Search

Jui-Wen Peng,1 Oswald Ndi Nfor,2 Chien-Chang Ho,3,4 Shu-Yi Hsu,2 Ming-Chih Chou,1 Yung-Po Liaw2,5 1Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 3Department of Physical Education, Fu-Jen Catholic University, New Taipei City, 24205, Taiwan; 4Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 5Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po Liaw, No. 110 Sec. 1 Jianguo N. Road, Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan, Tel +886436097501, Fax +886423248179, Email Liawyp@csmu.edu.tw Ming-Chih Chou, No. 110 Sec. 1 Jianguo N. Road, Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan, Tel +886424730022 ext. 11191, Fax +886423248130, Email juhan0223@yahoo.com.twPurpose: Stroke is a complex health condition caused by multiple risk factors. We investigated whether the Cytochrome P450 2C9 (CYP2C9) rs4918758 polymorphism and sex were independently and interactively associated with ischemic stroke risk among Taiwan Biobank (TWB) participants.Material and Methods: We analyzed TWB data pertaining to 9197 female and 8625 male individuals. Data collected between 2008 and 2015 were linked to medical records in the National Health Insurance Database (NHIRD). Based on multiple logistic regression analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for ischemic stroke.Results: We found that 441 women and 468 men had ischemic stroke. There were no differences in the risk of ischemic stroke between individuals with the TC/CC genotype and those with the TT genotype [OR (95% CI) = 1.04 (0.90– 1.21)]. When compared to women, men had an OR of 1.03 (95% CI = 0.87– 1.22) for ischemic stroke. Based on further analysis, sex was found to interact with polymorphism rs4918758 (p for interaction = 0.0019). After categorizing by sex, men with TC/CC genotype showed significant ORs but not women [OR (95% CI) = 1.32 (1.07– 16.33) vs 0.83 (0.68– 1.00)]. Further stratification by genotype showed that in comparison with their female counterparts, men with the TT and TC/CC genotypes had ORs of 0.59 (95% CI = 0.44– 0.80) and 1.36 (95% CI = 1.10– 1.68), respectively.Conclusion: According to our study, the TT genotype of rs4918758 was associated with a reduced risk of ischemic stroke in Taiwanese men when compared to women, whereas the TC/CC genotype was associated with a greater risk.Keywords: stroke, genetic variant, sex, ischemic heart, gender

Chun-Chang Ho,1 Giha Kim,1 Chin Hee Mun,2 Ju-Won Kim,3 Jieun Han,3 Ji Yoon Park,1 Yong-Beom Park,2– 4 Sang-Kyou Lee1,5 1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea; 2Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Medical Science, Brain Korea 21 PLUS Project, Yonsei University, Seoul, Republic of Korea; 4Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Good T Cells, Inc., Seoul, Republic of KoreaCorrespondence: Sang-Kyou LeeDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of KoreaTel +82 2 2123 2889Email sjrlee@yonsei.ac.krPurpose: Th17 cells and their cytokines are implicated in the pathogenesis of various autoimmune diseases. Retinoic acid-related orphan receptor alpha (RORα) is a transcription factor for the differentiation and the inflammatory functions of Th17 cells. In this study, we generated the nucleus-transducible form of transcription modulation domain of RORα (nt-RORα-TMD) to investigate the functional roles of RORα in vitro and in vivo under normal physiological condition without genetic alteration.Methods: The functions of nt-RORα-TMD were analyzed in vitro through flow cytometry, luciferase assay, ELISA, and transcriptome sequencing. Finally, the in vivo therapeutic effects of nt-RORα-TMD were verified in dextran sulfate sodium (DSS)-induced colitis mice.Results: nt-RORα-TMD was effectively delivered into the cell nucleus in a dose- and time-dependent manner without any cellular toxicity. nt-RORα-TMD competitively inhibited the RORα-mediated transcription but not RORγt-mediated transcription. Secretion of IL-17A from the splenocytes was suppressed by nt-RORα-TMD without affecting the secretion of Th1- or Th2-type cytokine and T cell activation events such as induction of CD69 and CD25. The differentiation potential of naïve T cells into Th17 cells, not into Th1, Th2, or Treg cells, was significantly blocked by nt-RORα-TMD. Consistently, mRNA sequencing analysis showed that nt-RORα-TMD treatment down-regulated the expression of the genes related to the differentiation and functions of Th17 cells. Treatment of DSS-induced colitis mice with nt-RORα-TMD improved the overall symptoms of colitis, such as body weight change, colon length, infiltration of inflammatory cells, and the level of inflammatory cytokines in the serum. In the mesenteric lymph node (MLN) of the nt-RORα-TMD-treated mice, the population of CD4+IL-17A+ Th17 cells was reduced, and the population of CD4+Foxp3+ Treg cells increased.Conclusion: nt-RORα-TMD has a potential to be developed as a novel therapeutic reagent for treating various inflammatory diseases in which Th17 cells are the leading pathological player.Keywords: retinoic acid-related orphan receptor, T helper 17, transcriptional modulation, DSS-induced colitis, inflammatory disease

Chun-Sheng Hsu,1– 4 Shin-Tsu Chang,1,5,6 Oswald Ndi Nfor,2 Kuan-Jung Lee,2 Chien-Chang Ho,7,8 Chuan-Ching Liu,1 Shiuan-Shinn Lee,2 Yung-Po Liaw2,9 1Department of Physical Medicine and Rehabilitation, Taichung Veterans General Hospital, Taichung City, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, 40201, Taiwan; 3School of Medicine, National Defense Medical Center, Taipei City, 11490, Taiwan; 4College of Medicine, National Chung Hsing University, Taichung City, 402, Taiwan; 5Department of Physical Medicine and Rehabilitation, Tri-Service General Hospital, School of Medicine, National Defense Medical Centre, Taipei City, 11490, Taiwan; 6Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung City, 813414, Taiwan; 7Department of Physical Education, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 8Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 9Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po Liaw; Shiuan-Shinn LeeDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110 Sec. 1 Jianguo N. Road, Taichung City, 40201, TaiwanTel +886 424730022 ext. 11838; +886 424730022 ext.12185Fax +886 423248179Email Liawyp@csmu.edu.tw; shinn@csmu.edu.twPurpose: The Lipoprotein lipase (LPL) gene is a significant contributor to dyslipidemia. It has shown associations with several conditions including atherosclerosis, obesity, and metabolic syndrome (MetS). We assessed the interactive association between MetS and rs3779788 of the LPL gene based on aerobic exercise.Materials and Methods: Data were available for 7532 Taiwan Biobank (TWB) participants recruited between 2008 and 2016. We used multiple logistic regression to determine the odds ratios (OR) for MetS and their 95% confident intervals (C.I.). Potential variables included LPL rs3779788, aerobic exercise, sex, age, education, marital status, body mass index (BMI), smoking, alcohol consumption, midnight snacking, vegetarian diet, coffee, dietary fat, and tea drinking.Results: Aerobic exercise was protective against MetS (OR, 0.858; 95% C.I., 0.743– 0.991). Compared to CC/CT genotype, the OR for developing MetS was 0.875, (95% C.I., 0.571– 1.341) in TT individuals. The test for interaction was significant for the rs3779788 variant and aerobic exercise (p = 0.0484). In our group analyses, the OR for MetS was 0.841 (95% C.I., 0.727– 0.974) in CC/CT and 4.076 (95% C.I., 1.158– 14.346) in TT individuals who did aerobic exercise compared to those who did not.Conclusion: Our study indicated that aerobic exercise improved metabolic syndrome in Taiwanese adults with rs3779788 CC/CT genotype relative to those with TT genotype.Keywords: polymorphisms, variant, physical activity, metabolic disorders

Jui-Wen Peng,1 Oswald Ndi Nfor,2 Chien-Chang Ho,3,4 Shu-Yi Hsu,2 Chia-Chi Lung,2 Disline Manli Tantoh,2,5 Ming-Chih Chou,1 Yung-Po Liaw2,5 1Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 3Department of Physical Education, Fu-Jen Catholic University, New Taipei City, 24205, Taiwan; 4Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 5Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po LiawDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11838Fax +886423248179Email Liawyp@csmu.edu.twMing-Chih ChouInstitute of Medicine, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11191Fax +886423248130Email juhan0223@yahoo.com.twPurpose: Ischemic stroke accounts for approximately 85% of all strokes. Risk factors include atrial fibrillation, metabolic disorders, and genetic and lifestyle factors. There is limited evidence to support the association between atrial fibrillation and the risk of ischemic stroke based on genetic variants. We assessed the relationship between ischemic stroke and atrial fibrillation among participants in Taiwan Biobank (TWB) based on the rs2860905 variant of the cytochrome P450 Family 2 Subfamily C Member 9 (CYP2C9) gene.Materials and Methods: Using logistic regression analysis, we estimated the odds ratios (OR) and 95% confidence intervals (CI) for ischemic stroke among 17,726 biobank adults recruited from 2008 through 2015.Results: Of the eligible participants (n = 17,726), 906 were identified with ischemic stroke. Atrial fibrillation was positively associated with ischemic stroke (OR=3.70; 95% CI, 2.21– 6.20), whereas the rs2860905 variant was not. The OR for ischemic stroke among those with GA/AA genotype was 1.00 (95% CI, 0.82– 1.22) compared to those with the GG genotype. Based on the genotype-stratified analysis, the OR for ischemic stroke was 4.68 (95% CI, 2.70– 8.09) among individuals with GG genotype who had atrial fibrillation compared to those who did not.Conclusion: These results demonstrate that the GG genotype of the CYP2C9 rs2860905 variant appears to enhance the risk of ischemic stroke among adults in Taiwan. It could be essential to factor this genotype-specific contributor to ischemic stroke into clinical and experimental investigations of the disease in Taiwan.Keywords: genetic variation, risk prediction, stroke

Huan-Cheng Chang,1,2 Oswald Ndi Nfor,3 Chien-Chang Ho,4,5 Pei-Hsin Chen,3 Ya-Yu Kung,6 Shu-Yi Hsu,3 Disline Manli Tantoh,3,7 Yi-Ching Liaw,8 Chuan-Fa Hsieh,9,10 Yung-Po Liaw3,7 1Division of Family Medicine, Department of Community Medicine, Landseed International Hospital, Taoyuan City 324, Taiwan; 2Department of Health Business Management Administration, Hungkuang University, Taichung City 43302, Taiwan; 3Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City 40201, Taiwan; 4Department of Physical Education, Fu Jen Catholic University, New Taipei 24205, Taiwan; 5Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei 24205, Taiwan; 6Division of Health Management, Landseed International Hospital, Taoyuan City 324, Taiwan; 7Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan; 8Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan; 9Department of Medical Education, Research & Quality Management, Landseed International Hospital, Taoyuan City 324, Taiwan; 10College of Health Sciences & Technology, National Central University, Taoyuan City 32001, TaiwanCorrespondence: Yung-Po LiawDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung City 40201, TaiwanTel +886-4-24730022 ext.11838Fax +886-4-23248179Email Liawyp@csmu.edu.twChuan-Fa HsiehDepartment of Medical Education, Research & Quality Management, Landseed International Hospital, No. 77, Guangtai Road, Pingzhen City, Taoyuan, TaiwanTel +886-3-4941234 ext. 2172Fax +886-3-20641333-4246Email hsiehcf@landseed.com.twPurpose: High-density lipoprotein cholesterol (HDL-C) is essential for cardiometabolic health. Coffee consumption influences the body’s ability to regulate serum lipid profile. Although there is extensive information on coffee and cholesterol, not much is known whether changes in HDL-C concentrations are affected by coffee with or without flavoring substances.Materials and Methods: Using historical data collected from 1272 participants in Li-Shin (Landseed) International Hospital in Northern Taiwan, we examined the relationship between HDL-C and consumption of plain black coffee with and without additives. Data on coffee consumption between 2006 and 2019 were collected based on self-reported questionnaires while HDL-C measurements were obtained from the electronic medical records of the hospital. t-test, chi-square test and multivariate linear regression analysis were used for analysis.Results: In our primary analysis, we found that coffee consumption of ≥ 5 cups per week was positively associated with HDL-C (β = 1.9586, p=0.0442) compared with the lowest level (< 1 cup/week) of consumption. We found in a separate model that higher (≥ 5 cups/week) or lower (1– 4 cups/week) consumption of plain black coffee without additives was associated with higher HDL-C. The corresponding β values were 4.0674 (p = 0.0007) and 4.1253 (p = 0.0008), respectively. However, HDL-C levels were not affected by coffee with additives.Conclusion: We found that consumption of black coffee without additives was associated with higher concentrations of HDL-C among Taiwanese adults over the age of 30. However, HDL-C levels did not change significantly among individuals who consumed black coffee with additives.Keywords: coffee, cardiometabolic health, caffeine, lipid

Wei-Yu Chen,1 Yi-Hsien Cheng,2 Nan-Hung Hsieh,3 Bo-Chun Wu,2 Wei-Chun Chou,4 Chia-Chi Ho,4 Jen-Kun Chen,5 Chung-Min Liao,2,* Pinpin Lin4,* 1Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 2Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 3Institute of Labor, Occupational Safety and Health, Ministry of Labor, New Taipei City, 4National Institute of Environmental Health Sciences, 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan *These authors contributed equally to this work Abstract: Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of 65ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm 65ZnO NPs and zinc nitrate (65Zn(NO3)2) in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of 65ZnO NPs were greater than those of 65Zn(NO3)2, particularly the lung partition coefficient of 10 nm 65ZnO NPs. Sensitivity analysis revealed that 71 nm 65ZnO NPs and 65Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for 65ZnO NPs and 65Zn(NO3)2. The simulation of 65Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of 65ZnO NPs with those of 65Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to 65ZnO NPs

Our objective was to quantify the absorption and conversion to retinoids of a 1.01-nmol, 3.7-kBq oral dose of (14)C-beta-carotene in 8 healthy adults. The approach was to quantify, using AMS, the elimination of (14)C in feces for up to 16 d after dosing and in urine for up to 30 d after dosing. The levels of total (14)C in undiluted serial plasma samples were measured for up to 166 d after dosing. Also, the levels of (14)C in the retinyl ester (RE), retinol (ROH), and beta-carotene fractions that were isolated from undiluted plasma using HPLC were measured. The apparent digestibility of the (14)C was 53 +/- 13% (mean +/- SD), based on the mass balance data, and was generally consistent with the area under the curve for zero to infinite period of (14)C that was eliminated in the feces collections made up to 7.5 d after dosing. Metabolic fecal elimination, calculated as the slope per day (% (14)C-dose/collection from d 7.5 to the final day), was only 0.05 +/- 0.02%. The portion of the (14)C dose eliminated via urine was variable (6.5 +/- 5.2%). Participants [except participant 6 (P6)] had a distinct plasma peak of (14)C at 0.25 d post-dose, preceded by a shoulder at approximately 0.1 d, and followed by a broad (14)C peak that became indistinguishable from baseline at approximately 40 d. Plasma (14)C-RE accounted for most of the absorbed (14)C early after dosing and P1 had the longest delay in the first appearance of (14)C-RE in plasma. The data suggest that plasma RE should be considered in estimating the ROH activity equivalent of ingested beta-carotene. [ABSTRACT FROM AUTHOR]

RATIONALE: Triggering receptor expressed on myeloid cells (TREM)-1 is a molecule crucial for the triggering and amplification of inflammatory response and a new biomarker for sepsis. Tumor-associated macrophages and inflammation in the tumor microenvironment are also involved in cancer progression. OBJECTIVES: To determine the role of TREM-1 in tumor-associated macrophage and cancer progression. METHODS: Using ELISA and Western blot, we measured soluble TREM-1 levels in 65 pleural effusions of various etiologies. We evaluated TREM-1-positive cells by immunocytochemistry in malignant pleural effusion and in lung tumor versus adjacent normal tissue in surgical specimens from 68 patients with non-small cell lung cancer (NSCLC). TREM-1 expression was correlated with patient survival. TREM-1 expression in primary isolated peripheral blood macrophages cocultured with lung cancer cell lines was determined by quantitative real-time reverse transcriptase-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Soluble TREM-1 and tumor-associated macrophage TREM-1 expression was increased in malignant pleural effusions in patients with NSCLC. Lung cancer cells could directly up-regulate TREM-1 and proinflammatory cytokine (tumor necrosis factor-alpha, IL-1beta) expression in primary isolated peripheral blood macrophages in coculture experiments. Increased TREM-1-positive tumor-associated macrophages in tumor tissue of patients with NSCLC were associated with reduced disease-free (P = 0.011) and overall survival (P = 0.004). Multivariate Cox regression analysis indicated that TREM-1 was an independent predictor of patient survival (hazard ratio, 2.72; 95% confidence interval, 1.33-5.57; P = 0.006). CONCLUSIONS: Cancer cells can directly up-regulate TREM-1 expression in patients' macrophages. TREM-1 expression in tumor-associated macrophages is associated with cancer recurrence and poor survival of patients with NSCLC. TREM-1 and the inflammatory response may play an important role in cancer progression. [ABSTRACT FROM AUTHOR]

BACKGROUND: Excentral cleavage of beta-carotene to retinoids and apocarotenoids occurs in vitro and in animal models. Whether it occurs in humans is unclear. OBJECTIVE: We tested the hypothesis of whether humans can cleave beta-carotene excentrally. DESIGN: A healthy man was given an oral dose of all-trans [10,10',11,11'-(14)C]-beta-carotene (1.01 nmol; 100 nCi). Its fate and that of its metabolites were measured in serial plasma samples. Its fate in feces and urine was also measured over time. Selected plasma samples were spiked with reference standards of retinol, beta-apo-12'-carotenal, beta-apo-8'-carotenal, 13-cis-retinoic acid, all-trans-retinoic acid, beta-carotene-5,6-epoxide, all-trans-beta-carotene, and retinyl palmitate and subjected to reverse-phase HPLC fractionation. The plasma, plasma fractions, urine, and feces were measured for (14)C with the use of accelerator mass spectrometry. RESULTS: Sixty-five percent of administered (14)C was absorbed, and 15.7% was eliminated in urine during the first 21 d after dosing. (14)C-beta-carotene and (14)C-retinyl palmitate appeared in plasma 0.25 d after the dose. (14)C-beta-carotene and (14)C-retinol both appeared at 0.5 d only. On day 3 after the dose, 2 large (14)C peaks appeared in plasma: one matched the retention time of beta-apo-8'-carotenal, and the other did not match any of the reference standards used. The delayed appearance of (14)C-beta-apo-8'-carotenal in plasma suggests that the excentral cleavage occurred after the (14)C-beta-apo-8'-carotene was absorbed into the body. CONCLUSION: These data suggest that excentral cleavage of ingested beta-carotene occurs in vivo in humans. Confirmation of that possibility and further study to identify and characterize additional metabolites are needed. Copyright © 2007 American Society for Nutrition [ABSTRACT FROM AUTHOR]

BACKGROUND: Quantitation of human vitamin E metabolism is incomplete, so we quantified RRR- and all-rac-alpha-tocopherol metabolism in an adult. OBJECTIVE: The objective of the study was to quantify and interpret in vivo human vitamin E metabolism. DESIGN: A man was given an oral dose of 0.001821 micromol [5-14CH3]RRR-alpha-tocopheryl acetate (with 101.5 nCi 14C), and its fate in plasma, plasma lipoproteins, urine, and feces was measured over time. Data were analyzed and interpreted by using kinetic modeling. The protocol was repeated later with 0.001667 micromol [5-14CH3]all-rac-alpha-tocopheryl acetate (with 99.98 nCi 14C). RESULTS: RRR-alpha-tocopheryl acetate and all-rac-alpha-tocopheryl acetate were absorbed equally well (fractional absorption: approximately 0.775). The main route of elimination was urine, and approximately 90% of the absorbed dose was alpha-2(2'-carboxyethyl)-6-hydroxychroman. Whereas 93.8% of RRR-alpha-tocopherol flow to liver kinetic pool B from plasma was returned to plasma, only 80% of the flow of all-rac-alpha-tocopherol returned to plasma; the difference (14%) was degraded and eliminated. Thus, for newly digested alpha-tocopherol, the all-rac form is preferentially degraded and eliminated over the RRR form. Respective residence times in liver kinetic pool A and plasma for RRR-alpha-tocopherol were 1.16 and 2.19 times as long as those for all-rac-alpha-tocopherol. Model-estimated distributions of plasma alpha-tocopherol, extrahepatic tissue alpha-tocopherol, and liver kinetic pool B for RRR-alpha-tocopherol were, respectively, 6.77, 2.71, and 3.91 times as great as those for all-rac-alpha-tocopherol. Of the lipoproteins, HDL had the lowest 14C enrichment. Liver had 2 kinetically distinct alpha-tocopherol pools. CONCLUSIONS: Both isomers were well absorbed; all-rac-alpha-tocopherol was preferentially degraded and eliminated in urine, the major route. RRR-alpha-tocopherol had a longer residence time and larger distribution than did all-rac-alpha-tocopherol. Liver had 2 distinct alpha-tocopherol pools. The model is a hypothesis, its estimates are model-dependent, and it encourages further testing. Copyright © 2006 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Introduction: Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.Methods: Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.Results: In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.Conclusions: These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation. [ABSTRACT FROM AUTHOR]

Background: Highly pathogenic avian influenza (HPAI) H5N1 virus is entrenched in poultry in Asia and Africa and continues to infect humans zoonotically causing acute respiratory disease syndrome and death. There is evidence that the virus may sometimes spread beyond respiratory tract to cause disseminated infection. The primary target cell for HPAI H5N1 virus in human lung is the alveolar epithelial cell. Alveolar epithelium and its adjacent lung microvascular endothelium form host barriers to the initiation of infection and dissemination of influenza H5N1 infection in humans. These are polarized cells and the polarity of influenza virus entry and egress as well as the secretion of cytokines and chemokines from the virus infected cells are likely to be central to the pathogenesis of human H5N1 disease.Aim: To study influenza A (H5N1) virus replication and host innate immune responses in polarized primary human alveolar epithelial cells and lung microvascular endothelial cells and its relevance to the pathogenesis of human H5N1 disease.Methods: We use an in vitro model of polarized primary human alveolar epithelial cells and lung microvascular endothelial cells grown in transwell culture inserts to compare infection with influenza A subtype H1N1 and H5N1 viruses via the apical or basolateral surfaces.Results: We demonstrate that both influenza H1N1 and H5N1 viruses efficiently infect alveolar epithelial cells from both apical and basolateral surface of the epithelium but release of newly formed virus is mainly from the apical side of the epithelium. In contrast, influenza H5N1 virus, but not H1N1 virus, efficiently infected polarized microvascular endothelial cells from both apical and basolateral aspects. This provides a mechanistic explanation for how H5N1 virus may infect the lung from systemic circulation. Epidemiological evidence has implicated ingestion of virus-contaminated foods as the source of infection in some instances and our data suggests that viremia, secondary to, for example, gastro-intestinal infection, can potentially lead to infection of the lung. HPAI H5N1 virus was a more potent inducer of cytokines (e.g. IP-10, RANTES, IL-6) in comparison to H1N1 virus in alveolar epithelial cells, and these virus-induced chemokines were secreted onto both the apical and basolateral aspects of the polarized alveolar epithelium.Conclusion: The predilection of viruses for different routes of entry and egress from the infected cell is important in understanding the pathogenesis of influenza H5N1 infection and may help unravel the pathogenesis of human H5N1 disease. [ABSTRACT FROM AUTHOR]

Purpose: Clinical shadowing(CS) offers preclinical medical students the opportunity to observe certified physicians in practice. Analyzing the content of students' reflective writings(RWs) to understand core competencies they perceived during CS, as well as stages of their reflections, can offer valuable insights for course design and instructor guidance. This study aimed to address this matter by employing a thematic analysis of students' RWs to explore the learning outcomes derived from CS., Materials and Methods: The dataset of the thematic analysis comprised de-identified RWs from preclinical medical students who participated in the clinical shadowing program during the first semester of the 2019 academic year at National Taiwan University College of Medicine. Two researchers independently extracted and categorized pertinent content from the texts of RWs, aligning them with the six core competencies of ACGME and mapping them to the stages of Kolb's learning cycle. Additionally, correlation with shadowing specialties and fields was investigated., Results: In total, 155 RWs were analyzed. Patient care emerged as the most frequently reflected competency(30%), followed by systems-based practice(23%), and medical knowledge(21%). The shadowing specialties and fields had an impact on the core competencies students perceived. In terms of Kolb's learning stages, concrete experience(66%) predominated in RWs, while abstract conceptualization(19%) and reflective observation(14%) were less prevalent. For each competency, concrete experience was the prevailing stage, with active experimentation being the least dominant one. Students exhibited varying proportions of reflections at different stages for each core competency., Conclusions: Clinical shadowing experiences enable preclinical medical students to explore required clinical core competencies, with emphases depending on the shadowing specialties and fields. Currently, most reflections are concentrated at Kolb's concrete experience stage. This study offers valuable insights for designing future CS programs and improving faculty development, aimed at helping students achieve deeper and more comprehensive reflective learning in relation to core competencies, and even professional identity.

Background/aim: Chronic low back pain (CLBP) significantly reduces quality of life and increases reliance on healthcare resources. Despite many individuals opting for vitamin D supplementation to alleviate CLBP, its efficacy remains debatable. This meta-analysis aimed to evaluate the potential benefits of vitamin D supplementation in treating this condition., Patients and Methods: Adhering to PRISMA guidelines, we systematically reviewed the effectiveness of vitamin D supplementation in adults with CLBP, focusing exclusively on randomized controlled trials (RCTs). A comprehensive literature search was conducted up to May 2024 across multiple databases, including PubMed, Scopus, Cochrane Library, and Web of Science., Results: Ten RCTs meeting our inclusion criteria were analyzed. The results indicated that vitamin D supplementation did not significantly reduce pain scores compared to control groups (SMD: -0.130, 95%CI=-0.260 to 0.000; I 2 =0%), regardless of participants' baseline vitamin D levels. Moreover, long-term supplementation showed no notable improvement in CLBP outcomes (SMD: -0.097, 95%CI=-0.290 to -0.097; I 2 =19.878%). Additionally, supplementation with active forms of vitamin D (SMD: -0.321, 95%CI=-0.670 to 0.028; I 2 =0.000%) did not result in significant pain relief for chronic lower back pain., Conclusion: Vitamin D supplementation does not substantially alleviate CLBP. Nevertheless, it may still be considered as part of a comprehensive treatment plan. Further research is necessary to explore its long-term effects and the underlying mechanisms that may explain the observed lack of benefit., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Benzophenones (BPs) are widely used as photoinitiators (PIs) or printing inks in food packaging, which may migrate into foods. However, the toxicity information of some BP analogues, such as 4,4'-bis(diethylamino)-benzophenone (DEAB), 4-phenylbenzophenone (4-PBP), 4 (hydroxymethyl)benzophenone (4-HMBP), those are used as PIs is lacking. Developmental toxicity is a health concern associated with PIs exposure. Recently, alternative non-in vivo methods have been proposed to evaluate the concerned chemicals or better understand the modes of action of certain toxicological endpoints. In this study, using in silico methods, we predicted that BP, DEAB, 4-PBP and 4-HMBP might exhibit developmental toxicity. However, we found that only DEAB is strong embryotoxic and disturbs the early differentiation of mouse embryonic stem cells into three germ layers and cardiomyocytes. DEAB treatment also prevented cardiomyocyte differentiation in human induced pluripotent stem cells (hiPSCs) on day 10. However, BP, 4-PBP and 4-HMBP had no similar effects on cardiomyocyte differentiation on day 10. Transcriptomic analysis revealed that treatment with DEAB significantly decreased the mRNA levels of differentiation-related transcription factors SOX17 and FOXA1, in hiPSCs on day 4. Furthermore, DEAB treatment caused tail malformations and yolk sac edema in zebrafish embryos. To conclude, DEAB may be embryotoxic because it disturbs the early differentiation of stem cells. Further studies are warranted to better understand the health effects of DEAB exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nonsymmetric 6π-electron ("oxidized") 6-oxoverdazyls have been synthesized for the first time. After formal incorporation of a hydrogen atom, the corresponding 7π-electron neutral verdazyl radical is generated. The 7π radical can undergo a further electrochemically reversible reduction to an 8π anion. Both redox processes occur at more moderate potentials than the parent verdazyl, tuning the accessible potential windows of 6π, 7π, and 8π verdazyl species.

Protein phosphorylation plays a crucial role in regulating disease phenotypes and serves as a key target for drug development. Mapping nanoscale-to-single-cell samples can unravel the heterogeneity of cellular signaling events. However, it remains a formidable analytical challenge due to the low detectability, abundance, and stoichiometry of phosphorylation sites. Here, we present a Chip-DIA strategy, integrating a microfluidic-based phosphoproteomic chip (iPhosChip) with data-independent acquisition mass spectrometry (DIA-MS) for ultrasensitive nanoscale-to-single-cell phosphoproteomic profiling. The iPhosChip operates as an all-in-one station that accommodates both quantifiable cell capture/imaging and the entire phosphoproteomic workflow in a highly streamlined and multiplexed manner. Coupled with a sample size-comparable library-based DIA-MS strategy, Chip-DIA achieved ultra-high sensitivity, detecting 1076±158 to 15869±1898 phosphopeptides from 10±0 to 1013±4 cells, and revealed the first single-cell phosphoproteomic landscape comprising druggable sites and basal phosphorylation-mediated networks in lung cancer. Notably, the sensitivity and coverage enabled the illumination of heterogeneous cytoskeleton remodeling and cytokeratin signatures in patient-derived cells resistant to third-generation EGFR therapy, stratifying mixed-lineage adenocarcinoma-squamous cell carcinoma subtypes, and identifying alternative targeted therapy for late-stage patients. With flexibility in module design and functionalization, Chip-DIA can be adapted to other PTM-omics to explore dysregulated PTM landscapes, thereby guiding therapeutic strategies toward precision oncology., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Collaborative learning is an essential pedagogy in medical education, within which small group learning constitutes an integral component. Online small group teaching has been widely applied and blended with in-person sessions in the aftermath of the Covid-19 pandemic. This study examined whether group metacognition was associated with teamwork satisfaction in an online small group teaching curriculum for medical students., Methods: We enrolled medical students of the 2nd and 4th years during the 2021 fall semester after they participated in 3 consecutive sessions of online small group tutorials (SGTs), which have been implemented in our medical school for more than 20 years. The students completed a group metacognitive scale (GMS) and a teamwork satisfaction scale (TSS) after the sessions. We analyzed whether group metacognition in 4 dimensions (knowledge of cognition, planning, evaluating, and monitoring) could be connected with medical students' teamwork satisfaction using partial least squares-structural equation modeling (PLS-SEM)., Results: A total of 263 medical students participated in this study. Both GMS and TSS exhibited good reliability and validity. Three of the 4 dimensions of group metacognition (cognition, planning, and evaluating) positively correlated with teamwork satisfaction (path coefficients 0.311, 0.279, and 0.21; p = 0.002, 0.002, and 0.043, respectively) following the online SGT curriculum, whereas the monitoring dimension did not (path coefficient 0.087; p = 0.357). The model achieved an adjusted R square of 0.683., Conclusion: We discovered that group metacognition correlated positively with better teamwork satisfaction, supporting the importance of group metacognitive competency for online collaborative learning., (© 2024. The Author(s).)

Aims: Molecular classification according to The Cancer Genome Atlas (TCGA) improves endometrial endometrioid carcinoma (EEC) prognostication and has specific treatment implications; however, original data were skewed towards low-grade and low-stage tumours. Herein, we molecularly classify EECs metastatic at the time of diagnosis or with subsequently documented recurrent/metastatic disease to examine correlation with clinical outcomes., Methods: TCGA categories include POLE-mutated, microsatellite instability (MSI), p53 abnormal (p53 abnl) and no specific molecular profile (NSMP). POLE targeted sequencing at exons 9, 11, 13 and 14 and immunohistochemistry (IHC) for PMS2, MSH6 and p53 were performed to establish molecular classification., Results: The distribution in our cohort of 141 EECs was similar to that generally reported in EEC, with nine POLE-mutated (6%), 45 MSI (32%), 16 p53 abnl (11%) and 71 NSMP (50%), with similar distributions between low- and high-stage cohorts. We demonstrate that when stratified by molecular subtype, disease-specific survival from the time of high-stage (stages III-IV) presentation or time of recurrence in low-stage (stages I-II) disease among metastatic and/or recurrent EEC is strongly associated with TCGA classification (high-stage P = 0.02, low-stage P = 0.017). Discordant molecular classification between primary and metastatic/recurrent tumours occurred in four of 105 (3.8%) patients, two related to PMS2/MSH6 IHC and two related to p53 IHC., Conclusions: We demonstrate that molecular classification is prognostically relevant not only at the time of diagnosis, but also at the time of recurrence and in the metastatic setting. Rare subclonal alterations occur and suggest a role for confirming TCGA classification in recurrent/metastatic tumours., (© 2024 John Wiley & Sons Ltd.)

This integrated computational and experimental study comprehensively examines the viability of competing inner-sphere electron transfer (ISET) and outer-sphere electron transfer (OSET) processes in [Cu(dap) 2 ] + -mediated atom-transfer radical additions (ATRA) of olefins and CF 3 SO 2 Cl that can deliver both R-SO 2 Cl and R-Cl products. Five sterically- and electronically-varied representative alkenes were selected from which to explore and reconcile a range of experimentally observed outcomes. Findings are consistent with photoexcited [Cu(dap) 2 ] + initiating photoelectron transfer via ISET and the subsequent regeneration of the oxidized catalyst via ISET in the ground state to close the catalytic cycle and liberate products. R-SO 2 Cl/R-Cl product ratios appear to be primarily governed by the relative rates of direct catalyst regeneration {i.e., [Cu(dap) 2 SO 2 Cl]⋅ + +R⋅} and ligand exchange {i.e., [Cu(dap) 2 SO 2 Cl]⋅ + +Cl - }. Through this work, a more consistent and more complete conceptual framework has been developed to better understand this chemistry and how catalyst regeneration occurs. It is this important ground state process, which closes the catalytic cycle, and ultimately controls the enantioselectivity of ATRA reactions employing chiral copper photocatalysts., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The purpose of this study was to examine the impact of caffeinated chewing gum on the physical performance of elite ice hockey players after a jet lag intervention. Fourteen national-level (age: 25.2 ± 5.4; height: 176.5 ± 5.3; weight: 78.1 ± 13.4) ice hockey players were tested late at night after a full day awake schedule with jet lag. A randomised, double-blind experimental design was employed in which participants either chewed caffeinated gum (CAF) containing 3 mg/kg caffeine or a caffeine-free placebo gum (PLA) for 10 min prior to undertaking a series of on-ice and off-ice tests. The off-ice tests included grip force, the counter-movement jump (CMJ), and the squat jump (SJ). The on-ice tests included a 35 m sprint, the S-Shape agility test, and the Yo-Yo intermittent recovery test (Yo-Yo IR1 test). The CMJ height (CAF: 47.2 ± 4.4; PL: 45.9 ± 3.5; p = 0.035; Cohen's d = 0.32) and SJ height (CAF: 46.7 ± 4.1; PL: 44.9 ± 3.8; p = 0.047; Cohen's d = 0.44) were found to be significantly higher in the CAF than in the PL trial. However, there were no significant differences ( p > 0.05) in grip force, as well as in the 35 m sprint, the S-Shape agility test, and the Yo-Yo IR1 test. The present study found that, following a jet lag intervention, although the consumption of caffeinated gum resulted in an increase in vertical jump height, it had no impact on performance in the ice tests. The results of this study may help coaches and athletes consider the need for caffeine supplementation when experiencing jet lag.

Extracellular vesicles (EVs) show promise in drug loading and delivery for medical applications. However, the lack of scalable manufacturing processes hinders the generation of clinically suitable quantities, thereby impeding the translation of EV-based therapies. Current EV production relies heavily on non-physiological two-dimensional (2D) cell culture or bioreactors, requiring significant resources. Additionally, EV-derived ribonucleic acid cargo in three-dimensional (3D) and 2D culture environments remains largely unknown. In this study, we optimized the biofabrication of 3D auxetic scaffolds encapsulated with human embryonic kidney 293 T (HEK293 T) cells, focusing on enhancing the mechanical properties of the scaffolds to significantly boost EV production through tensile stimulation in bioreactors. The proposed platform increased EV yields approximately 115-fold compared to conventional 2D culture, possessing properties that inhibit tumor progression. Further mechanistic examinations revealed that this effect was mediated by the mechanosensitivity of YAP/TAZ. EVs derived from tensile-stimulated HEK293 T cells on 3D auxetic scaffolds demonstrated superior capability for loading doxorubicin compared to their 2D counterparts for cancer therapy. Our results underscore the potential of this strategy for scaling up EV production and optimizing functional performance for clinical translation., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: The symptom variability in major depressive disorder (MDD) complicates treatment assessment, necessitating a thorough understanding of MDD symptoms and potential biomarkers., Methods: In this prospective study, we enrolled 54 MDD patients and 39 controls. Over the course of weeks 1, 2, and 4 participants underwent evaluations, with electroencephalograms (EEG) recorded at baseline and week 1. Our investigation considered five previously identified syndromal factors derived from the 17-item Hamilton Depression Rating Scale (17-item HAMD) for assessing depression: core, insomnia, somatic anxiety, psychomotor-insight, and anorexia. We assessed treatment response and EEG characteristics across all syndromal factors and total scores, all of which are based on the 17-item HAMD. To analyze the topology of brain networks, we employed functional connectivity (FC) and a graph theory-based method across various frequency bands., Results: The healthy control group had notably higher values in delta band EEG FC compared to the MDD patient group. Similar distinctions were observed between the responder and non-responder patient groups. Further exploration of baseline FC values across distinct syndromal factors revealed significant variations among the core, psychomotor-insight, and anorexia subgroups when using a specific graph theory-based approach, focusing on global efficiency and average clustering coefficient., Limitations: Different antidepressants were included in this study. Therefore, the results should be interpreted with caution., Conclusions: Our findings suggest that delta band EEG FC holds promise as a valuable predictor of antidepressant efficacy. It demonstrates an ability to adapt to individual variations in depressive symptomatology, offering insights into personalized treatment for patients with depression., Competing Interests: Declaration of competing interest There were no conflicts of interest from funding sources. All authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Ravishankar Asokkumar: Apollo Endosurgery. Christopher J. Khor: Boston Scientific, ERBE, FujiFilm. Damien Meng Yew Tan: Boston Scientific, Pentax Medical.

Introduction: EGFR tyrosine kinase inhibitors (TKIs) are the standard therapy for non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations in the first-line setting. Despite initial efficacy, resistance to EGFR-TKIs often develops, and platinum-based chemotherapy is the predominant subsequent treatment. For this study, we aimed to identify prognostic factors for overall survival (OS) and progression-free survival (PFS) among advanced EGFR-mutant NSCLC patients receiving platinum-pemetrexed after progression on EGFR-TKIs. Our analysis specifically focuses on 1st-line treatments limited to 1st- or 2nd-generation EGFR-TKIs, while not restricting later-line treatments involving osimertinib prior to chemotherapy., Materials and Methods: From 2012 to 2017, 363 patients who received first-line treatment with first- or second-generation EGFR-TKIs, including gefitinib, erlotinib, and afatinib were enrolled. Some patients received different EGFR-TKIs, including osimertinib, as later-line treatment before platinum-pemetrexed., Results: Median OS from the initiation of platinum-pemetrexed was 22.0 months and median PFS with platinum-pemetrexed was 6.2 months. In the multivariate Cox model, we identified three independent prognostic factors for better OS: postoperative recurrence (HR: 0.34, p = 0.004), first-line EGFR-TKI PFS ≥12 months (HR: 0.54, p = 0.002), and osimertinib treatment after platinum-pemetrexed (HR: 0.56, p = 0.005) while BMI <18.5 indicated poor prognosis (HR:1.76, p = 0.049). No statistically significant independent prognostic factors for PFS were found. Receiving osimertinib before platinum-pemetrexed treatment did not impact PFS with platinum-pemetrexed treatment (HR: 1.11, p = 0.64)., Conclusion: Postoperative recurrence, first-line EGFR-TKI PFS ≥12 months and osimertinib treatment after platinum-pemetrexed predicted better OS, while BMI <18.5 predicted worse OS. Osimertinib treatment before platinum-pemetrexed treatment did not affect the efficacy of platinum-pemetrexed., Competing Interests: Declaration of competing interest Dr. Yao reports personal fees from AstraZeneca, Boehringer Ingelheim, and Pfizer, outside the submitted work. Dr. Liao reports personal fees from AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, MSD Oncology, Novartis, Bristol-Myers Squibb, and Chugai Pharma Taiwan, outside the submitted work. Dr. Ho reports personal fees from Boehringer Ingelheim, Eli Lilly, Amgen, Roche/Genentech/Chugai, MSD, and Pfizer, outside the submitted work; Dr. Shih reports grants from Taipei City Thoracic Disease Academic Research and Education Foundation and personal fees from ACTgenomics, Amgen, Genconn Biotech, AstraZeneca, Roche, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharma, Takeda, CStone Pharmaceuticals, Janssen, TTY Biopharm, Orient EuroPharma, MundiPharma, Ono Pharmaceutical, and Bristol-Myers Squibb, outside the submitted work. Dr. Chen reports personal fees from AstraZeneca, Roche, Novartis, Pfizer, Eli Lilly, Merck Sharp and Dohme, Ono Pharmaceutical, and Boehringer Ingelheim, outside the submitted work. Dr. Yang reports personal fees and other from Amgen, grants, personal fees and other from AstraZeneca, personal fees and other from Bayer, personal fees and other from Boehringer Ingelheim, personal fees and other from Bristol Myers Squibb, personal fees and other from Daiichi Sankyo, other from Eli Lilly, personal fees and other from Merck KGaA, Darmstadt, Germany, personal fees and other from Merck Sharp & Dohme, personal fees and other from Novartis, personal fees from Ono Pharmaceuticals, personal fees from Pfizer, personal fees and other from Roche/Genentech, personal fees and other from Takeda Oncology, personal fees and other from Yuhan Pharmaceuticals, other from JNJ, other from Puma Technology, other from Gilead, other from GSK, outside the submitted work. The other authors declare no conflict of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of gastric cancer (GC) and individuals with hereditary diffuse gastric cancer (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of the stool of a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells [known as Triple Conditional (TCON) mice] identified differentially abundant proteins compared with littermate controls. Immunoblot assays validated a panel of proteins, including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP), as enriched in TCON stool compared with littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression compared with littermate controls. Proteomic mass spectrometry of stool obtained from patients with HDGC with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 relative to stool from healthy sex- and age-matched donors. Chemical inhibition of ASAH2 using C6 urea ceramide was toxic to GC cell lines and GC patient-derived organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, which suggested a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features that correlated with patient tumors. Herein, we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC. Prevention Relevance: This study highlights a novel panel of stool protein biomarkers that correlate with the presence of DGC and has potential use as early detection to improve clinical outcomes., (©2024 American Association for Cancer Research.)

Osteoporosis is a prevalent condition marked by reduced bone density and an elevated risk of fractures, especially among postmenopausal women. Exercise plays a crucial role in preventing and managing osteoporosis, with weight-bearing and impact exercises being particularly effective in enhancing bone density and mitigating disease risk. This study investigated the relationship between various types of impact exercises and osteoporosis using data from the Taiwan Biobank (TWB). The study sample comprised 5,123 individuals without osteoporosis and 1,770 individuals with the condition. Student's t-test and logistic regression analyses were utilized to assess the associations between exercise types and osteoporosis risk. Results indicated that high-impact exercise significantly reduced the likelihood of developing osteoporosis compared to no exercise (odds ratio; OR = 0.573, 95% CI: 0.406-0.810, P = 0.002). Conversely, low-impact exercises did not show a significant overall association with osteoporosis (OR = 1.160, 95% CI: 0.932-1.445, P = 0.184). Stratified analysis by sex revealed that high-impact exercise was protective against osteoporosis in men (OR = 0.391, 95% CI: 0.202-0.755, P = 0.005), but not significantly so in women (OR = 0.671, 95% CI: 0.438-1.027, P = 0.066). These findings suggest that high-impact exercise is associated with a reduced risk of osteoporosis, particularly among Taiwanese men aged 30 to 70., (© 2024. The Author(s).)

Objectives: To prospectively evaluate how the Prostate Health Index (PHI) impacts on clinical decision in a real-life setting for men with a prostate-specific antigen (PSA) level between 4 and 10 ng/mL and normal digital rectal examination., Patients and Methods: Since 2016, the PHI has been available at no cost to eligible men in all Hong Kong public hospitals. All eligible patients who received PHI testing in all public Urology units (n = 16) in Hong Kong between May 2016 and August 2017 were prospectively included and followed up. All included men had a PHI test, with its result and implications explained; the subsequent follow-up plan was then decided via shared decision-making with urologists. Patients were followed up for 2 years, with outcomes including prostate biopsy rates and biopsy findings analysed in relation to the initial PHI measurements., Results: A total of 2828 patients were followed up for 2 years. The majority (82%) had PHI results in the lower risk range (score <35). Knowing the PHI findings, 83% of the patients with elevated PSA decided not to undergo biopsy. In all, 11% and 45% opted for biopsy in the PHI score <35 and ≥35 groups, respectively. The initial detection rate of International Society of Urological Pathology (ISUP) Grade Group (GG) ≥2 cancer was higher in the PHI score ≥35 group (23%) than in the PHI score <35 group (7.9%). Amongst patients with no initial positive biopsy findings, the subsequent positive biopsy rate for ISUP GG ≥2 cancer was higher in the PHI score ≥35 group (34%) than the PHI score <35 group (13%) with a median follow-up of 2.4 years., Conclusion: In a real-life setting, with the PHI incorporated into the routine clinical pathway, 83% of the patients with elevated PSA level decided not to undergo prostate biopsy. The PHI pathway also improved the high-grade prostate cancer detection rate when compared to PSA-driven strategies. Higher baseline PHI predicted subsequent biopsy outcome at 2 years. The PHI can serve as a tool to individualise biopsy decisions and frequency of follow-up visits., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Organ transplantation from donors with immune thrombocytopenia (ITP), a condition involving the autoantibody-mediated destruction of platelets, is a topic of debate due to the potential for transplantation-mediated autoimmune thrombocytopenia (TMAT), a rare but potentially fatal complication. Previous reports have described transplants from deceased liver donors with ITP who had very low platelet counts and disease largely refractory to treatment. Here, we present the first case of living kidney transplantation from a donor with ITP who underwent preoperative treatment, with concurrent splenectomy performed to reduce the long-term risk of spontaneous hemorrhage. To ensure the safety of the procedure, we monitored perioperative rotational thromboelastometry parameters and platelet counts, leading to the normalization of the donor's platelet levels. The recipient experienced an uneventful recovery of renal function without perioperative bleeding or the development of TMAT. Our report suggests that kidney transplantation from a donor with well-managed ITP is safe, and such a condition should not be considered a contraindication for donation.

Background: High soluble urokinase plasminogen activator receptor (suPAR) levels are correlated with cardiovascular (CV) disease. Arterial stiffness is associated with aging-related vascular diseases and is an independent risk factor for CV morbidity and mortality. It can be measured by the cardio-ankle vascular index (CAVI). We evaluated the association between serum suPAR levels and arterial stiffness according to the CAVI in kidney transplantation (KT) recipients., Methods: In this study, 82 patients undergoing KT were enrolled. Serum suPAR levels were analyzed using an enzyme immunoassay. The CAVI was measured using a plethysmograph waveform device, and patients with a CAVI of ≥ 9.0 were assigned to the peripheral arterial stiffness (PAS) group., Results: Twenty KT patients (24.4%) had PAS, were of older age ( p = 0.042), and had higher serum triglyceride ( p = 0.023) and suPAR levels ( p < 0.001) than the normal group. After adjusting for factors significantly associated with PAS by multivariate logistic regression analysis, serum suPAR levels (odds ratio [OR] 1.072, 95% confidence interval (CI) 1.023-1.123; p = 0.004) were independently associated with PAS in KT patients. The logarithmically transformed suPAR level (log-suPAR) was also positively correlated with the left or right CAVI values (all p < 0.001) from the results of the Spearman correlation analysis in KT patients., Conclusions: Serum suPAR levels are positively associated with left or right CAVI values and are independently associated with PAS in KT patients., Competing Interests: The authors declare no conflict of interest. Bang-Gee Hsu is serving as Guest Editor of this journal. We declare that Bang-Gee Hsu had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Dimitris Tousoulis., (Copyright: © 2024 The Author(s). Published by IMR Press.)

The WHO classifications of hematolymphoid malignancies have recognized several distinct entities within the large B cell lymphomas, including the more recently described high-grade B cell lymphoma with 11q aberration (HGBCL-11q). We utilized genomic array to assess for chromosome 11q abnormalities in a broad set of aggressive B cell lymphomas from 27 patients with a focus on younger adults. The findings suggest more frequent alterations of 11q in diffuse large B cell lymphoma (DLBCL)/HGBCL-GC BCL2-, in comparison to cases of Burkitt lymphoma (BL) or DLBCL-GC BCL2+, and confirm a low genomic complexity score of BL. Variability identified in patterns of 11q alterations suggests genomic array studies may afford value over FISH testing as we continue to understand HGBCL-11q as a distinct entity, and interrogate cases of DLBCL/HGBCL-GC BCL2-., Competing Interests: Declaration of competing interest None. The authors of this manuscript have no financial or personal relationships to declare that could influence (bias) their work., (Copyright © 2024. Published by Elsevier Inc.)

Importance: With the rising prevalence of mental disorders among children and adolescents, identifying modifiable associations is critical., Objective: To examine the association between physical fitness and mental disorder risks., Design, Setting, and Participants: This nationwide cohort study used data from the Taiwan National Student Fitness Tests and National Health Insurance Research Databases from January 1, 2009 to December 31, 2019. Participants were divided into 2 cohorts targeting anxiety and depression (1 996 633 participants) and attention-deficit/hyperactivity disorder (ADHD; 1 920 596 participants). Participants were aged 10 to 11 years at study entry and followed up for at least 3 years, had a nearly equal gender distribution, and an average follow-up of 6 years. Data were analyzed from October 2022 to February 2024., Exposures: Assessments of physical fitness included cardiorespiratory fitness (CF), muscular endurance (ME), muscular power (MP), and flexibility, measured through an 800-m run time, bent-leg curl-ups, standing broad jump, and sit-and-reach test, respectively., Main Outcomes and Measures: Kaplan-Meier method calculated the cumulative incidence of anxiety, depression, and ADHD across fitness quartiles. Additionally, multivariable Cox proportional hazards models were used that included all 4 fitness components and explored sex and income as modifiers., Results: The anxiety and depression cohort had 1 996 633 participants (1 035 411 participants were male [51.9%], and the median [IQR] age was 10.6 [10.3-11.0] years), while the ADHD cohort had 1 920 596 (975 568 participants were male [51.9%], and the median [IQR] age was 10.6 [10.3-11.0] years). Cumulative incidence of mental disorders was lower among participants in better-performing fitness quartiles, suggesting a dose-dependent association. Gender-specific analyses, controlling for confounders, revealed that improved CF, indicated by a 30-second decrease in run times, was associated with reduced risks of anxiety, depression, and ADHD in female participants, and lower risks of anxiety and ADHD in male participants (adjusted hazard ratio [aHR] for ADHD risk for female participants, 0.92; 95% CI, 0.90-0.94; P < .001; for male participants, 0.93; 95% CI, 0.92-0.94; P < .001). Enhanced ME, marked by an increase of 5 curl-ups per minute, was associated with decreased risks of depression and ADHD in female participants, and lower anxiety and ADHD risks in male participants (aHR for ADHD risk for female participants, 0.94; 95% CI, 0.92-0.97; P < .001; for male participants, 0.96; 95% CI, 0.95-0.97; P < .001). Improved MP, reflected by a 20-cm increase in jump distance, was associated with reduced risks of anxiety and ADHD in female participants and reduced anxiety, depression, and ADHD in male participants (aHR for ADHD risk for female participants, 0.95; 95% CI, 0.91-1.00; P = .04; for male participants, 0.96; 95% CI, 0.94-0.99; P = .001)., Conclusions and Relevance: This study highlights the potential protective role of cardiorespiratory fitness, muscular endurance, and muscular power in preventing the onset of mental disorders. It warrants further investigation of the effectiveness of physical fitness programs as a preventive measure for mental disorders among children and adolescents.

Background: Although electronic nose (eNose) has been intensively investigated for diagnosing lung cancer, cross-site validation remains a major obstacle to be overcome and no studies have yet been performed., Methods: Patients with lung cancer, as well as healthy control and diseased control groups, were prospectively recruited from two referral centers between 2019 and 2022. Deep learning models for detecting lung cancer with eNose breathprint were developed using training cohort from one site and then tested on cohort from the other site. Semi-Supervised Domain-Generalized (Semi-DG) Augmentation (SDA) and Noise-Shift Augmentation (NSA) methods with or without fine-tuning was applied to improve performance., Results: In this study, 231 participants were enrolled, comprising a training/validation cohort of 168 individuals (90 with lung cancer, 16 healthy controls, and 62 diseased controls) and a test cohort of 63 individuals (28 with lung cancer, 10 healthy controls, and 25 diseased controls). The model has satisfactory results in the validation cohort from the same hospital while directly applying the trained model to the test cohort yielded suboptimal results (AUC, 0.61, 95% CI: 0.47─0.76). The performance improved after applying data augmentation methods in the training cohort (SDA, AUC: 0.89 [0.81─0.97]; NSA, AUC:0.90 [0.89─1.00]). Additionally, after applying fine-tuning methods, the performance further improved (SDA plus fine-tuning, AUC:0.95 [0.89─1.00]; NSA plus fine-tuning, AUC:0.95 [0.90─1.00])., Conclusion: Our study revealed that deep learning models developed for eNose breathprint can achieve cross-site validation with data augmentation and fine-tuning. Accordingly, eNose breathprints emerge as a convenient, non-invasive, and potentially generalizable solution for lung cancer detection., Clinical Trial Registration: This study is not a clinical trial and was therefore not registered., (© 2024. The Author(s).)

The ancient Chinese medical book "Compendium of Materia Medica" records that pears can relieve symptoms of respiratory-related diseases. Previous research has shown that pear Pyrus Pyrifolia (Burm.f.) Nakai has antioxidant and anti-inflammatory properties. However, the anti-inflammatory, antioxidant, and anti-photoaging protective effects of Pyrus pyrifolia (Burm.f.) Nakai seed components have not been studied. Ultraviolet light (UV) causes skin inflammation, damages the skin barrier, and is an important cause of skin photoaging. Therefore, UV light with a wavelength of 365 nm was used to irradiate HaCaT and mice. Western blot, real-time quantitative polymerase chain reaction, and fluorescence imaging system were used to explore its anti-UVA mechanism. Dialysis membrane and nuclear magnetic resonance were used for the chemical constituent analysis of pear seed water extract (PSWE). We found that PSWE can significantly reduce UVA-induced skin cell death and mitogen-activated protein kinase phosphorylation and can inhibit the mRNA expression of UVA-induced cytokines (including IL-1β, IL-6, and TNF-α). In addition, PSWE can also reduce the generation of oxidative stress within skin cells. In vivo experimental studies found that PSWE pretreatment effectively reduced transepidermal water loss, inflammation, redness, and dryness in hairless mice. The molecular weight of the active part of pear water extract is approximately 384. Based on the above results, we first found that pear seeds can effectively inhibit oxidative stress and damage caused by UVA. It is a natural extract with antioxidant properties and anti-aging activity that protects skin cells and strengthens the skin barrier.

Background: Over the past few decades, gout and diseases like metabolic syndrome (MetS) have become more prevalent. Attempts have been made in Taiwan to identify the genes responsible for gout. A few gene loci, among them SLC2A9 , have been identified using Taiwan Biobank (TWB) data. We, therefore, examined whether MetS could also account for the association between polymorphism SLC2A9 rs3733591 and gout., Methods: The final analysis consisted of 73,558 subjects, of whom 2,709 had gout. To estimate the likelihood of gout occurrence based on rs3733591 and MetS, we used logistic regression models., Results: Rs3733591-TC + CC compared to TT genotype was associated with gout (OR, 1.15; 95% CI, 1.06-1.25). Also associated with gout was MetS (OR, 1.21; 95% CI, 1.10-1.33). A significant interaction was seen between rs3733591 and MetS ( p -value = 0.039). Using rs3733591-TT/no MetS as the reference group, the ORs (95% CI) for gout was 1.24 (1.11-1.38) for TC + CC/no MetS, 1.35 (1.17-1.56) for TT/MetS, and 1.39 (1.22-1.58) for TC + CC/MetS. However, subgroup analysis defined by sex showed no significant associations in women., Conclusion: In summary, metabolic syndrome and SLC2A9 rs3733591 genotypes were interactively associated with gout in Taiwanese men, but not women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Ho, Hsieh, Hsiao, Nfor and Liaw.)

Background: This study aimed to compare patient experiences during bronchoscopy procedures using either topical anesthesia (TA) or monitored anesthesia care (MA). The goal was to identify circumstances where patients could achieve similar levels of tolerance and satisfaction using only TA, especially in resource-limited settings., Methods: This study included consecutive patients who underwent bronchoscopy with either TA or MA. Data collected included demographics, indications for bronchoscopy, procedure time, and complications during the procedure. A quality assurance survey was administered to assess patient experience and satisfaction with both procedures. A pre-specified subgroup analysis was performed based on procedure invasiveness and time., Results: This study enrolled 350 (TA 251; MA 99) patients, with an average age of 65 years. Main indications for bronchoscopy included tumor diagnosis (38%), esophageal cancer staging (18%), and pulmonary infection (17%). The average duration of the procedures was 20 min, with MA being associated with a significantly longer procedure time than TA (31 min vs. 16 min; P < 0.001). The overall satisfaction rating with bronchoscopy was significantly higher in the MA group (visual analogue scale, 8.9 vs. 8.2; P = 0.001). Subgroup analyses showed that when less invasive or shorter procedures were performed, TA patients reported tolerance and satisfaction levels comparable to MA patients., Conclusions: Bronchoscopy with MA offered patients a better experience and greater satisfaction; however, in settings with limited resources, TA alone may provide similar levels of patient tolerance and satisfaction during less invasive or shorter procedures., (© 2024. The Author(s).)