The anti-tumor activity of diosgenin, a new steroidal constituent present in fenugreek, on two human breast cancer cell lines, MCF-7 and Hs578T, was studied. Diosgenin treatment resulted in cell ...growth inhibition, cell cycle arrest, and apoptosis in concentration- and time-dependent manners in both cell lines. Western blot analyses of whole cell lysates for cell cycle proteins showed that diosgenin altered phosphorylated cyclin checkpoint1 (p-Chk1
) and cyclin B expression, which resulted in G2/M phase blockade. Mechanistically, Cdc25C-Cdc2 signaling was involved in inactivating Chk1
by p53-dependence in MCF-7 cells and p21-dependence in Hs578T cells that are p53-deficient. Moreover, diosgenin induced a significant loss of the mitochondrial membrane potential in breast cancer cells, and prominently affected cell death through down-regulation of the anti-apoptotic protein, Bcl-2. This released cytochrome c and activated the caspase signaling cascade. Taken together, these findings reveal that the anti-proliferative activity of diosgenin involves the induction of G2/M phase arrest via modulating the Cdc25C-Cdc2-cyclin B pathway and mitochondria-mediated apoptosis in human breast cancer cell lines. This suggests the potential usefulness of diosgenin in treating breast cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Transition of aromatic and antioxidant components from mei fruit into liqueur.
Summary
This study evaluated the effects of high hydrostatic pressure (HHP) treatment on the physicochemical ...composition, level of aromatic compounds and antioxidant properties of mei liqueur, as well as the microstructure of mei fruits during a 180‐day ageing process. The titratable acidity, pH, and browning index of mei liqueur and HHP‐treated mei liqueur did not exhibit significant differences. The HHP‐treated mei liqueur displayed significantly higher ∆E, sugar and alcohol concentration during the 180‐day maceration period (P ≤ 0.05). Electron microscopy revealed that HHP treatment damaged the cellular structure of mei fruits, promoting the penetration of rice wine into the fruits as well as the dissolution of aromatic and antioxidant components into rice wine, leading to the completion of the maturation of the mei liqueur. Thus, HHP technology could be used to accelerate mei liqueur maturation, shorten the time required for its ageing, exhibiting tremendous potential for applications in the liqueur industry.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Exposure to residues of antibiotics (e.g., sulfonamides) and insecticides (e.g., organophosphorus insecticides) in aquacultured food can adversely affect humans and animals and thus affect public ...health globally. Here, using a validated method, we examined the levels of residues of 12 sulfonamides as well as 18 organophosphorus insecticides in aquacultured fish in Taiwan. A total of 52 fish samples (i.e., 20 tilapia, 16 milk fish, and 16 perch samples) were obtained from Taiwanese aquafarms from June 2018 to October 2019. We detected 0.02 and 0.03 mg/kg of sulfamethazine (a sulfonamide) in one tilapia and one milk fish, respectively, and 0.02, 0.05, and 0.03 mg/kg of chlorpyrifos (an organophosphorus insecticide) in one tilapia, one milk fish, and one perch, respectively; thus, among the samples, 3.85% and 5.77% contained sulfonamides and organophosphorus insecticide residues, respectively. Furthermore, we assessed human health risk based on the estimated daily intakes (EDIs) of these residues: EDIs of sulfonamide and organophosphorus insecticide residues were <1.0% of the acceptable daily intake recommended by the Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Committee on Food Additives. The risk of exposure to sulfonamide and organophosphorus insecticide residue by consuming aquacultured fish in Taiwan was thus negligible, signifying no immediate health risk related to the consumption of fish. Our findings can constitute a reference in efforts geared toward ensuring food safety and monitoring veterinary drug and insecticide residue levels in aquacultured organisms. Residue levels in fish must be continually monitored to further determine possible effects of these residues on human health.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine ...(CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Objective To carry out a comprehensive analysis on the clinical spectrum and HLA genotype–phenotype correlations in CBZ-induced hypersensitivity reactions. Methods We analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects. Results CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc = 5.8 × 10−43 ; odds ratio (OR) (95% CI) = 97.6(42.0–226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc = 8.3 × 10−5 ; OR (95% CI) = 0.22(0.1–0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02 , but linked to HLA-A*31:01 (Pc = 2.7 × 10−3 ; OR (95% CI) = 6.86(2.4–19.9), and HLA-B*51:01 (Pc = 0.01; OR (95% CI) = 4.56(2.0–10.5)). No gene dosage or CBZ dosage effects was observed. Conclusion This study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype–phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
White matter hyperintensities (WMHs) of presumed vascular origin are common in ageing population, especially in patients with acute cerebral infarction and the volume has been reported to be ...associated with mental impairment and the risk of hemorrhage from antithrombotic agents. WMHs delineation can be computerized to minimize human bias. However, the presence of cerebral infarcts greatly degrades the accuracy of WMHs detection and thus limits the application of computerized delineation to patients with acute cerebral infarction. We propose a computer-assisted segmentation method to depict WMHs in the presence of cerebral infarcts in combined T1-weighted, fluid attenuation inversion recovery, and diffusion-weighted magnetic resonance imaging (MRI). The proposed method detects WMHs by empirical threshold and atlas information, with subtraction of white matter voxels affected by acute infarction. The method was derived using MRI from 25 hemispheres with WMHs only and 13 hemispheres with both WMHs and cerebral infarcts. Similarity index (SI) and correlation were utilized to assess the agreement between the new automated method and a gold standard visually guided semi-automated method done by an expert rater. The proposed WMHs segmentation approach produced average SI, sensitivity and specificity of 83.142±11.742, 84.154±16.086 and 99.988±0.029% with WMHs only and of 68.826±14.036, 74.381±18.473 and 99.956±0.054% with both WMHs and cerebral infarcts in the derivation cohort. The performance of the proposed method with an external validation cohort was also highly consistent with that of the experienced rater.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Yttrium iron garnet ferrite using the chosen stoichiometry of (Y3)(MnxAl0.8‐xFe4.2)O12 with x = 0.1 and different milling powder sizes were prepared through ball milling for various milling times to ...study the effect of powder size reduction on the resulting microstructural and magnetic properties. Sintered yttrium iron garnet ferrites were characterized by X‐ray diffraction analysis and scanning electron microscopy. The particle size (D50) of as‐milled calcined powder was decreased using ball milling (from 3.682 μm for a 0.5‐hour‐long milling to 1.606 μm for a 2.5‐hour‐long milling). Scanning electron microscopy analyses confirmed that the sintered grain exhibited a crystal size that was increased from initial values (average crystal grain sizes of 3.5 ± 0.1 μm for 0.5 hour of milling) up to 6.2 ± 0.1 μm after 2.5 hour of ball milling and the subsequent sintering process. The same sintered specimen after 2.5 hour of ball milling exhibited an obvious increase in saturation magnetization (4πMs), remanence (Br), and squareness ratio (namely Br/4πMs); it also caused a notable decline in coercivity (Hc) and ferromagnetic resonance line width (∆H), which were attributed to the introduction of a smaller size of calcined powder after milling and subsequently resulted in a larger sintered grain. Furthermore, a sufficient spin‐wave line width (∆Hk) and low insertion loss (|S21|) were obtained for the operation of the microwave device. The aforementioned results are all beneficial to the use of yttrium iron garnet ferrite in microwave applications. A correlation between the calcined powder size after milling, grain crystal size after sintering, and magnetic properties was evident in this study. The strict control of calcined powder size after milling is critical in tailoring suitable magnetic properties for yttrium iron garnet ferrite manufacturing processes.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in ...Asian populations (Chinese and Thai).
METHODS:We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)–induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database.
RESULTS:We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10; odds ratio 27.90; 95% confidence interval CI 7.84–99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077–0.584).
CONCLUSIONS:Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.
To examine the relationships among therapist-reported, patient-reported, and objective assessment scores of balance function.
Inpatients with stroke and occupational therapists were recruited. The ...objective balance scores were measured using the Balance Computerized Adaptive Testing (Balance CAT) system. The therapist and patient-reported scores were evaluated using a visual analogue scale (VAS) and Likert-type scale.
Eighty-eight patients and 16 therapists participated. The correlations (r= 0.64 and 0.65; R-squared about 0.42 at baseline and follow-up assessments, respectively) between the therapist-reported VAS scores and the Balance CAT system were larger than those (r = 0.31 and 0.21) between the patient-reported VAS scores and the Balance CAT system. Low correlations (r = 0.27 and 0.26 for VAS and Likert-type scores, respectively) were found between the therapist-reported and patient-reported change scores. Low correlations (r = 0.12-0.17) were found between the change scores of therapist- and patient-reported ratings and those of the Balance CAT system.
The therapists' judgments explained <50% of variance of the Balance CAT system scores. Neither therapist-reported nor patient-reported change scores reflected the changes demonstrated by the objective assessments. Further studies are warranted to confirm our findings.
Implications for Rehabilitation
Neither therapist- nor patient-reported balance function and change could effectively reflect the scores resulting from objective assessments.
The routine use of objective balance assessments should not be replaced by therapists' subjective judgments.
Communications regarding the balance function measured by objective assessments between therapists and patients can help patients to better understand their balance function and progress.
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IJS, NUK, UL, UM, UPUK, VSZLJ
Located to the south of East China Sea, the Southern Okinawa Trough (SOT) is a back-arc basin, which belongs to the Ryukyu subduction system. SOT is characterized by an active normal faulting system ...and numerous volcanic outcrops, which could have marine mineral and geo-hazard potential for its nearby areas. By analyzing the data from the inland Central Weather Bureau Seismic Network (CWBSN) stations, we manually exanimated the waveforms of 2263 earthquakes collected from 1991 to the end of 2011 to identify the possible low frequency (LF) volcanic events. In total, 80 LF earthquakes were recognized. An updated relocation seismicity catalog was used to obtain a more reliable epicenter location. These LF events were mainly located along the central graben of SOT and to the southeast of the Kueishantao (KST) Island. The depths of the LF events are mostly shallower than 15 km near KST, and become deeper when the hypocenters get closer to the central axis of SOT. The LF earthquakes located near KST have relatively higher tendency to occur in cluster with a time interval of 1 to 4 years and the epicenters show a spatial migration. By comparing the distribution of the LF earthquakes with the available geophysical data, we suggest the major faults in SOT do not only influence the distribution for shallow volcanic bodies, but also confine the area of the deep magmatic activity.
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FFLJ, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UL, UM, UPUK
BackgroundTumor-associated macrophages (TAMs) are a significantly-poor prognostic factor for patients with triple-negative breast cancer (TNBC). The tumor microenvironment of TNBC features ...highly-infiltrating TAMs that contribute to tumor progression and metastasis. Therefore, TAM-targeted immunotherapies are recognized as a potential approach for treating TNBC. However, depleting TAMs alone by use of monoclonal antibodies against colony-stimulating factor 1 receptor (CSF1R) was insufficient to cause substantial tumor control. Recent studies revealed that interleukin-10 (IL-10) can directly activate terminally-exhausted CD8+ T cells to boost anti-tumor activity. We set forth to investigate whether a combination of anti-CSF1R antibody with a half-life-extended IL-10-Fc fusion protein (IL-10-Fc) may enhance anti-tumor immunity, and whether synergistic effects could be achieved with bifunctional antibody forms.MethodsAntibodies and recombinant proteins were produced in-house. In vitro CSF1R activity was evaluated by Western blot analysis of CSF1-mediated CSF1R phosphorylation and monocyte proliferation assays. In vitro IL10 activity was evaluated by MC/9 cell proliferation and CD8 T cell activation assays. 4T1 mouse breast tumor studies were performed at the National Yang Ming Chiao Tung University (Taiwan). Other tumor model studies employed the services of Crownbio (China). Methods of RNAseq analysis of 4T1 tumor masses included Cibersort, gene set enrichment analysis (GSEA) and immune gene signature score analysis.ResultsCo-treatment with a recombinant human IL-10-Fc protein significantly improved the anti-tumor efficacy of anti-mouse CSF1R antibody in a mouse CT26 colon tumor model. It was then hypothesized that a better synergistic effect could be achieved by a bifunctional anti-mouse CSF1R-IL-10 fusion protein (anti-mCSF1R-IL-10), to allow targeted-delivery of IL-10 to CSF1R-positive-TAM-rich tumor microenvironments. Indeed, anti-mCSF1R-IL-10 showed greatly increased anti-tumor efficacy in both EMT-6 and 4T1 mouse models of breast cancer. Consistent with the in vivo efficacy, gene expression profiling revealed an enhanced intratumoral interferon-gamma signature by treatment with anti-mCSF1R-IL-10 as compared to either anti-mCSF1R or IL-10-Fc alone. An anti-human CSF1R-IL-10 (hCSF1R-IL-10) was also constructed using a newly-produced anti-human CSF1R antibody and tested in cell-based functional assays, demonstrating that anti-hCSF1R-IL-10 could both inhibit CSF1-dependent cell growth and activate tumor-infiltrating T cells isolated from tumor biopsies of triple-negative breast cancer patients. Further validation of this bifunctional form will be presented.ConclusionsOur findings provide a potential strategy for simultaneously targeting TAM and exhausted T cells to potentiate anti-tumor immunity for treatment of triple-negative breast cancer.Ethics ApprovalThe studies were approved by the institutional animal care and use committee of National Yang Ming Chiao Tung University; approval numbers 1081025 and 109060.
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