serial mediation models to determine the causal ordering of these variables., Results: Nearly one-quarter of the family caregivers suffered from clinically significant depressive symptoms and the severity of their depression remained unchanged throughout the 8-month follow-up period. Both cross-sectional and longitudinal path analyses revealed that the relationship between self-compassion and depressive symptoms was mediated sequentially by trait mindfulness and caregiver stress. The subscale analysis indicated that the association of higher compassionate action with fewer depressive symptoms was through chain-mediating effects of higher mindful awareness and lower caregiver stress., Conclusions: Family caregivers who have higher levels of self-compassion tend to have more mindfulness; greater mindfulness leads to lower levels of perceived caregiving stress which, in turn, links to fewer symptoms of depression. Both self-compassion and mindfulness could be regarded as protective factors for caregivers to reduce caregiving stress and depression., Competing Interests: Conflict of InterestThe authors declared that they have no conflicts of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)

Background: The diagnostic yield of peripheral pulmonary lesions (PPLs) using radial endobronchial ultrasound (EBUS) remains challenging without navigation systems. Cone-beam computed tomography-derived augmented fluoroscopy (CBCT-AF) represents a recently developed technique, and its clinical utility remains to be investigated., Objectives: The aim of this study was to investigate the diagnostic yield of transbronchial biopsy (TBB) using a combination of CBCT-AF and radial EBUS., Methods: We recruited consecutive patients with PPLs who underwent radial EBUS-guided TBB, with or without AF, between October 2018 and July 2019. Following propensity score 1:1 matching, we recorded the procedure-related data and measured their efficacy and safety., Results: While 72 patients received EBUS-plus-AF, 235 patients received EBUS only. We included 53 paired patients following propensity score matching. The median size of lesions was 2.8 and 2.9 cm in the EBUS-plus-AF group and EBUS-only group, respectively. Diagnostic yield was higher in the former group (75.5 vs. 52.8%; p = 0.015). The diagnostic yield for the EBUS-plus-AF group was significantly higher for lesions ≤30 mm (73.5 vs. 36.1%; p = 0.002). Moreover, there was no significant difference in the complication rates (3.8 vs. 5.7%; p = 1.000). Twenty-four nodules (45.3%) were invisible by fluoroscopy in the EBUS-plus-AF group. All of them were identifiable on CBCT images and successfully annotated for AF. The mean radiation dose of total procedure, CBCT, and fluoroscopy was 19.59, 16.4, and 3.17 Gy cm2, respectively., Conclusions: TBB using a combination of CBCT-AF and EBUS resulted in a satisfactory diagnostic yield and safety., (© 2021 S. Karger AG, Basel.)

The relationships between different functional fitness performance and abdominal obesity among the elderly have not been widely discussed in the literature. The present study aimed to investigate the associations between functional fitness test performance and abdominal obesity in Taiwanese elderly people. A total of 22,399 items of data from the National Physical Fitness Survey Databases in Taiwan (NPFSD 2014-15) were reviewed and analyzed. The quartiles of functional fitness test results were identified as the dependent variable in the multiple linear regression analysis to examine the association between functional fitness and abdominal obesity status. The results showed that body balance (odds ratios (ORs) listed from 1.18 to 2.29, p < 0.05) and flexibility (ORs listed from 1.23 to 2.16, p < 0.05) were critically associated with abdominal obesity. However, measurements related to muscle strength revealed the limited effect sizes for abdominal obesity. From a disability prevention perspective, the development of muscle strength in the elderly should be emphasized and encouraged to maintain their daily capabilities instead of satisfaction with a lean body., Competing Interests: The authors declare no conflict of interest.

Wound healing is a complex process that requires specific interactions between multiple cells such as fibroblasts, mesenchymal, endothelial, and neural stem cells. Recent studies have shown that calcium silicate (CS)-based biomaterials can enhance the secretion of growth factors from fibroblasts, which further increased wound healing and skin regeneration. In addition, gelatin methacrylate (GelMa) is a compatible biomaterial that is commonly used in tissue engineering. However, it has low mechanical properties, thus restricting its fullest potential for clinical applications. In this study, we infused Si ions into GelMa hydrogel and assessed for its feasibility for skin regeneration applications by observing for its influences on human dermal fibroblasts (hDF). Initial studies showed that Si could be successfully incorporated into GelMa, and printability was not affected. The degradability of Si-GelMa was approximately 20% slower than GelMa hydrogels, thus allowing for better wound healing and regeneration. Furthermore, Si-GelMa enhanced cellular adhesion and proliferation, therefore leading to the increased secretion of collagen I other important extracellular matrix (ECM) remodeling-related proteins including Ki67, MMP9, and decorin. This study showed that the Si-GelMa hydrogels were able to enhance the activity of hDF due to the gradual release of Si ions, thus making it a potential candidate for future skin regeneration clinical applications.

Nonalcoholic fatty liver disease (NAFLD) is considered to be a serious clinical complication, which could cause significant liver dysfunction including fibrosis, cirrhosis, and cancer. Obesity could lead to NAFLD and contributes to liver disorder and related complicated liver diseases. Effect of exercise combined with alcalase treatment derived potato protein hydrolysate (APPH) on high-fat diet (HFD)-induced hepatic injury was investigated in senescence accelerated mouse-prone 8 (SAMP8) mice in the present study. Mice were divided into six groups (n = 6): Group I-Control, Group II-HFD, Group III-Exercise, Group IV-HFD + APPH, Group V-HFD + Exercise, and Group VI-HFD + Exercise + APPH. Combined APPH treatment and exercise offer better cytoprotection in HFD-induced histological changes than APPH treatment and exercise alone. Further, APPH and exercise activate the cell survival proteins PI3K/Akt and prevent FasL/FADD-mediated apoptosis in HFD fed SAMP8 mouse. APPH with swimming exercise effectively modulate HFD-induced liver damage and apoptosis in aged mice through activation of PI3K/Akt protein. PRACTICAL APPLICATIONS: Exercise training is proven to reduce the health problems associated with aging and obesity, however, intensity and duration of the exercise differs between individuals. We used integrated pharmacological and nonpharmacological approach as a therapeutic strategy for preventing HFD-induced hepatic injury in aged subjects., (© 2020 Wiley Periodicals LLC.)

Recommending a retail business given a particular location of interest is nontrivial. Such a recommendation process requires careful study of demographics, trade area characteristics, sales performance, traffic, and environmental features. It is not only human effort taxing but often introduces inconsistency due to subjectivity in expert opinions. The process becomes more challenging when no sales data can be used to make a recommendation. As an attempt to overcome the challenges, this study used the machine learning approach that utilizes similarity measures to perform the recommendation. However, two challenges required careful attention when using the machine learning approach: (1) how to prepare a feature set that can commonly represent different types of retail business and (2) which similarity measure approach produces optimal recommendation accuracy? The data sets used in this study consist of points of interest, population, property, job type, and education level. Empirical studies were conducted to investigate (1) the overall accuracy of proposed similarity measure approaches to the retail business recommendation, and (2) whether the proposed approaches have a bias toward certain retail categories. In summary, the findings suggested that the proposed similarity-based techniques elicited an accuracy of above 70% and demonstrated higher accuracy when the recommendation was made within a set of similar retail businesses.

Background/purpose: There is a lack of data on nivolumab treatment outcomes in Taiwanese patients with advanced or recurrent non-small cell lung cancer (NSCLC) ineligible for radical radiotherapy and resistant to platinum-based chemotherapy. We investigated the safety and efficacy of nivolumab in this population., Methods: In this ongoing, multicenter, open-label, single-arm, phase II study, patients aged ≥20 years with a performance status of 0-1 and stage IIIB/IV or recurrent NSCLC received nivolumab 3 mg/kg every 2 weeks in 6-week cycles. Interim data obtained between 27 January 2016 and 21 May 2017 were analyzed. Safety, based on adverse event (AE) reporting, was the primary endpoint. Efficacy assessment parameters included overall response rate (ORR), overall survival (OS), and progression-free survival (PFS)., Results: Among 53 treated patients with advanced NSCLC (median age 61.0 years; 62.3% male), mean treatment duration was 99.7 days. AEs (any grade) and serious AEs were reported by 92.5% and 47.2% of patients, respectively. Adverse drug reactions (ADRs; any) occurred in 58.5% of patients; grade ≥3 ADRs occurred in 13.2% of patients. Five deaths occurred; two cases (neoplasm progression and septic shock) were considered treatment-emergent. Common ADRs were fatigue (17.0%) and rash (13.2%). Common immune-related treatment-emergent AEs were rash (17.0%) and pruritus (13.2%). The centrally assessed ORR was 9.4% (5/53). The median OS and median PFS were 11.5 months and 1.4 months, respectively., Conclusion: Nivolumab appeared to be safe and effective in Taiwanese patients. These interim results suggest that nivolumab is a suitable treatment option for this population., Clinical Trial Registration: NCT02582125., Competing Interests: Declaration of competing interest Yuh-Min Chen, Wu-Chou Su, Inn-Wen Chong, Te-Chun Hsia, Meng-Chih Lin, Gee-Chen Chang, Shang-Yin Wu, Jen-Yu Hung, Chin-Chou Wang, Tsung-Ying Yang, and Chong-Jen Yu have no conflicts of interest to declare in relation to the present work. James Chih-Hsin Yang declares having received personal fees as honoraria for advisory board participation or speaker bureaus from Boehringer Ingelheim, Eli Lilly, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceutical, Daiichi Sankyo, AstraZeneca, Hansoh Pharmaceuticals, and Takeda Pharmaceuticals. Chao-Hua Chiu declares having received personal fees as honoraria from BMS, MSD Roche, AstraZeneca, Novartis, and Pfizer. Chao-Chi Ho declares having received grants from AstraZeneca., (Copyright © 2020. Published by Elsevier B.V.)

Background: The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear., Methods: Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo., Results: Pemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274 ) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS-ROS-NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth., Conclusions: Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background/purpose: Rapid on-site cytologic evaluation (ROSE) has been shown to improve the diagnostic accuracy of endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB). However, ROSE by a cytopathologist or cytotechnologist is not always available during the procedure. The purposes of this study were to verify that a pulmonologist, after receiving training in cytology, could accurately assess an EBUS-TBB specimen on-site, and to evaluate the contribution of ROSE to EBUS-TBB., Methods: A retrospective chart review of patients who underwent EBUS-TBB for diagnosis of peripheral pulmonary lesions (PPLs) from January 2014 to June 2017 was performed. PPLs without a malignant diagnosis were excluded. The ROSE result determined by a pulmonologist was compared to the formal imprint cytologic report and pathologic report. The diagnostic accuracy of EBUS-TBB was also compared between those with and without ROSE., Results: Two hundred ninety-three patients who underwent 336 EBUS-TBB procedures for PPL diagnosis and were found to have proven malignancy were enrolled. Eighty-six procedures were performed with ROSE. With the formal imprint cytologic diagnosis as the standard, ROSE had 96.9% sensitivity, 68.2% specificity, 89.9% positive predictive value (PPV), 88.2% negative predictive value (NPV), and 89.5% diagnostic accuracy. With the formal pathologic result as the standard, ROSE had 88.2% sensitivity, 80% specificity, 97.1% PPV, 47.1% NPV, and 87.2% diagnostic accuracy, respectively. The diagnostic accuracy was significantly higher when ROSE was performed during EBUS-TBB (88.4% vs 68.0%, P < 0.001)., Conclusion: A trained pulmonologist can interpret adequately cytologic smears on-site and effectively improve the accuracy of EBUS-TBB in the diagnosis of PPLs., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

This study compared effects of plasma-activated medium (PAM) with effects of conventional clinical thermal therapy on both lung cancer cells and benign cells for management of malignant pleural effusion (MPE). For MPE treatment, chemotherapy, photodynamic therapy, and thermal therapy are used but caused systemic side effects, patient photosensitivity, and edema, respectively. Recent studies show that plasma induces apoptosis in cancer cells with minor effects on normal cells and is cost-effective. However, the effects of plasma on MPE have not been investigated previously. This study applied a nonthermal atmospheric-pressure plasma jet to treat RPMI medium to produce PAM, carefully controlled the long-life reactive oxygen and nitrogen species concentration in PAM, and treated the cells. The influence of PAM treatment on the microenvironment of cells was also checked. The results indicated that PAM selectively inhibited CL1-5 and A549 cells, exerting minor effects on benign mesothelial and fibroblast cells. In contrast to selective lethal effects of PAM, thermal therapy inhibited both CL1-5 and benign mesothelial cells. This study also found that fibroblast growth factor 1 is not the factor explaining why PAM can selectively inhibit CL1-5 cells. These results indicate that PAM is potentially a less-harmful and cost-effective adjuvant therapy for MPE.

Introduction: The aim of this study was to investigate whether mineral trioxide aggregate (MTA) can be modified with caffeic acid (CA) to form caffeic acid/mineral trioxide aggregate (CAMTA) cement and to evaluate its physicochemical and biological properties as well as its capability in immune suppression and angiogenesis., Methods: MTA was immersed in trishydroxymethyl aminomethane buffer with CA to allow coating onto MTA powders. X-ray diffractometry and tensile stress-strain tests were conducted to assess for physical characteristics of CAMTA and to evaluate for successful modification of MTA. Then, the CAMTA cement was immersed in simulated body fluid to evaluate its hydroxyapatite formation capabilities and Si release profiles. In addition, RAW 264.7 cells and human dental pulp stem cells were used to evaluate CAMTA's immunosuppressive capabilities and cell responses, respectively. hDPSCs were also used to assess CAMTA's angiogenic capabilities., Results: The X-ray diffractometry results showed that CA can be successfully coated onto MTA without disrupting or losing MTA's original structural properties, thus allowing us to retain the initial advantages of MTA. CAMTA was shown to have higher mechanical properties compared with MTA and had rougher pitted surfaces, which were hypothesized to lead to enhanced adhesion, proliferation, and secretion of angiogenic- and odontogenic-related proteins. In addition, it was found that CAMTA was able to enhance hydroxyapatite formation and immunosuppressive capabilities compared with MTA., Conclusions: CAMTA cements were found to have improved physicochemical and biological characteristics compared with their counterpart. In addition, CAMTA cements had enhanced odontogenic, angiogenic, and immunosuppressive properties compared with MTA. All of the results of this study proved that CAMTA cements could be a biomaterial for future clinical applications and tissue engineering use., (Copyright © 2020 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Recent advances in the detection of genomic DNA from plasma samples allow us to follow tumor DNA shedding in plasma during systemic treatment. Osimertinib is the standard of care for patients with NSCLC with acquired EGFR T790M mutations. We assessed changes in serial plasma cell-free circulating tumor DNA (ctDNA) genomic alterations to predict osimertinib efficacy., Methods: We prospectively collected plasma from patients having EGFR -mutated advanced NSCLC previously treated with EGFR tyrosine kinase inhibitor therapy and with acquired EGFR T790M mutation detected by standard methods. Plasma samples were collected before starting osimertinib treatment, 4 weeks after osimertinib treatment, and on progression. ctDNA was analyzed using the Guardant360 assay., Results: A total of 15 eligible patients received osimertinib. Before starting treatment, EGFR -activating mutations were detected in the ctDNA of all patients, and EGFR T790M was detected in 93% of the cases. Osimertinib treatment was associated with an objective response rate of 53% and a median progression-free survival of 7.3 months. A total of 12 of the 15 patients had undetectable plasma T790M and decreased activating mutation allelic frequency (AF) at week 4. None of the 12 patients had disease progression within 16 weeks. For the remaining three patients, with detectable plasma T790M (n = 2) or increased activating mutation AF (n = 1) at week 4, two had progressive disease within 16 weeks ( p  = 0.03)., Conclusions: In patients with EGFR -mutated advanced NSCLC, persistent EGFR T790M or increasing activating mutation AF as detected in ctDNA 4 weeks after the start of osimertinib treatment may predict disease progression within 16 weeks., (© 2020 The Authors.)