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Jung Lo,1,2 Ching-Chih Liu,3,4 Yueh-Shan Li,3 Po-Yen Lee,3,5 Po-Len Liu,6 Pei-Chang Wu,1,2 Tzu-Chieh Lin,7 Chi-Shuo Chen,8 Chien-Chih Chiu,9 Yu-Hung Lai,3,5,10 Yo-Chen Chang,3,5,10 Hsin-En Wu,3 Yuan-Ru Chen,3 Yu-Kai Huang,3,11 Shu-Pin Huang,1,12– 14 Shu-Chi Wang,15– 17 Chia-Yang Li3,16– 18 1Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 2Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 3Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 4Department of Ophthalmology, Chi Mei Medical Center, Tainan, 71004, Taiwan; 5Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 6Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 7Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 8Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 30013, Taiwan; 9Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 10Department of Ophthalmology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 11Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan; 12Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 13Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 14Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 15Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 16Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 17Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80756, Taiwan; 18Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, 91201, TaiwanCorrespondence: Shu-Chi Wang; Chia-Yang Li, Email shuchiwang@kmu.edu.tw; chiayangli@kmu.edu.twPurpose: Neurodegenerative diseases are associated with neuroinflammation along with activation of microglia and oxidative stress, but currently lack effective treatments. Punicalagin is a natural bio-sourced product that exhibits anti-inflammatory effects on several chronic diseases; however, the anti-inflammatory and anti-oxidative effects on microglia have not been well examined. This study aimed to investigate the effects of punicalagin on LPS-induced inflammatory responses, NLRP3 inflammasome activation, and the production of ROS using murine microglia BV2 cells.Methods: BV2 cells were pre-treated with punicalagin following LPS treatment to induce inflammation. The secretion of NO and PGE2 was analyzed by Griess reagent and ELISA respectively, while the expressions of iNOS, COX-2, STAT3, ERK, JNK, and p38 were analyzed using Western blotting, the production of IL-6 was measured by ELISA, and the activity of NF-κB was detected using promoter reporter assay. To examine whether punicalagin affects NLRP3 inflammasome activation, BV2 cells were stimulated with LPS and then treated with ATP or nigericin. The secretion of IL-1β was measured by ELISA. The expressions of NLRP3 inflammasome-related proteins and phospho IκBα/IκBα were analyzed using Western blotting. The production of intracellular and mitochondrial ROS was analyzed by flow cytometry.Results: Our results showed that punicalagin attenuated inflammation with reduction of pro-inflammatory mediators and cytokines including iNOS, COX-2, IL-1β, and reduction of IL-6 led to inhibition of STAT3 phosphorylation by LPS-induced BV2 cells. Punicalagin also suppressed the ERK, JNK, and p38 phosphorylation, attenuated NF-κB activity, inhibited the activation of the NLRP3 inflammasome, and reduced the production of intracellular and mitochondrial ROS by LPS-induced BV2 cells.Conclusion: Our results demonstrated that punicalagin attenuated LPS-induced inflammation through suppressing the expression of iNOS and COX-2, inhibited the activation of MAPK/NF-κB signaling pathway and NLRP3 inflammasome, and reduced the production of ROS in microglia, suggesting that punicalagin might have the potential in treating neurodegenerative diseases.Graphical Abstract: Keywords: punicalagin, microglia, NLRP3 inflammasome, MAPK, NF-κB

David Mannino,1 Michael Bogart,2 Guillaume Germain,3 Shirley P Huang,2 Afisi S Ismaila,4,5 François Laliberté,3 Young Jung,3 Sean D MacKnight,3 Marjorie A Stiegler,6,7 Mei Sheng Duh8 1Department of Medicine, University of Kentucky, Lexington, KY, USA; 2GlaxoSmithKline, Value Evidence and Outcomes, Research Triangle Park, NC, USA; 3Groupe d’analyse, Ltée, Montréal, QC, Canada; 4GlaxoSmithKline, Value Evidence and Outcomes, Collegeville, PA, USA; 5Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada; 6GlaxoSmithKline, Medical Affairs, Research Triangle Park, NC, USA; 7Department of Anesthesiology and Critical Care, University of North Carolina, Chapel Hill, NC, USA; 8Analysis Group, Boston, MA, USACorrespondence: Michael Bogart, GlaxoSmithKline, Value Evidence and Outcomes, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC, 27709-3398, USA, Tel +1919-889-7413, Email michael.r.bogart@gsk.comPurpose: Triple therapy (TT; inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2-agonist) is recommended for patients with chronic obstructive pulmonary disease (COPD) at risk of exacerbation, although the optimum timing of TT initiation remains unclear. This study evaluated the impact of prompt versus delayed initiation of single-inhaler TT (fluticasone furoate, umeclidinium, and vilanterol [FF/UMEC/VI]) following a COPD exacerbation.Patients and Methods: This retrospective cohort study used data from the IQVIA PharMetrics® Plus database. Patients initiating FF/UMEC/VI following a COPD exacerbation between September 18, 2017 and September 30, 2019 (exacerbation = index date) were categorized as prompt (within 30 days of index) or delayed (31– 180 days after index) FF/UMEC/VI initiators. Patients were aged ≥ 40 years at index, had ≥ 12 months’ continuous health insurance coverage before index (baseline), and ≥ 6 months’ coverage after index (follow-up). Patients with a COPD exacerbation or claim for FF/UMEC/VI during baseline were excluded. Inverse probability weighting was used to adjust for differences in baseline characteristics between cohorts. Exacerbations (overall, moderate, and severe), healthcare costs, and readmissions were evaluated during follow-up.Results: A total of 1904 patients (prompt: 529; delayed: 1375) were included. After weighting, baseline characteristics were well balanced between cohorts. Patients in the prompt cohort had significantly lower rates per person-year (PPY) of overall (0.98 vs 1.23; rate ratio [RR] [95% CI] = 0.79 [0.65– 0.94], p = 0.004), moderate (0.86 vs 1.03; RR [95% CI] = 0.84 [0.69– 0.99], p = 0.038), and severe (0.11 vs 0.20; RR [95% CI] = 0.57 [0.37– 0.79], p = 0.002) exacerbations, compared with delayed initiators. Mean all-cause and COPD-related healthcare costs were significantly lower among prompt initiators (all-cause: $26,107 vs $32,400 PPY, p = 0.014; COPD-related: $12,694 vs $17,640 PPY, p = 0.002).Conclusion: Prompt initiation of FF/UMEC/VI following a moderate or severe COPD exacerbation was associated with significant reductions in exacerbations and healthcare costs relative to delayed initiation.Keywords: chronic obstructive pulmonary disease, exacerbation, healthcare cost, single-inhaler triple therapy

Weiming Xue,1 Yanyan Liu,1 Na Zhang,1 Youdong Yao,2 Pei Ma,1 Huiyun Wen,1 Saipeng Huang,1 Yane Luo,3 Haiming Fan4 1School of Chemical Engineering, Northwest University, Xi’an, Shaanxi 710069, China; 2Pediatrics, Egang Hospital, Ezhou, Hubei 436000, China; 3College of Food Science and Technology, Northwest University, Xi’an, Shaanxi 710069, China; 4Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi’an, Shaanxi 710069, China Introduction: In vivo distribution of polyethylene glycol (PEG)ylated functional nanoparticles is vital for determining their imaging function and therapeutic efficacy in nanomedicine. However, contradictory results have been reported regarding the effect of core size and PEG surface of the nanoparticles on biodistribution.Methods: To clarify this ambiguous understanding, using iron oxide nanoparticles (IONPs) as a model system, we investigated the effect of core size and PEG molecule weights on in vivo distribution in mice. Three PEGylated IONPs, including 14 nm IONP@PEG2,000, 14 nm IONP@PEG5,000, and 22 nm IONP@PEG5,000, were prepared with a hydrodynamic size of 26, 34, and 81 nm, respectively. The blood pharmacokinetics and tissue distribution were investigated in detail.Results: The results indicated that the PEG layer, rather than core size, played a dominant role in determining the half-life time of IONPs. Specifically, increased molecular weight of the PEG layer led to a longer half-life time. These PEGylated IONPs were mainly excreted by liver clearance. While the PEG molecular layer constituted the key factor to determine the clearance ratio, core size affected the clearance rate.Conclusion: Complete blood count analysis and histopathology suggested excellent biocompatibility of PEGylated IONPs for future clinical trials. Keywords: IONPs, pharmacokinetics, tissue distribution, metabolism, histocompatibility

Yan Chen,1 Lifang Yang,1,2 Suping Huang,3 Zhi Li,1 Lu Zhang,1 Jiang He,1 Zhijie Xu,2 Liyu Liu,2 Ya Cao,2 Lunquan Sun11Center for Molecular Medicine, Xiangya Hospital, 2Cancer Research Institute, 3State Key Laboratory of Powder Metallurgy, Central South University, Changsha, People's Republic of ChinaAbstract: DNAzymes are synthetic, single-stranded, catalytic nucleic acids that bind and cleave target mRNA in a sequence-specific manner, and have been explored for genotherapeutics. One bottleneck restricting their application is the lack of an efficient delivery system. As an inorganic nanomaterial with potentially wide application, nanohydroxyapatite particles (nHAP) have attracted increasing attention as new candidates for nonviral vectors. In this study, we developed an nHAP-based delivery system and explored its cellular uptake mechanisms, intracellular localization, and biological effects. Absorption of arginine-modified nanohydroxyapatite particles (Arg-nHAP) and DZ1 (latent membrane protein 1 [LMP1]-targeted) reached nearly 100% efficiency under in vitro conditions. Using specific inhibitors, cellular uptake of the Arg-nHAP/DZ1 complex was shown to be mediated by the energy-dependent endocytosis pathway. Further, effective intracellular delivery and nuclear localization of the complex was confirmed by confocal microscopy. Biologically, the complex successfully downregulated the expression of LMP1 in nasopharyngeal carcinoma cells. In a mouse tumor xenograft model, the complex was shown to be delivered efficiently to tumor tissue, downregulating expression of LMP1 and suppressing tumor growth. These results suggest that Arg-nHAP may be an efficient vector for nucleic acid-based drugs with potential clinical application.Keywords: hydroxyapatite nanoparticles, DNAzymes, latent membrane protein 1, transfection efficiency, cellular uptake

Background: BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529, which inhibits human immunodeficiency virus type 1 (HIV-1) infection by binding to gp120 and interfering with the attachment of virus to CD4+ T-cells.Methods: Fifty HIV-1-infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068.Results: The maximum median decrease in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log(10) copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding-adjusted 90% inhibitory concentration (inhibitory quotient), were linked with antiviral response. BMS-663068 was generally well tolerated.Conclusions: Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted. Clinical Trials Registration.NCT01009814. [ABSTRACT FROM AUTHOR]

This study examined a new emotional writing paradigm, that is PDDP. PDDP instructs participants to write diary in first-person pronoun first, and then narrate the same event from a different perspective using second-person pronoun. Finally, the participants write it again with third-person pronoun from yet another perspective. These three narrations were to be written in a consecutive sequential order. Results demonstrated that diary writers indeed benefited from features of PDDP. It also showed that highly anxious people received most long-term therapeutic effect from PDDP. We argue that PDDP enacts the needed mechanism to balance psychological distance prolonging and self-disclosure making in emotional writing. [ABSTRACT FROM AUTHOR]

AIMS: Single nucleotide polymorphisms in matrix metalloproteinase-2 (MMP-2) -1306 C/T and tissue inhibitor of metalloproteinase-2 (TIMP-2) -418 G/C abolish the Sp-1 binding site and down-regulate expression of these genes. We aim to elucidate the role of MMP-2 and TIMP-2 in clinicopathological manifestations of gastric cancer. METHODS: We enrolled 240 gastric cancer patients and 283 controls. DNA was extracted from peripheral blood leucocytes. MMP-2 and TIMP-2 genotypes were analysed by PCR-direct sequencing and PCR-RFLP method, respectively. RESULTS: MMP-2 and TIMP-2 genotypes were not associated with gastric cancer development. However, patients with MMP-2 -1306 C/C genotype showed higher risk of lymphatic invasion (odds ratio (OR)=2.77, p=0.01) and venous invasion (OR=2.93, p=0.012). TIMP-2 G/G genotype was associated with serosal invasion (OR=1.89, p=0.009), lymph node metastasis (OR=2.19, p=0.021), lymphatic invasion (OR=2.87, p=0.016) and venous invasion (OR=2.65, p=0.033). CONCLUSION: Our results suggest MMP-2 and TIMP-2 genotypes play a crucial role in gastric cancer invasion, but not with development of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) patients with elevated level of androgen receptor (AR) correlate with higher metastatic incidence. Protein expression of AR and its target gene prostate-specific antigen (PSA) are elevated in metastatic prostate tumors as compared to organ-confined tumors. Androgen treatment or elevation of AR promotes metastasis of PCa in cell culture and murine model. However, under androgen depleted condition, AR suppressed cell mobility and invasiveness of PCa cells. Androgen deprivation therapy in PCa patients is associated with higher risk of cancer metastasis. We therefore investigated the dual roles of AR and miRNAs on PCa metastasis., Methods: The PC-3 AR (PC-3 cells re-expressing AR) and LNCaP cells were used as PCa cell model. Transwell migration and invasion assay, wound-healing assay, zebrafish xenotransplantation assay, and zebrafish vascular exit assay were used to investigate the role of AR and androgen on PCa metastasis. Micro-Western Array, co-immunoprecipitation and Immunofluorescence were applied to dissect the molecular mechanism lying underneath. The miRNA array, miRNA inhibitors or plasmid, and chromatin immunoprecipitation assay were used to study the role of miRNAs on PCa metastasis., Results: In the absence of androgen, AR repressed the migration and invasion of PCa cells. When androgen was present, AR stimulated the migration and invasion of PCa cells both in vitro and in zebrafish xenotransplantation model. Androgen increased phospho-AR Ser81 and yes-associated protein 1 (YAP), decreased phospho-YAP Ser217, and altered epithelial-mesenchymal transition (EMT) proteins in PCa cells. Co-IP assay demonstrated that androgen augmented the interaction between YAP and AR in nucleus. Knockdown of YAP or treatment with YAP inhibitor abolished the androgen-induced migration and invasion of PCa cells, while overexpression of YAP showed opposite effects. The miRNA array revealed that androgen decreased hsa-miR-5001-5p but increased hsa-miR-203a and hsa-miR-210-3p in PC-3AR cells but not PC-3 cells. Treatment with inhibitors targeting hsa-miR-203a/hsa-miR-210-3p, or overexpression of hsa-miR-5001-5p decreased YAP expression as well as suppressed the androgen-induced migration and invasion of PCa cells. Chromatin immunoprecipitation (ChIP) assay demonstrated that AR binds with promoter region of has-miR-210-3p in the presence of androgen., Conclusions: Our observations indicated that miRNAs 203a/210-3p/5001-5p regulate the androgen/AR/YAP-induced PCa metastasis., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Renal cell carcinoma (RCC) is characterized by high mortality and morbidity rates. Vav guanine nucleotide exchange factors (VAVs), crucial for signal transduction between cell membrane receptors and intracellular mediators, have been implicated in carcinogenesis. However, their potential prognostic value in RCC remains unclear. The impact of 150 common VAV polymorphisms on RCC risk and survival was investigated in a cohort of 630 individuals. Publicly available gene expression datasets were utilized to analyze VAV gene expression in relation to patient outcomes. The VAV3 rs17019888 polymorphism was significantly associated with RCC risk and overall survival after adjusting for false discovery rates. Expression quantitative trait loci analysis revealed that the risk allele of rs17019888 is linked to reduced VAV3 expression. Analysis of 19 kidney cancer gene expression datasets revealed lower VAV3 expression in RCC tissues compared to normal tissues, with higher expression correlating with better prognosis. Gene set enrichment analysis demonstrated that VAV3 negatively regulates the ubiquitin-proteasome system, extracellular matrix and membrane receptors, inflammatory responses, matrix metalloproteinases, and cell cycle pathways. Furthermore, elevated VAV3 expression was associated with increased infiltration of B cells, macrophages, and neutrophils into the RCC tumor microenvironment. Our findings suggest that VAV3 gene variants influence RCC risk and survival, contributing to a favorable prognosis in RCC.

Metal-organic frameworks (MOFs) are porous materials with applications in gas separations and catalysis, but a lack of water stability often limits their practical use given the ubiquity of water. Consequently, it is useful to predict whether a MOF is water-stable before investing time and resources into synthesis. Existing heuristics for designing water-stable MOFs lack generality and limit the diversity of explored chemistry due to narrowly defined criteria. Machine learning (ML) models offer the promise to improve the generality of predictions but require data. In an improvement on previous efforts, we enlarge the available training data for MOF water stability prediction by over 400%, adding 911 MOFs with water stability labels assigned through semiautomated manuscript analysis to curate the new data set WS24. The additional data are shown to improve ML model performance (test ROC-AUC > 0.8) over diverse chemistry for the prediction of both water stability and stability in harsher acidic conditions. We illustrate how the expanded data set and models can be used with a previously developed activation stability model in combination with genetic algorithms to quickly screen ∼10,000 MOFs from a space of hundreds of thousands for candidates with multivariate stability (upon activation, in water, and in acid). We uncover metal- and geometry-specific design rules for robust MOFs. The data set and ML models developed in this work, which we disseminate through an easy-to-use web interface, are expected to contribute toward the accelerated discovery of novel, water-stable MOFs for applications such as direct air gas capture and water treatment.

Background: Several studies have suggested a potential correlation between menopause and airflow limitation. However, the presence of protective factors in postmenopausal women remains uncertain. Therefore, our study seeks to examine potential protective factors associated with a reduced prevalence of airflow limitation among postmenopausal women., Methods: Postmenopausal women were recruited from the Taiwan Biobank for this cross-sectional study. Airflow limitation was defined by a forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio <0.7. The participants were categorized into two groups: non-coffee drinkers and coffee drinkers, and the association between coffee consumption and airflow limitation was examined using binary logistic regression models., Results: A total of 8149 women with available information were enrolled. Compared to the non-coffee drinkers, the coffee drinkers had a significantly lower prevalence of airflow limitation (7% vs. 5%). The odds ratio (OR) for airflow limitation was lower in the coffee drinkers than in the non-coffee drinkers (OR = 0.77; 95% confidence interval [CI] = 0.63 to 0.94) after adjusting for confounding factors. We also examined the association between daily coffee consumption in cups and airflow limitation. The women who consumed ≥2 cups of coffee per day had an OR of 0.74 (95% CI = 0.59 to 0.94) compared to those who did not consume coffee., Conclusions: Our results suggest that habitual coffee consumption is associated with a reduction in the prevalence of airflow limitation in postmenopausal women, warranting further prospective studies to explore possible causal effects and mechanisms., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals regulating multiple responses of cells, including metastatic cancer cells, dispersing in blood vessels. We, therefore, studied the effect of shear flow on circulating CRC cells in the present study. The CRC cell line SW620 was subjected to shear flow of 12.5 dynes/cm 2 for 1 and 2 h separately. Resulting elevated caspase-9 and -3 indicated that shear flow initiated the apoptosis of SW620. Enlarged cell size associated with a higher level of cyclin D1 was coincident with the flow cytometric results indicating that the cell cycle was arrested at the G 1 phase. An elevated phosphor-eNOS S1177 increased the production of nitric oxide and led to reactive oxygen species-mediated oxidative stress. Shear flow also regulated epithelial-mesenchymal transition (EMT) by increasing E-cadherin and ZO-1 while decreasing Snail and Twist1. The migration and invasion of sheared SW620 were also substantially decreased. Further investigations showed that mitochondrial membrane potential was significantly decreased, whereas mitochondrial mass and ATP production were not changed. In addition to the shear flow of 12.5 dynes/cm 2 , the expressions of EMT were compared at lower (6.25 dynes/cm 2 ) and at higher (25 dynes/cm 2 ) shear flow. The results showed that lower shear flow increased mesenchymal characteristics and higher shear flow increased epithelial characteristics. Shear flow reduces the malignancy of CRC in their metastatic dispersal that opens up new ways to improve cancer therapies by applying a mechanical shear flow device., (© 2024 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Glaucine is an aporphine alkaloid with anti-inflammatory, bronchodilator and anti-cancer activities. However, the effects of glaucine in the regulation of age-related macular degeneration (AMD) remain unclear. Herein, we aimed to investigate the anti-angiogenetic and anti-inflammatory effects of glaucine in ARPE-19 cells. ARPE-19 cells were treated with N-(methoxyoxoacetyl)-glycine, methyl ester (DMOG) and cobalt chloride (CoCl 2 ) for induction of hypoxia, while lipopolysaccharide (LPS) treatment was used for elicitation of inflammatory response. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The expression of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by Western blot. The secretion of VEGF, interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was detected using enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were used for tube formation analysis. Expression of HIF-1α and secretion of VEGF were significantly increased under DMOG and CoCl 2 induction, whereas glaucine significantly attenuated both HIF-1α expression and VEGF secretion by DMOG- and CoCl 2 -induced ARPE-19 cells. In addition, glaucine suppressed the tube formation by DMOG- and CoCl 2 -induced HUVEC cells. Moreover, glaucine also attenuated the production of IL-6 and MCP-1 by LPS-induced ARPE-19 cells. This study indicated that glaucine exhibited anti-angiogenic and anti-inflammatory effects, suggesting that glaucine might have benefits for the treatment of AMD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride ( 223 Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223 Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223 Ra was prescribed as part of routine practice by investigators. Patients with prior 223 Ra treatment were excluded. The primary objective was to assess 223 Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223 Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223 Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223 Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223 Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223 Ra injections and earlier 223 Ra use had longer OS than those receiving fewer injections and later 223 Ra use. 223 Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Vitamin D deficiency is common in patients with inflammatory bowel disease (IBD). In this study, we aimed to evaluate the prevalence and risk factors of vitamin D deficiency in a Taiwanese IBD cohort. Vitamin D levels were checked in adult patients with IBD who were treated at Changhua Christian Hospital, a medical center in central Taiwan, from January 2017 to December 2023. The risk factors for vitamin D deficiency were evaluated. 106 adult IBD patients were included, including 20 patients with Crohn's disease and 86 with ulcerative colitis. The median age at diagnosis was 39.2 years. The mean vitamin D level was 22.2 ± 8 ng/mL. Forty-five patients (42.5%) had vitamin D deficiency (vitamin D level < 20 ng/mL). Comparing patients with normal vitamin D levels and those with vitamin D deficiency after multivariate adjustment, female sex and early age at diagnosis were identified as statistically significant risk factors. We found a prevalence of 42.5% of vitamin D deficiency in the Taiwanese IBD population. Understanding this issue is essential for teaching patients and doctors about vitamin D deficiency screening and improving patient outcomes., (© 2024. The Author(s).)

Background: Nutritional administration in acute pancreatitis (AP) management has sparked widespread discussion, yet contradictory mortality results across meta-analyses necessitate clarification. The optimal nutritional route in AP remains uncertain. Therefore, this study aimed to compare mortality among nutritional administration routes in patients with AP using consistency model., Methods: This study searched four major databases for relevant randomized controlled trials (RCTs). Two authors independently extracted and checked data and quality. Network meta-analysis was conducted for estimating risk ratios (RRs) with 95% confidence interval (CI) based on random-effects model. Subgroup analyses accounted for AP severity and nutrition support initiation., Results: A meticulous search yielded 1185 references, with 30 records meeting inclusion criteria from 27 RCTs (n = 1594). Pooled analyses showed the mortality risk reduction associated with nasogastric (NG) (RR = 0.34; 95%CI: 0.16-0.73) and nasojejunal (NJ) feeding (RR = 0.46; 95%CI: 0.25-0.84) in comparison to nil per os. Similarly, NG (RR = 0.45; 95%CI: 0.24-0.83) and NJ (RR = 0.60; 95%CI: 0.40-0.90) feeding also showed lower mortality risk than total parenteral nutrition. Subgroup analyses, stratified by severity, supported these findings. Notably, the timing of nutritional support initiation emerged as a significant factor, with NJ feeding demonstrating notable mortality reduction within 24 and 48 h, particularly in severe cases., Conclusion: For severe AP, both NG and NJ feeding appear optimal, with variations in initiation timings. NG feeding does not appear to merit recommendation within the initial 24 h, whereas NJ feeding is advisable within the corresponding timeframe following admission. These findings offer valuable insights for optimizing nutritional interventions in AP., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Background: We aimed to describe healthcare resource utilization (HCRU) and healthcare costs in patients with newly confirmed lupus nephritis (LN) in the United States over a 5-year follow-up period., Methods: This retrospective, longitudinal cohort study (GSK Study 214102) utilized administrative claims data to identify individuals with a newly confirmed diagnosis of LN between August 01, 2011, and July 31, 2018, based on LN-specific International Classification of Diseases diagnosis codes. Index was the date of first LN-related diagnosis code claim. HCRU, healthcare costs, and incidence of systemic lupus erythematosus (SLE) flares were reported annually among eligible patients with at least 5 years continuous enrollment post-index., Results: Of 2,159 patients with a newly confirmed diagnosis of LN meeting inclusion and exclusion criteria, 335 had at least 5 years continuous enrollment post-index. HCRU was greatest in the first year post-LN diagnosis across all categories (inpatient admission, emergency room [ER] visits, ambulatory visits, and pharmacy use), and trended lower, though remained substantial, in the 5-year follow-up period. Among patients with LN and HCRU, the mean (standard deviation [SD]) number of ER visits and inpatient admissions were 3.7 (4.6) and 1.8 (1.5), respectively, in Year 1, which generally remained stable in Years 2-5; the mean (SD) number of ambulatory visits and pharmacy fills were 35.8 (25.1) and 62.9 (43.8), respectively, in Year 1, and remained similar for Years 2-5. Most patients (≥ 91.6%) had ≥ 1 SLE flare in each of the 5 years of follow-up. The proportion of patients who experienced a severe SLE flare was higher in Year 1 (31.6%) than subsequent years (14.3-18.5%). Total costs (medical and pharmacy; mean [SD]) were higher in Year 1 ($44,205 [71,532]) than subsequent years ($29,444 [52,310]-$32,222 [58,216]), driven mainly by inpatient admissions (Year 1: $21,181 [58,886]; subsequent years: $7,406 [23,331]-$9,389 [29,283])., Conclusions: Patients with a newly confirmed diagnosis of LN have substantial HCRU and healthcare costs, particularly in the year post-diagnosis, largely driven by inpatient costs. This highlights the need for improved disease management to prevent renal damage, improve patient outcomes, and reduce costs among patients with renal involvement., (© 2024. The Author(s).)

We present an integrated single-cell RNA sequencing atlas of the primary breast tumor microenvironment (TME) containing 236,363 cells from 119 biopsy samples across eight datasets. In this study, we leverage this resource for multiple analyses of immune and cancer epithelial cell heterogeneity. We define natural killer (NK) cell heterogeneity through six subsets in the breast TME. Because NK cell heterogeneity correlates with epithelial cell heterogeneity, we characterize epithelial cells at the level of single-gene expression, molecular subtype, and 10 categories reflecting intratumoral transcriptional heterogeneity. We develop InteractPrint, which considers how cancer epithelial cell heterogeneity influences cancer-immune interactions. We use T cell InteractPrint to predict response to immune checkpoint inhibition (ICI) in two breast cancer clinical trials testing neoadjuvant anti-PD-1 therapy. T cell InteractPrint was predictive of response in both trials versus PD-L1 (AUC = 0.82, 0.83 vs. 0.50, 0.72). This resource enables additional high-resolution investigations of the breast TME., Competing Interests: Declaration of interests I.S.C., L.X., and K.S. are co-inventors on a pending patent application for a method to determine a predominant immune signal in a breast tumor microenvironment., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Four ethanol fractionated crude extracts (EFCEs [A-D]) purified from the leaves of Cinnamomum macrostemon Hayata were screened for antioxidative effects and mitochondrial function in HaCaT cells. The higher cell viability indicated that EFCE C was mildly toxic. Under the treatment of 50 ng/mL EFCE C, the hydrogen peroxide (H2O2)-induced cytosolic and mitochondrial reactive oxygen species levels were reduced as well as the H2O2-impaired cell viability, mitochondrial membrane potential (MMP), ATP production, and mitochondrial mass. The conversion of globular mitochondria to tubular mitochondria is coincident with EFCE C-restored mitochondrial function. The mitophagy activator rapamycin showed similar effects to EFCE C in recovering the H2O2-impaired cell viability, MMP, ATP production, mitochondrial mass, and also mitophagic proteins such as PINK1, Parkin, LC3 II, and biogenesis protein PGC-1α. We thereby propose the application of EFCE C in the prevention of oxidative stress in skin cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Due to the comprehensive hepatitis B virus vaccination program in Taiwan since 1986, the development of antiviral therapy for chronic hepatitis B and chronic hepatitis C infection and covered by National health insurance. Besides, the increased prevalence of nonalcoholic fatty liver disease (NAFLD) and currently, approved therapy for NAFLD remain developing. The etiology of liver-related diseases such as cirrhosis and hepatocellular carcinoma required reinterpretation. This study aimed to analyze the incidence and outcome of hepatocellular carcinoma (HCC) due to viral (hepatitis B and hepatitis C) infection compared to that of nonviral etiology. We retrospectively analyzed patients with HCC from January 2011 to December 2020 from the cancer registry at our institution. Viral-related hepatitis was defined as hepatitis B surface antigen positivity or anti-hepatitis C virus (HCV) antibody positivity. A total of 2748 patients with HCC were enrolled, of which 2188 had viral-related HCC and 560 had nonviral-related HCC. In viral HCC group, the median age at diagnosis was significantly lower (65 years versus 71 years, p < 0.001), and the prevalence of early-stage HCC, including stage 0 and stage A Barcelona Clinic Liver Cancer, was significantly higher (52.9% versus 33.6%, p < 0.001). In nonviral HCC group, alcohol use was more common (39.9% versus 30.1%, p < 0.001), the prevalence of type 2 diabetes mellitus (T2DM) was higher (54.5% versus 35.1%, p < 0.001), and obesity was common (25.0% versus 20.5%, p = 0.026). The prevalence of nonviral HCC increased significantly from 19.2 to 19.3% and 23.0% in the last 10 years (p = 0.046). Overall survival was better in the viral HCC group (5.95 years versus 4.00 years, p < 0.001). In the early stage of HCC, overall survival was still better in the viral HCC group (p < 0.001). The prevalence of nonviral HCC has significantly increased in the last ten years. The overall survival was significantly lower in the nonviral HCC, perhaps because the rate of early HCC detection is lower in nonviral HCC and anti-viral therapy. To detect nonviral HCC early, we should evaluate liver fibrosis in high-risk groups (including people with obesity or T2DM with NAFLD/NASH and alcoholic liver disease) and regular follow-up for those with liver fibrosis, regardless of cirrhosis., (© 2024. The Author(s).)

This study investigates the correlation between body mass index (BMI) and osteoporosis utilizing data from the Taiwan Biobank. Initially, a comprehensive analysis of 119,009 participants enrolled from 2008 to 2019 was conducted to assess the association between BMI and osteoporosis prevalence. Subsequently, a longitudinal cohort of 24,507 participants, initially free from osteoporosis, underwent regular follow-ups every 2-4 years to analyze the risk of osteoporosis development, which was a subset of the main cohort. Participants were categorized into four BMI groups: underweight (BMI < 18.5 kg/m 2 ), normal weight (18.5 kg/m 2  ≤ BMI < 24 kg/m 2 ), overweight (24 kg/m 2  ≤ BMI < 27 kg/m 2 ), and obese groups (BMI ≥ 27 kg/m 2 ). A T-score ≤ - 2.5 standard deviations below that of a young adult was defined as osteoporosis. Overall, 556 (14.1%), 5332 (9.1%), 2600 (8.1%) and 1620 (6.7%) of the participants in the underweight, normal weight, overweight and obese groups, respectively, had osteoporosis. A higher prevalence of osteoporosis was noted in the underweight group compared with the normal weight group (odds ratio [OR], 2.20; 95% confidence interval [95% CI], 1.99 to 2.43; p value < 0.001) in multivariable binary logistic regression analysis. Furthermore, in the longitudinal cohort during a mean follow-up of 47 months, incident osteoporosis was found in 61 (9%), 881 (7.2%), 401 (5.8%) and 213 (4.6%) participants in the underweight, normal weight, overweight and obese groups, respectively. Multivariable Cox proportional hazards analysis revealed that the risk of incident osteoporosis was higher in the underweight group than in the normal weight group (hazard ratio [HR], 1.63; 95% CI 1.26 to 2.12; p value < 0.001). Our results suggest that BMI is associated with both the prevalence and the incidence of osteoporosis. In addition, underweight is an independent risk factor for developing osteoporosis. These findings highlight the importance of maintaining normal weight for optimal bone health., (© 2024. The Author(s).)

Hereditary factor X deficiency (HFXD) is a rare bleeding disorder causing delayed haemostasis and potentially life-threatening bleeds. Patient/caregiver burden and diagnosis path have not been well characterized., The Aim of This Study Was to: describe the diagnosis path, disease burden, and HFXD impact on quality of life (QoL) in patients and caregivers.This was a prospective, cross-sectional, web-based survey of patients with HFXD and caregivers addressing the patient/caregiver experience, QoL, humanistic and unmet needs.Thirty patients and 38 caregivers completed the survey with mean ages 24.7 and 44.6 years, respectively. Mean age at diagnosis was 4.1 years. The diagnostic process was somewhat/very difficult for 23% of patients and 26% of caregivers. Approximately half (53%) received single factor replacement (SFR) as prophylaxis or on-demand. Most patients (71%) reported regular prophylaxis treatment. Over one-fourth (27%) reported treatment with fresh frozen plasma. Bleeding episodes were less common in patients using SFR versus non-SFR: three bleeds or fewer were reported by 92% SFR and 75% non-SFR patients. HFXD patients reported low well being in work/school/social activities with mean HFXD-adapted Hemophilia Well being Index. Patient symptoms negatively impacted caregiver burden with a mean HFXD-adapted Hemophilia Caregiver Index (±SD) of 15.9 (4.6), but also unexpectedly had a positive impact on self-worth and inner strength.To our knowledge, this is the first study to assess patient and caregiver burden of HFXD and impact on QoL. Improvements in symptom recognition, prompt diagnosis, and adherence to expert recommendations for treatment could improve QoL and decrease burden on HFXD patients and caregivers., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Smoking is the most important risk factor for chronic obstructive pulmonary disease (COPD), however evidence from large-scale studies on whether secondhand smoke (SHS) increases the risk of COPD is still lacking. We conducted this large longitudinal study to investigate the association between SHS and the development of COPD. This is a longitudinal study. Data on 6519 subjects who were never-smokers, had no history of COPD, and had complete lung function records were extracted from the Taiwan Biobank. They were divided into two groups according to SHS exposure: no exposure and exposure groups. Data were collected when participants enrolled in the study and during regular follow-up. Cox proportional hazards regression models were used to estimate the relative risk (RR) and 95% confidence interval (CI) for the association between SHS and the risk of developing COPD. At 48 months of follow-up, 260 (4%) participants in the no exposure group and 34 (7%) participants in the exposure group developed COPD. The RR of incident COPD development was significantly higher in the exposure group than that in the no exposure group after adjusting for confounders (RR = 1.49; 95% CI 1.04 to 2.14; P value = 0.031). There is a dose-response relationship between the duration of exposure to SHS and the risk of incident COPD, which demonstrates that an additional hour of exposure to SHS per week was associated with a 1.03-fold increased likelihood of developing COPD after adjusting for confounders (RR = 1.03; 95% CI 1.00 to 1.05; P value = 0.027). SHS exposure contributes to the development of COPD. This finding can help raise awareness of the harms of SHS and provide a reference for formulating anti-smoking policies., (© 2024. The Author(s).)

Background: There is no doubt that both Hashimoto thyroiditis and Graves' disease are autoimmune thyroid diseases (AITDs), but the relationship between anti-nuclear antibody (ANA) and AITDs is poorly studied. The association between thyroid autoantibody levels and ANA positivity was evaluated to assess the role of ANA in AITDs., Methods: We conducted an analysis using data from 1,149,893 patients registered at our hospital and 53,021 patients registered in the National Health and Nutrition Examination Survey databases. We focused on patients with data for thyroid peroxidase antibody (TPOAb)/ANA, TPOAb/immunoglobulin G (IgG), thyroid-stimulating hormone (TSH) receptor antibody (TRAb)/ANA, TRAb/IgG, TSH/ANA, or TSH/IgG., Results: ANA positivity rates were 12.88% and 21.22% in TPOAb/ANA and TSH/ANA patients, respectively. In TPOAb/IgG and TSH/IgG data, high IgG levels (≥15 g/L) were detected in 2.23% and 4.06% of patients, respectively. There were significant differences in ANA positivity rates and high IgG proportions among patients with different TPOAb and TSH levels. TPOAb level was correlated with ANA positivity rate and high IgG proportion, and TSH level was correlated with ANA positivity rate. Regression analysis showed positive correlations between TPOAb levels and ANA positivity risk or high IgG risk, TSH levels and high IgG risk, and elevated TSH and ANA positivity risk. Of patients with TRAb/ANA data, 35.99% were ANA-positive, and 13.93% had TRAb levels ≥1.75IU/L; 18.96% of patients with TRAb/IgG data had high IgG levels, and 16.51% had TRAb levels ≥1.75IU/L. ANA positivity rate and high IgG proportion were not significantly different among different TRAb levels. TRAb levels, ANA positivity risk and high IgG risk were not correlated., Conclusion: ANA positivity and high IgG are related to Hashimoto thyroiditis but not Graves' disease, which implies distinct pathophysiological mechanisms underlying the AITDs., 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 Ruan, Heng, Yang, He, Li, Wang, Huang, Chen and Han.)

Introduction: Guidelines for infant CPR recommend the two-thumb encircling hands technique (TTT) and the two-finger technique (TFT) for chest compression. Some devices have been designed to assist with infant CPR, but are often not readily available. Syringe plungers may serve as an alternative infant CPR assist device given their availability in most hospitals. In this study, we aimed to determine whether CPR using a syringe plunger could improve CPR quality measurements on the Resusci-Baby manikin compared with traditional methods of infant CPR., Methods: Compression area with a diameter of 1 to 2 cm is recommended in previous infant CPR device researches. In this is a randomized crossover manikin study, we examined the efficacy of the Syringe Plunger Technique (SPT) which uses the plunger of the 20 ml syringe with a 2 cm diameter flat piston, commonly available in hospital, for infant External Chest Compressions (ECC). Participants performed TTT, TFT and SPT ECC on Resusci® Baby QCPR® according to 2020 BLS guidelines., Results: Sixty healthcare providers participated in this project. The median (IQR) ECC depths in the TTT, TFT and SPT in the first minute were 41 mm (40-42), 40 mm (38-41) and 40 mm (39-41), respectively, with p < 0.001. The median (IQR) ECC recoil in the TTT, TFT and SPT groups in the first minute was 15% (1-93), 64% (18-96) and 53% (8-95), respectively, with p = 0.003. The result in the second minute had similar findings. The SPT had the best QCPR score and less fatigue., Conclusion: The performance of chest compression depth and re-rebound ratio was statistically different among the three groups. TTT has good ECC depth and depth accuracy but poor recoil. TFT is the complete opposite. SPT can achieve a depth close to TTT and has a good recoil performance as TFT. Regarding comprehensive performance, SPT obtains the highest QCPR score, and SPT is also less fatigued. SPT may be an effective alternative technique for infant CPR., 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 © 2023. Published by Elsevier Inc.)

Background: Chronic kidney disease (CKD) is a prevalent condition in Taiwan, and the incidence of total knee arthroplasty (TKA) is on the rise. This study aimed to evaluate the postoperative results of patients with different degrees of CKD after TKA, using data from the Taiwan National Health Insurance Research Database., Methods: The study analyzed 3078 patients who received TKA from 2012 to 2017, equally divided into three groups: none-CKD, mild CKD (without dialysis), and severe CKD (with dialysis). Propensity score matching was used to minimize selection bias., Results: After TKA, there was no significant difference in the risk of debridement surgery for infection between the three groups (adjusted HR of mild CKD: 0.71 95% CI=0.36-1.38, p=0.3073; adjusted HR of severe CKD: 1.14, 95% CI=0.63-2.06, p=0.6616). However, CKD patients requiring dialysis had a significantly higher risk of mortality (adjusted HR: 1.98, 95% CI=1.57-2.50, p<0.001) and readmission within 90days of any causes (adjusted HR: 1.83, 95% CI=1.48-2.26, p<0.001) than non-CKD and mild CKD patients., Conclusion: Severe CKD patients needing dialysis after TKA have a higher risk of mortality and readmission rates than that of the non-CKD or mild CKD patients. If the patient is in the early stage of CKD, their prognosis after receiving TKA is expected to be as good as non-CKD patients., Level of Evidence: IV; well-designed cohort study., (Copyright © 2024. Published by Elsevier Masson SAS.)

Objective: To measure the association between ambient heat and hypoglycemia-related emergency department visit or hospitalization in insulin users., Research Design and Methods: We identified cases of serious hypoglycemia among adults using insulin aged ≥65 in the U.S. (via Medicare Part A/B/D-eligible beneficiaries) and Taiwan (via National Health Insurance Database) from June to September, 2016-2019. We then estimated odds of hypoglycemia by heat index (HI) percentile categories using conditional logistic regression with a time-stratified case-crossover design., Results: Among ∼2 million insulin users in the U.S. (32,461 hypoglycemia case subjects), odds ratios of hypoglycemia for HI >99th, 95-98th, 85-94th, and 75-84th percentiles compared with the 25-74th percentile were 1.38 (95% CI, 1.28-1.48), 1.14 (1.08-1.20), 1.12 (1.08-1.17), and 1.09 (1.04-1.13) respectively. Overall patterns of associations were similar for insulin users in the Taiwan sample (∼283,000 insulin users, 10,162 hypoglycemia case subjects)., Conclusions: In two national samples of older insulin users, higher ambient temperature was associated with increased hypoglycemia risk., (© 2024 by the American Diabetes Association.)

Background: Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer., Methods: We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer., Results: After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer., Conclusion: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted., (© 2024. The Author(s).)

Background: Circulating metabolites (CM) play a pivotal role in our overall health, yet the current evidence concerning the involvement of diverse CM in benign prostatic hyperplasia (BPH) remains limited. Mendelian randomization (MR) offers a promising avenue to explore the potential impact of CM on BPH., Methods: In a forward MR analysis, a cohort of 249 circulating metabolites was employed as exposures to investigate their potential associations with BPH risk. Conversely, in a reverse MR analysis, BPH was employed as an exposure to assess its effects on CM., Results: The forward MR analysis discerned a linkage between six metabolites and BPH, with careful consideration to excluding heterogeneity and pleiotropy. Subsequently, the reverse MR analysis unveiled that nine metabolic compounds, mainly comprising phospholipids and triglycerides, potentially exhibit elevated levels in BPH patients., Conclusion: Bidirectional MR analysis furnishes genetic insight into the interplay between CM and BPH. The prominence of lipids and triglycerides emerges as significant factors intricately linked to BPH risk., (© 2024. The Author(s).)

One-carbon metabolism plays a crucial role in tumorigenesis as it supplies the one-carbon units necessary for nucleotide synthesis, epigenetic regulation, and redox metabolism, ensuring the rapid proliferation of cancer cells. However, their roles in prostate cancer progression remain poorly understood. In this study, we investigated the association between genetic variants in the one-carbon metabolism pathway and clinical outcomes in patients receiving androgen deprivation therapy for prostate cancer. The associations of 130 single-nucleotide polymorphisms located within 14 genes involved in the one-carbon metabolism pathway with cancer-specific survival (CSS), overall survival, and progression-free survival were assessed using Cox regression in 630 patients with prostate cancer. Subsequently, functional studies were performed using prostate cancer cell lines. After adjusting for covariates and multiple testing, MTHFD1L rs2073190 was found to be significantly associated with CSS ( P = 0.000184). Further pooled analysis of multiple datasets demonstrated that MTHFD1L was upregulated in prostate cancer and increased MTHFD1L expression was positively correlated with tumor aggressiveness and poor patient prognosis. Functionally, MTHFD1L knockdown suppressed prostate cancer cell proliferation and colony formation. RNA sequencing and pathway analysis revealed that differentially expressed genes were predominantly enriched in the cell cycle pathway. In conclusion, genetic variants in MTHFD1L of one-carbon metabolism may serve as promising predictors, and our findings offer valuable insights into the underlying genetic mechanisms of prostate cancer progression., Competing Interests: None., (AJCR Copyright © 2024.)

This research is dedicated to developing an automatic landing system for shipborne unmanned aerial vehicles (UAVs) based on wireless precise positioning technology. The application scenario is practical for specific challenging and complex environmental conditions, such as the Global Positioning System (GPS) being disabled during wartime. The primary objective is to establish a precise and real-time dynamic wireless positioning system, ensuring that the UAV can autonomously land on the shipborne platform without relying on GPS. This work addresses several key aspects, including the implementation of an ultra-wideband (UWB) circuit module with a specific antenna design and RF front-end chip to enhance wireless signal reception. These modules play a crucial role in achieving accurate positioning, mitigating the limitations caused by GPS inaccuracy, thereby enhancing the overall performance and reception range of the system. Additionally, the study develops a wireless positioning algorithm to validate the effectiveness of automatic landing on the shipborne platform. The platform's wave vibration is considered to provide a realistic landing system for shipborne UAVs. The UWB modules are practically installed on the shipborne platform, and the UAV and the autonomous three-body vessel are tested simultaneously in the outdoor open water space to verify the functionality, precision, and adaptability of the proposed UAV landing system. Results demonstrate that the UAV can autonomously fly from 200 m, approach, and automatically land on the moving shipborne platform without relying on GPS.

Our study presents a 319-gene panel targeting inherited retinal dystrophy (IRD) genes. Through a multi-center retrospective cohort study, we validated the assay's effectiveness and clinical utility and characterized the mutation spectrum of Taiwanese IRD patients. Between January 2018 and May 2022, 493 patients in 425 unrelated families, all initially suspected of having IRD without prior genetic diagnoses, underwent detailed ophthalmic and physical examinations (with extra-ocular features recorded) and genetic testing with our customized panel. Disease-causing variants were identified by segregation analysis and clinical interpretation, with validation via Sanger sequencing. We achieved a read depth of >200× for 94.2% of the targeted 1.2 Mb region. 68.5% (291/425) of the probands received molecular diagnoses, with 53.9% (229/425) resolved cases. Retinitis pigmentosa (RP) is the most prevalent initial clinical impression (64.2%), and 90.8% of the cohort have the five most prevalent phenotypes (RP, cone-rod syndrome, Usher's syndrome, Leber's congenital amaurosis, Bietti crystalline dystrophy). The most commonly mutated genes of probands that received molecular diagnosis are USH2A (13.7% of the cohort), EYS (11.3%), CYP4V2 (4.8%), ABCA4 (4.5%), RPGR (3.4%), and RP1 (3.1%), collectively accounted for 40.8% of diagnoses. We identify 87 unique unreported variants previously not associated with IRD and refine clinical diagnoses for 21 patients (7.22% of positive cases). We developed a customized gene panel and tested it on the largest Taiwanese cohort, showing that it provides excellent coverage for diverse IRD phenotypes., (© 2024. The Author(s).)

Docetaxel-based chemotherapy has generally been considered as one of the effective treatments for castration-resistant prostate cancer (PCa). However, clinical treatment with docetaxel often encounters a number of undesirable effects, including drug resistance. Tubulin isoforms have been previously examined for their resistance to docetaxel in many cancers, but their real mechanisms remained unclear. In this study, a series of docetaxel-resistant PC/DX cell sublines were established by chronically exposing PC3 to progressively increased concentrations of docetaxel. Western blotting results showed significantly higher expression of acetyl-tubulin, α-tubulin, β-tubulin, γ-tubulin, and βIII-tubulin in PC/DX25 than in parental PC3 cells. PC/DX25 with greater resistance to docetaxel had higher levels of acetyl-tubulin and mitotic centromere-associated kinesin (MCAK) than PC3 cells. This study found that docetaxel induced the expression of acetyl-tubulin and MCAK in PC3 cells at a dose- and time-dependent manner. Both mRNA and protein levels of histone deacetylase 6 (HDAC6) were significantly decreased in PC/DX25 compared with PC3 cells. PC3 increased the resistance to docetaxel by HDAC6 knockdown and Tubastatin A (HDAC6 inhibitor). Conversely, PC/DX25 reversed the sensitivity to docetaxel by MCAK knockdown. Notably, flow cytometry analysis revealed that MCAK knockdown induced significantly sub G1 fraction in PC/DX cells. Overexpression of polo-like kinase-1 increased the cell survival rate and resistance to docetaxel in PC3 cells. Moreover, epidermal growth factor receptor (EGFR) activation induced the upregulation of acetyl-tubulin in docetaxel-resistant PCa cells. These findings demonstrated that the EGFR-mediated upregulated expression of acetyl-tubulin played an important role in docetaxel-resistant PCa., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Apoptotic death of retinal ganglion cells (RGCs) is a common pathologic feature in different types of optic neuropathy, including ischemic optic neuropathy and glaucoma, ultimately leading to irreversible visual function loss. Potent and effective protection against RGC death is determinative in developing a successful treatment for these optic neuropathies. This study evaluated the neuroprotective effect of a HECT domain-E3 ubiquitin ligase inhibitor, M01, on retinal ganglion cells after ischemic injury. Experimental anterior ischemic optic neuropathy (AION) was induced by photothrombotic occlusion of microvessels supplying optic nerve in rats. M01 was administered (100 mg/Kg and 200 mg/Kg) subcutaneously for three consecutive days after AION induction. Administration of M01 (100 mg/Kg) significantly increased RGC survival and preserved visual function after AION induction. The number of TUNEL-positive cells and ED1-positive cells was significantly decreased, and optic disc edema was reduced considerably after ischemic infarction with M01 treatment. Moreover, M01 effectively ameliorated optic nerve demyelination and enhanced M2 microglial polarization after AION induction. M01 enhanced the expression of nuclear factor erythroid 2-related factor (Nrf2); subsequently, downregulated Thioredoxin interacting protein (TXNIP) expression, inhibited NLR family pyrin domain containing 3 (NLRP3) activation, and further decreased inflammatory factors, interleukin (IL)-1β and IL-6 in the retina after ischemic injury. These findings suggested that M01 has therapeutic potential by modulating Nrf2 and TXNIP/NLRP3 inflammasome pathways in the retina and optic nerve ischemic damage-related diseases., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The purpose of this study was to investigate genetic factors associated with metabolic syndrome (MetS) by conducting a large-scale genome-wide association study (GWAS) in Taiwan, addressing the limited data on Asian populations compared to Western populations. Using data from the Taiwan Biobank, comprehensive clinical and genetic information from 107,230 Taiwanese individuals was analyzed. Genotyping data from the TWB1.0 and TWB2.0 chips, including over 650,000 single nucleotide polymorphisms (SNPs), were utilized. Genotype imputation using the 1000 Genomes Project was performed, resulting in more than 9 million SNPs. MetS was defined based on a modified version of the Adult Treatment Panel III criteria. Among all participants (mean age: 50 years), 23% met the MetS definition. GWAS analysis identified 549 SNPs significantly associated with MetS, collectively mapping to 10 genomic risk loci. Notable risk loci included rs1004558, rs3812316, rs326, rs4486200, rs2954038, rs10830963, rs662799, rs62033400, rs183130, and rs34342646. Gene-set analysis revealed 22 associated genes: CETP , LPL , APOA5 , SIK3 , ZPR1 , APOC1 , BUD13 , MLXIPL , TOMM40 , GCK , YKT6 , RPS6KB1 , FTO , VMP1 , TUBD1 , BCL7B , C19orf80 (ANGPTL8) , SIDT2 , SENP7 , PAFAH1B2 , DOCK6 , and FOXA2. This study identified genomic risk loci for MetS in a large Taiwanese population through a comprehensive GWAS approach. These associations provide novel insights into the genetic basis of MetS and hold promise for the potential discovery of clinical biomarkers.

BACKGROUND: EMBARK, a controlled trial reported elsewhere, showed enzalutamide plus leuprolide (combination) and enzalutamide monotherapy prolonged metastasis-free survival versus placebo plus leuprolide (alone) in patients with high-risk biochemically recurrent prostate cancer. Health-related quality of life was also analyzed but not reported. METHODS: In EMBARK, patients with biochemical recurrence (prostate-specific antigen doubling time of ≤9 months) were randomly assigned (1:1:1) to combination (n=355), leuprolide-alone (n=358), or enzalutamide monotherapy (n=355). In this article we provide the patient-reported outcomes (PROs) from EMBARK at baseline and every 12 weeks until metastasis or death. The key end point was time to first and confirmed clinically meaningful deterioration (TTFD/TTCD) in pain and health-related quality of life using four PRO measures and predefined thresholds. RESULTS: At baseline, all groups had high health-related quality of life. For worst pain, the median TTFD was 19.35 months with leuprolide alone, 13.93 months with combination (hazard ratio, 1.08; 95% confidence interval [CI], 0.89 to 1.30) and 16.59 months with monotherapy (hazard ratio, 1.09; 95% CI, 0.90 to 1.31). The median TTCD was 66.27 months with leuprolide alone, 80.00 months with combination (hazard ratio, 0.82; 95% CI, 0.65 to 1.04), and 60.91 months with monotherapy (hazard ratio, 1.02; 95% CI, 0.82 to 1.28). For Functional Assessment of Cancer Therapy–Prostate total score, the median TTFD was 11.10 months with leuprolide alone, 8.31 months with combination (hazard ratio, 1.14; 95% CI, 0.95 to 1.36), and 8.38 months with monotherapy (hazard ratio, 1.17; 95% CI, 0.98 to 1.39). The median TTCD was 36.53 months with leuprolide alone, 38.77 months with combination (hazard ratio, 1.04; 95% CI, 0.85 to 1.28), and 30.55 months with monotherapy (hazard ratio, 1.16; 95% CI, 0.95 to 1.41). CONCLUSIONS: The PROs from EMBARK show that both enzalutamide combination and monotherapy versus leuprolide alone, with oncologic benefits noted above, preserved high health-related quality of life in patients with high-risk biochemical recurrence of prostate cancer. (Funded by Pfizer and Astellas Pharma; ClinicalTrials.gov number, NCT02319837.)

The safety of human papillomavirus (HPV) vaccines has been evaluated continuously in pre-licensure clinical trials, post-marketing surveillance systems, and observational studies. Most studies have found no significant association between serious adverse events and HPV vaccination. However, these studies have focused on Western populations; similar studies focusing on Asian populations are insufficient. Our retrospective cohort study used the HPV-vaccination records of junior high-school adolescent girls aged 12-15 years between 2013 and 2018 in Taiwan's National Immunization Information System and linked them to a registry for beneficiaries in Taiwan's National Health Insurance Database (NHID) to establish the vaccinated group. We selected 19 serious diseases as serious adverse events. We compared the incidence rates of these serious adverse events between the vaccinated group and girls in the same age group population, and we calculated the standardized incidence ratio (SIR) to evaluate the risk of serious adverse events after HPV vaccination. Because of the onset of different types of diseases, we set three periods after the subjects received HPV vaccination: within 3 months, within 1 year, and during the study period (2013-2018). The results showed the incidence rates and the SIRs of 19 selected adverse events. Among the 19 selected serious adverse events, the disease with the highest incidence rate during the study period was fibromyalgia (73.23 cases per million population), and the disease with the lowest incidence rate during the study period was Crohn's disease (0.15 cases per million population). The results showed no statistically significant increases in the risk of 19 selected serious adverse events and indicated no association between HPV vaccination and serious adverse events. Given the benefits and safety of HPV vaccination, our research can reduce concerns about vaccine side effects, inform health policies and improve public and clinician's acceptance of HPV vaccine policy., 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 © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hepatitis B surface antigen (HBsAg) seroclearance, an indicator of recovery from hepatitis B virus (HBV) infection, is uncommon in long-term nucleos(t)ide analog (NUC) therapy. We compared the incidence of HBsAg seroclearance in patients with and without NUC discontinuation to identify predictors of HBsAg seroclearance. This retrospective study enrolled adult patients with a chronic HBV infection followed for ≥12 months after NUC discontinuation (finite group) and those treated with NUCs for >3 years (non-finite group). Demographic, clinical, and laboratory data were analyzed. The study cohort included 978 patients, including 509 and 469 patients in the finite and non-finite groups, respectively. Cumulative HBsAg seroclearance incidence was significantly higher in the finite group than in the non-finite group ( p = 0.006). The 5- and 10-year cumulative HBsAg seroclearance incidence were 6.6% and 18.9% in the finite group and 3% and 14.6% in the non-finite group, respectively. The likelihood of HBsAg seroclearance was higher in those with end of treatment (EOT) HBsAg levels of <100 IU/mL and in those without clinical relapse (CR). The cumulative 3-year CR incidence was 16.8%. The incidence of liver decompensation and hepatocellular carcinoma were 4.1 and 0.4 per 1000 person-years, respectively. The hepatocellular carcinoma incidence did not significantly differ between the finite and non-finite groups ( p = 0.941). In conclusion, higher HBsAg seroclearance incidence in patients receiving finite therapy, and the increased likelihood of HBsAg seroclearance in those with EOT HBsAg levels of <100 IU/mL and in those without CR should be considered during decision-making of treatment options.

Background: To explore a novel scoring system to evaluate the efficacy of vagus nerve stimulation (VNS) in children with drug-resistant generalized epilepsy (DRGE) aged six and younger., Basic Procedures: The data of twelve children with DRGE under the age of 6 years who accepted VNS and have been followed up for at least 3 years were retrospectively reviewed. The outcome was evaluated with the McHugh Classification System and a novel scoring system we proposed., Main Findings: Based on the McHugh Classification System, the total response rate was 91.67% (11/12) and the rate of Grade I was 41.67% (5/12). A novel scoring system involving seizure frequency, seizure duration and quality of life (QOL) was proposed, by which the outcome was scored from -3 to 11 and graded from IV to I. Based on the novel scoring system, the total response rate was 91.67% (11/12) and the rate of Grade I was 33.33% (4/12). The incidence of complication was 16.67% (2/12). The efficacy of VNS appeared a gradually improving trend with plateau or fluctuation over time. Shorter course of epilepsy prior to VNS may be related to better outcome., Principal Conclusions: VNS could effectively reduce the seizure frequency and improve the QOL of children with DRGE aged six and younger. The novel scoring system was comprehensive and feasible to evaluate the efficacy of VNS. The time pattern of the long-term efficacy of VNS requires further investigation., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)