The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells

Chun-Yu Liu,Tzu-Ting Huang,Pei-Yi Chu,Chun-Teng Huang,Chia-Han Lee,Wan-Lun Wang,Ka-Yi Lau,Wen-Chun Tsai,Tzu-I Chao,Jung-Chen Su,Ming-Huang Chen,Chung-Wai Shiau,Ling-Ming Tseng,Kuen-Feng Chen 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-

Triple-negative breast cancer (TNBC) remains difficult to treat and urgently needs new therapeutic options. Nintedanib, a multikinase inhibitor, has exhibited efficacy in early clinical trials for HER2-negative breast cancer. In this study, we examined a new molecular mechanism of nintedanib in TNBC. The results demonstrated that nintedanib enhanced TNBC cell apoptosis, which was accompanied by a reduction of p-STAT3 and its downstream proteins. STAT3 overexpression suppressed nintedanib-mediated apoptosis and further increased the activity of purified SHP-1 protein. Moreover, treatment with either a specific inhibitor of SHP-1 or SHP-1-targeted siRNA reduced the apoptotic effects of nintedanib, which validates the role of SHP-1 in nintedanib-mediated apoptosis. Furthermore, nintedanib-induced apoptosis was attenuated in TNBC cells expressing SHP-1 mutants with constantly open conformations, suggesting that the autoinhibitory mechanism of SHP-1 attenuated the effects of nintedanib. Importantly, nintedanib significantly inhibited tumor growth via the SHP-1/p-STAT3 pathway. Clinically, SHP-1 levels were downregulated, whereas p-STAT3 was upregulated in tumor tissues, and SHP-1 transcripts were associated with improved disease-free survival in TNBC patients. Our findings revealed that nintedanib induces TNBC apoptosis by acting as a SHP-1 agonist, suggesting that targeting STAT3 by enhancing SHP-1 expression could be a viable therapeutic strategy against TNBC.

Delay of Surgery for Spinal Metastasis due to the COVID-19 Outbreak Affected Patient Outcomes

Chia-Jung Hsieh,Chun-Yu Wu,Yen-Heng Lin,Yu-Cheng Huang,Wen-Chi Yang,Tom Wei-Wu Chen,Wei-Li Ma,Wei-Hsin Lin,Feng-Ming Hsu,Furen Xiao,Shih-Hung Yang,Dar-Ming Lai,Chang-Mu Chen,Shin-Yi Chao,Fon-Yih Tsuan 대한척추신경외과학회 2023 Neurospine Vol.20 No.4

Objective: The present study is to analyze the effects of the coronavirus disease 2019 (COVID 2019) outbreak and the subsequent lockdown on the outcomes of spinal metastasis patients. Methods: The study was a retrospective analysis of data from a prospective cohort study. All patients underwent surgical intervention for spinal metastases between January 2019 and December 2021 and had at least 3 months of postoperative follow-up. The primary outcome was overall mortality during the 4 different stages (pre-COVID-19 era, COVID-19 pandemic except in Taiwan, national lockdown, lifting of the lockdown). The secondary outcomes were the oncological severity scores, medical/surgical accessibility, and patient functional outcome during the 4 periods as well as survival/mortality. Results: A total of 233 patients were included. The overall mortality rate was 41.20%. During the Taiwan lockdown, more patients received palliative surgery than other surgical methods, and no total en bloc spondylectomy was performed. The time from surgeon visit to operation was approximately doubled after the COVID-19 outbreak in Taiwan (75.97, 86.63, 168.79, and 166.91 hours in the 4 periods, respectively). The estimated survival probability was highest after the national lockdown was lifted and lowest during the lockdown. In the multivariate analysis, increased risk of mortality was observed with delay of surgery, with emergency surgery having a higher risk with delays above 33 hours, urgent surgery (below 59 and above 111 hours), and elective surgery (above 332 hours). Conclusion: The COVID-19 pandemic and related policies have altered daily clinical practice and negatively impacted the survival of patients with spinal metastases.

High-Performance Bottom-Contact Organic Thin-Film Transistors Based on Benzo[<i>d</i>,<i>d</i>′]thieno[3,2-<i>b</i>;4,5-<i>b</i>′]dithiophenes (BTDTs) Derivatives

Huang, Peng-Yi,Chen, Liang-Hsiang,Kim, Choongik,Chang, Hsiu-Chieh,Liang, You-jhih,Feng, Chieh-Yuan,Yeh, Chia-Ming,Ho, Jia-Chong,Lee, Cheng-Chung,Chen, Ming-Chou American Chemical Society 2012 ACS APPLIED MATERIALS & INTERFACES Vol.4 No.12

<P>Three benzo[<I>d</I>,<I>d</I>′]thieno[3,2-<I>b</I>;4,5-<I>b</I>′]dithiophene (<B>BTDT</B>) derivatives, end-functionalized with benzothiophenyl (<B>BT-BTDT</B>; <B>2</B>), benzothieno[3,2-b]thiophenyl (<B>BTT-BTDT</B>; 3), and benzo[<I>d</I>,<I>d</I>′]thieno[3,2-<I>b</I>;4,5-<I>b</I>′]dithiophenyl (<B>BBTDT</B>; <B>4</B>), were prepared for bottom-contact/bottom-gate organic thin-film transistors (OTFTs). An improved one-pot [2 + 1 + 1] synthetic method of <B>BTDT</B> with improved synthetic yield was achieved, which enabled the efficient realization of new <B>BTDT</B>-based semiconductors. All of the <B>BTDT</B> compounds exhibited high performance p-channel characteristics with carrier mobilities as high as 0.34 cm<SUP>2</SUP>/(V s) and a current on/off ratio of 1 × 10<SUP>7</SUP>, as well as enhanced ambient stability. The device characteristics have been correlated with the film morphologies and microstructures of the corresponding compounds.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/aamick/2012/aamick.2012.4.issue-12/am3022448/production/images/medium/am-2012-022448_0010.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/am3022448'>ACS Electronic Supporting Info</A></P>

Chlorella Protects Against Hydrogen Peroxide-Induced Pancreatic β-Cell Damage

Chia-Yu Lin,Pei-Jane Huang,Che-Yi Chao 한국식품영양과학회 2014 Journal of medicinal food Vol.17 No.12

Oxidative stress has been implicated in the etiology of pancreatic β-cell dysfunction and diabetes. Studies have shown that chlorella could be important in health promotion or disease prevention through its antioxidant capacity. However, whether chlorella has a cytoprotective effect in pancreatic β-cells remains to be elucidated. We investigated the protective effects of chlorella on H2O2-induced oxidative damage in INS-1 (832/13) cells. Chlorella partially restored cell viability after H2O2 toxicity. To further investigate the effects of chlorella on mitochondria function and cellular oxidative stress, we analyzed mitochondria membrane potential, ATP concentrations, and cellular levels of reactive oxygen species (ROS). Chlorella prevented mitochondria disruption and maintained cellular ATP levels after H2O2 toxicity. It also normalized intracellular levels of ROS to that of control in the presence of H2O2. Chlorella protected cells from apoptosis as indicated by less p-Histone and caspase 3 activation. In addition, chlorella not only enhanced glucose-stimulated insulin secretion (GSIS), but also partially restored the reduced GSIS after H2O2 toxicity. Our results suggest that chlorella is effective in amelioration of cellular oxidative stress and destruction, and therefore protects INS-1 (832/13) cells from H2O2-induced apoptosis and increases insulin secretion. Chlorella should be studied for use in the prevention or treatment of diabetes.

Myricetin Inhibits the Release of Glutamate in Rat Cerebrocortical Nerve Terminals

Yi Chang,Chia-Ying Chang,Su-Jane Wang,Shu-Kuei Huang 한국식품영양과학회 2015 Journal of medicinal food Vol.18 No.5

The excessive release of glutamate is a critical element in the neuropathology of acute and chronic brain disorders. The purpose of the present study was to investigate the effect and possible mechanism of myricetin, a naturally occurring flavonoid with a neuroprotective profile, on endogenous glutamate release in the nerve terminals (synaptosomes) of the rat cerebral cortex. The release of glutamate was evoked by the K+ channel blocker 4-aminopyridine (4-AP) and measured by one-line enzyme-coupled fluorometric assay. We also used a membrane potential-sensitive dye to assay the synaptosomal plasma membrane potential, and a Ca2 + indicator Fura-2 to monitor cytosolic Ca2 + concentrations ([Ca2 + ]C). Results show that myricetin inhibited 4-AP-evoked glutamate release, and this effect was prevented by chelating extracellular Ca2 + ions and the vesicular transporter inhibitor bafilomycin A1. However, the glutamate transporter inhibitor dl-threo-beta-benzyl-oxyaspartate had no effect on myricetin action. Myricetin did not alter the synaptosomal membrane potential, but decreased 4-APinduced increases in the cytosolic free Ca2 + concentration. Furthermore, the myricetin effect on 4-AP-evoked glutamate release was prevented by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but not by blocking intracellular Ca2 + release. These results suggest that myricetin inhibits glutamate release from cerebrocortical synaptosomes by attenuating voltage-dependent Ca2 + entry. This implies that the inhibition of glutamate release is an important pharmacological activity of myricetin that may play a critical role in the apparent clinical efficacy of this compound.

Correlation between goose circovirus and goose parvovirus with gosling feather loss disease and goose broke feather disease in southern Taiwan

Chiu-Huang Ting,Chia-Ying Lin,Yang-Chieh Huang,Shyh-Shyan Liu,Shao-Yu Peng,Chen-Wei Wang,Hung-Yi Wu 대한수의학회 2021 Journal of Veterinary Science Vol.22 No.1

Background: Goslings in several Taiwanese farms experienced gosling feather loss disease (GFL) at 21–35 days and goose broke feather disease (GBF) at 42–60 days. The prevalence ranges from a few birds to 500 cases per field. It is estimated that about 12,000 geese have been infected, the morbidity is 70–80% and the mortality is 20–30%. Objectives: This study aims to investigate the pathogens that cause GFL and GBF. Focus on the study of the correlation between goose circovirus (GoCV) and goose parvovirus (GPV) with the goose feather loss in southern Taiwan. Furthermore, a phylogenetic tree was established to align the differences between southern and northern Taiwan and compare with virus strains from China and Europe. Methods: Samples were collected from animal hospitals. Molecular and microscopy diagnostics were used to examine 92 geese. Specific quantitative polymerase chain reaction (Q-PCR) assays are performed to evaluate GPV and GoCV viral loads and simultaneously evaluated the feather loss conditions in geese with the scoring method. Results: High prevalence of GoCV and GPV infection in geese showing signs of GFL and GBF. Inclusion body was detected in the feather follicles and Lieberkühn crypt epithelial cells. The Q-PCR showed the high correlation between feather loss and viruses during 3rd–5th week. However, the infection was not detected using the same test in 60 healthy geese. Conclusions: Thus, GFL and GBF appear to be significantly closely related to GoCV and GPV. The geese feathers showed increasing recovery after being quarantined and disinfected.

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma

Yen-Hsiang Huang,Kuo-Hsuan Hsu,Jeng-Sen Tseng,Kun-Chieh Chen,Chia-Hung Hsu,Kang-Yi Su,Jeremy J. W. Chen,Huei-Wen Chen,Sung-Liang Yu,Tsung-Ying Yang,Gee-Chen Chang 대한암학회 2018 Cancer Research and Treatment Vol.50 No.4

Purpose The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)mutant lung adenocarcinoma patients with acquired resistance after firstline EGFRtyrosine kinase inhibitor (TKI) treatment. Materials and Methods We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFRmutation status. Results A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression- free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). Conclusion PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746- A750 mutation are associated with the frequency of T790M mutation.

Health Care Utilization and Expenditures of Patients with Diabetes Comorbid with Depression Disorder: A National Population-Based Cohort Study

Chun-Jen Huang,Hui-Min Hsieh,Herng-Chia Chiu,Peng-Wei Wang,Mei-Hsuan Lee,Chih-Yi Li,Ching-Hua Lin 대한신경정신의학회 2017 PSYCHIATRY INVESTIGATION Vol.14 No.6

Objective: The study investigated to compare health care utilization and expenditures between diabetic patients with and without depression in Taiwan. Methods: Health care utilization and expenditure among diabetic patients with and without depression disorder during 2000 and 2004 were examined using Taiwan’s population-based National Health Insurance claims database. Health care utilization included outpatient visits and the use of inpatient services, and health expenditures were outpatient, inpatient, and total medical expenditures. Moreover, general estimation equation models were used for analyzing the factors associated with outpatient visits and expenditures. Multiple logistic regression analysis was applied for identifying the factors associated with hospitalization. Results: The average annual outpatient visits and annual total medical expenditures in the study period were 44.23–52.20; NT$87,496–133,077 and 30.75–32.92; NT$64,411–80,955 for diabetic patients with and without depression. After adjustment for covariates, our results revealed that gender and complication were associated with out-patient visits. Moreover, the time factor was associated with the total medical expenditure, and residential urbanization and complication factors were associated with hospitalization. Conclusion: Health care utilization and expenditures for diabetic patients with depression were significantly higher than those without depression. Sex, complications, time, and urbanization are the factors associated with health care utilization and expenditures.

Where Are Landscape Designers' Spatial Abilities in the Brain? An fMRI Study

Shih-Han Hung,Chia-Yi Huang,Tsung-Ren Huang,Shih-An Tang,Yu-Ping Tsai,Chun-YenChang 인간식물환경학회 2023 인간식물환경학회지 Vol.26 No.5

Background and objective: To effectively understand and communicate their work, landscape designers should possessexcellent spatial abilities. Neurological methods have confirmed that activation of the occipital lobe, parietal cortex, andprefrontal cortex affect the judgment of space; however, few studies have measured spatial abilities in landscape design. This study aimed to identify the potential role of various brain regions during spatial interpretation processes by landscapedesigners, particularly the effect of stimulating the frontal lobe on enhancing design capabilities. Methods: This study tested the spatial abilities of landscape designers when transforming a planar drawing into a sectionaldrawing and the brain regions activated in this process. The subjects were asked to identify the correct option whenmatching given section lines in a planar drawing. The correct answer rate and response time were used to score brainactivation during spatial task processes. A total of 16 valid subjects were divided into high- and low-accuracy groupsaccording to the correct answer rate. Results: The results for the high-accuracy group showed that the left inferior frontal gyrus was activated during spatialdesign tasks. In contrast, the findings for the low-accuracy group revealed that the left middle occipital gyrus was activatedfor processing visual information. Conclusion: The findings suggest that the frontal lobe plays a role in allowing landscape designers to make planar tocross-sectional inferences via mental rotations and categorical spatial relations. The findings offer implications forlandscape designers in stimulating the frontal lobe and enhancing their design capabilities.

Arsenic Toxicity on Duck Spermatozoa and the Ameliorating Effect of L-Ascorbic Acid

Lin, Chai-Ching,Huang, Chia-Cherng,Chen, Ming-Cheng,Huang, Andrew Jeng-Fang,Chiou, Hung-Yi Asian Australasian Association of Animal Productio 2002 Animal Bioscience Vol.15 No.1

The objectives of this study were to understand the possible mechanism of duck sperm toxicity induced by arsenic exposure in vivo, and to investigate the roles of the antioxidant L-ascorbic acid in ameliorating the arsenic-induced sperm impairment. To test the acute toxicity, the percentages of mortality of mature drakes treated with different concentrations of trivalent sodium arsenite, As (III), and pentavalent sodium arsenate, As (V) were measured. The LD50 value of As (III) for mature drakes was $4.89{\pm}1.49$ ppm. Although As (V) didn't cause any deaths even at a concentration of 40 ppm, the chronic toxicity of As (V) on sperm quality was shown by a decreased fertilization rate. When the concentrations of As (V) were above 0.4 ppm, fertilization rates were lower than those of 0.04 ppm and control. Drakes treated with 40 ppm of As (V) had the highest malondialdehyde (MDA) level in the testis tissue, $3.100{\pm}0.218{\mu}mole/g$ testis. This showed that 40 ppm of As (V) significantly induced lipid peroxidation in testis tissue. For the 1.2 ppm As (III) treatment, several significant effects were observed: (1) sperm motility was decreased most dramatically by $52.0{\pm}9.1$% after three days of incubation; (2) fertilization rate of artificially inseminated semen was the lowest, $26.4{\pm}15.4$; (3) the MDA concentration in testis tissue, $7.846{\pm}0.246{\mu}mole/g$ testis, was significantly higher than the others (p<0.05); (4) the sperm number, $1.17{\pm}0.40({\times}10^9)$, was significantly lower than with the 60 ppb and control treatments (p<0.05); (5) a black appearance and soft texture was observed in the testis tissue. The antioxidant L-ascorbic acid administered along with 1.2 ppm As (III) decreased the toxicity of arsenic. The ameliorating effects included: improved sperm motility, increased sperm number and fertilization rate, and decreased MDA concentration in the testis tissue. This study suggests that the toxicity of the trivalent arsenic on sperm quality is partly from free radicals generated by its metabolic pathway, and the antioxidant ascorbic acid ameliorates arsenic-caused sperm impairment.