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.

Advanced Application of Centralized Control for a Scanning Mirror System Based on EtherCAT Fieldbus

Ruei-Yu Huang,Yen-Jen Chen,Yu-Xian Chen,Chung-Wei Cheng,Mi-Ching Tsai,An-Chen Lee 제어·로봇·시스템학회 2021 International Journal of Control, Automation, and Vol.19 No.3

Distributed control is the most popular control strategy for controlling numerous slave devices. However, the performance of slave devices is hard to improve because the control algorithm is handled by the commercial slave devices. Therefore, this paper proposes a hybrid control structure that follows the concept of centralized control strategy and handles part of the control loop on the master computer in a distributed control system through EtherCAT fieldbus. In this study, different advanced control methods such as robust control and learning control were applied to handle the position control loop of a scanning mirror system in a selective laser melting (SLM) system with stringent demand of position error around 40 µm based on EtherCAT fieldbus. By designing a proper controller, the experiment results showed that the tracking performance was significantly improved. The tracking error dropped by about 80% after the proposed hybrid control structure was applied. By applying the proposed hybrid control structure, one can improve the high-performance-requirement devices, while reducing the calculationburden of the master computer for other low-performance-requirement devices by retaining the benefit of distributed Control.

Improvement of ulcerative colitis control by searching and restricting of inflammatory trigger factors in daily clinical practice

Kun-Yu Tsai,Jeng-Fu You,Tzong-Yun Tsai,Yih Jong Chern,Yu-Jen Hsu,Shu-Huan Huang,Wen-Sy Tsai 대한장연구학회 2023 Intestinal Research Vol.21 No.1

Background/Aims: Exacerbating factors of ulcerative colitis (UC) are multiple and complex with individual influence. We aimed to evaluate the efficacy of disease control by searching and restricting inflammation trigger factors of UC relapse individually in daily clinical practice. Methods: Both patients with UC history or new diagnosis were asked to avoid dairy products at first doctor visit. Individual-reported potential trigger factors were restricted when UC flared up (Mayo endoscopy score ≥1) from remission status. The remission rate, duration to remission and medication were analyzed between the groups of factor restriction complete, incomplete and unknown. Results: The total remission rate was 91.7% of 108 patients with complete restriction of dairy product. The duration to remission of UC history group was significantly longer than that of new diagnosis group (88.5 days vs. 43.4 days, P=0.006) in patients with initial endoscopic score 2–3, but no difference in patients with score 1. After first remission, the inflammation trigger factors in 161 relapse episodes of 72 patients were multiple and personal. Milk/dairy products, herb medicine/Chinese tonic food and dietary supplement were the common factors, followed by psychological issues, non-dietary factors (smoking cessation, cosmetic products) and discontinuation of medication by patients themselves. Factor unknown accounted for 14.1% of patients. The benefits of factor complete restriction included shorter duration to remission (P<0.001), less steroid and biological agent use (P=0.022) when compared to incomplete restriction or factor unknown group. Conclusions: Restriction of dairy diet first then searching and restricting trigger factors personally if UC relapse can improve the disease control and downgrade the medication usage of UC patients in daily clinical practice.

Hericium erinaceus Mycelium and Its Isolated Compound, Erinacine A, Ameliorate High-Fat High-Sucrose Diet-Induced Metabolic Dysfunction and Spatial Learning Deficits in Aging Mice

Yun-Chieh Tsai,Yu-Chen Lin,Chun-Chih Huang,Oliver B. Villaflores,Tzong-Yuan Wu,Shih-Ming Huang,Ting-Yu Chin 한국식품영양과학회 2019 Journal of medicinal food Vol.22 No.5

Aging and lifestyle factors, including high-sugar and high-fat diets, promote a systemic metabolic imbalance that promotes neurodegeneration. Hericium erinaceus has long been used in traditional Chinese medicine. Recently, its functional activities, such as antimetabolic dysfunction, antineuroinflammatory activities, and stimulation of nerve growth factor (NGF) synthesis, have been revealed. This study demonstrated that Hericium erinaceus mycelium (HEM) and an isolated diterpenoid derivative, erinacine A (EA), may reverse spatial learning disabilities in aging mice (15 months old) fed with a high-fat and high-sucrose diet (HFSD). Aging mice were randomly assigned to one of four treatment groups: (1) a chow diet (control), (2) an HFSD, and an HFSD supplemented with either (3) HEM or (4) EA for 18 weeks. The Morris water maze (MWM) and Y-maze were used for behavioral assessments. Both HEM- and EA-treated mice had shorter mean daily escape latencies than HFSD-treated mice in the MWM. In addition, HEM-treated mice had a slightly increased exploratory time and frequency in the novel arm in the Y-maze. Quantitative PCR revealed that both HEM- and EA-treated mice exhibited reduced messenger RNA (mRNA) expression of tumor necrosis factor-α, interleukin-1β, and HEM-treated mice exhibited increased mRNA expression of NGF and NeuN in the hippocampus. Moreover, HEM and EA also decreased body weight, abdominal fat, plasma glucose, serum and liver total cholesterol, and liver triacylglycerol. Thus, HEM may be a potential health-promoting supplement for minimizing the progression of aging and obesity-induced neurodegeneration by reducing metabolic abnormalities and neuroinflammatory cytokines and increasing neurogenesis factors.

Heart Rate Variability Biofeedback Increased Autonomic Activation and Improved Symptoms of Depression and Insomnia among Patients with Major Depression Disorder

I-Mei Lin,Sheng-Yu Fan,Cheng-Fang Yen,Yi-Chun Yeh,Tze‐Chun Tang,Mei-Feng Huang,Tai-Ling Liu,Peng-Wei Wang,Huang-Chi Lin,Hsin-Yi Tsai,Yu-Che Tsai 대한정신약물학회 2019 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.17 No.2

Objective: Autonomic imbalance is considered a psychopathological mechanism underlying major depressive disorder (MDD). Heart rate variability (HRV) is an index for autonomic activation. Poor sleep quality is common among patients with MDD. HRV biofeedback (BF) has been used for regulating autonomic balance among patients with physical illness and mental disorders. The purpose of present study was to examine the effects of HRV-BF on depressive symptoms, sleep quality, pre-sleep arousal, and HRV indices, in patients with MDD and insomnia. Methods: In this case-controlled study, patients with MDD and Pittsburgh Sleep Quality Index (PSQI) score higher than 6 were recruited. The HRV-BF group received weekly 60-minute protocol for 6 weeks, and the control group who have matched the age and sex received medical care only. All participants were assessed on Beck Depression Inventory-II, Back Anxiety Inventory, PSQI, and Pre-Sleep Arousal Scale. Breathing rates and electrocardiography were also performed under resting state at pre-testing, and post-testing conditions and for the HRV-BF group, also at 1-month follow-up. Results: In the HRV-BF group, symptoms of depression and anxiety, sleep quality, and pre-sleep arousal were significantly improved, and increased HRV indices, compared with the control group. Moreover, in the HRV-BF group, significantly improved symptoms of depression and anxiety, decreased breathing rates, and increased HRV indices were detected at post-testing and at 1-month follow-up, compared with pre-testing values. Conclusion: This study confirmed that HRV-BF is a useful psychosocial intervention for improving autonomic balance, baroreflex, and symptoms of depression and insomnia in MDD patients.

Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo

( Ching-ling Lin ),( Ming-lin Tsai ),( Yu-hsin Chen ),( Wei-ni Liu ),( Chun-yu Lin ),( Kai-wen Hsu ),( Chien-yu Huang ),( Yu-jia Chang ),( Po-li Wei ),( Shu-huey Chen ),( Li-chi Huang ),( Chia-hwa Lee 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.5

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.

Experimental study and modeling of masonry-infilled concrete frames with and without CFRP jacketing

Huang, Chao-Hsun,Sung, Yu-Chi,Tsai, Chi-Hsin Techno-Press 2006 Structural Engineering and Mechanics, An Int'l Jou Vol.22 No.4

Most existing concrete structures in Taiwan are considered nonductile due to insufficient transverse reinforcement and poor detailing of frame elements. Such features are fairly typical for buildings constructed prior to 1997, at which time the local building code was revised based on ACI 318-95. Among these structures, many contain perimeter or partition walls made of concrete or clay brick for architectural purposes. These walls, though treated as non-structural components in common design practice, could affect the structural behavior of the buildings during an earthquake. To study the behavior of such structures under seismic load, experiments were conducted on concrete frames of various configurations to show the force-deformation relationships, damage patterns, and other characteristics of the frames. For further interest, similar units with columns jacketed by carbon-fiber-reinforced-polymer (CFRP) were also tested to illustrate the effectiveness of this technique in the retrofit of concrete frames.

Fabrication and Study of Novel Piezoresistive Polymer Composites Sensor for 3D Printing Applications

( Yu-yen Chen ),( Cheng-chun Huang ),( Ching-yuan Su ),( Yao-chuan Tsai ) 한국농업기계학회 2018 한국농업기계학회 학술발표논문집 Vol.23 No.1

With the technology development, the technique of 3D printing has gradually matured. The characteristic of 3D printing is that it can print the product directly without another complex process. If the 3D printing could be applied to manufacturing sensor elements, it could be quicker and cheaper for the sensor element fabrication and the sensor forms will be applicable. Piezoresistive effect is a common sensor sensing principle which is through the deformation of the material to cause the resistance changes. In this study, a piezoresistive polymer composites material was developed, which can be manufactured by the photo-curable 3D printing. The different amount of the conductive carbon black (CB) nanoparticles was employed and added into photo-curable resin for obtaining the conductive percolation threshold of the polymer composites and measuring the piezoresistivity of the polymer composites. The conductive percolation threshold is around 1.0~1.5wt%, and the gauge factor of 1.5wt% is 9~17. The gauge factor was found which would decrease with the increasing strains. This study can be applied on fabricating the piezoresistive pressure and tactile sensors which can be used to the agricultural, industrial and various industries.

Clinical Features of Patients with Esophageal and Second Primary Cancers

Tsai, Huang-Wen,Chang, Chih-Chun,Sun, Jen-Tang,Liou, Ching-Biau,Lin, Hsiu-Chen,Lin, I-Hsin,Yu, Yun-Chieh,Weng, Wei-Ling,Leong, Ka-I,Yen, Tzung-Hai,Wu, Jiann-Ming Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.22

Background: The prevalence of esophageal cancer (EC) with second primary cancers (SPC) is increasing worldwide. This study was aimed to understand the clinical features of EC patients with SPC in the Taiwanese population. Materials and Methods: Clinical and laboratory data for 180 EC patients with or without SPC were collected between January 2009 and December 2013. Information on treatment approaches, location of SPCs and ABO blood type were also collected and stratified. Results: The most common SPC in EC patients was hypopharyngeal cancer, followed by laryngeal cancer and hepatocellular carcinoma in our study. Malignancies of colon, prostate and lung were also found. There was a significant higher portion of blood type A in the EC patients with SPC compared with those without (42.4% vs 19.5%, P=0.006). Conclusions: The frequency and SPC site distribution and blood type A should be considered in clinical evaluation of EC patients with a high risk of developing SPC in the Taiwanese population.

Pyogenic Liver Abscess as a Warning Sign for Primary Liver Cancer: A Nationwide Population-based Study

Huang, Wen-Kuan,Lin, Yung-Chang,Chiou, Meng-Jiun,Yang, Tsai-Sheng,Chang, John Wen-Cheng,Yu, Kuang-Hui,Kuo, Chang-Fu,See, Lai-Chu Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.8

Background: There have been no large-scale population-based studies to estimate the subsequent risk of primary liver cancer (PLC) among patients with pyogenic liver abscess (PLA). This study aimed to provide relevant data. Materials and Methods: The Taiwan Longitudinal Health Insurance Database for the years 2000 and 2005 was used. The PLA group were adult inpatients who were newly diagnosed with PLA from 2000 to 2008. The control group was randomly selected and matched with the PLA group in terms of age, sex, and date in which medical treatment was sought other than for PLA. Results: There were 1,987 patients each in the PLA and control groups. In total, 56 had PLC, 48 (2.4%, 601.5 per 100,000 person-years) from the PLA group, and 8 from the control group. After adjusting for potential covariates, the hazard ratio of PLC for the PLA group was 3.4 times that of the control group (95% confidence interval = 1.6-7.3, p <0.001). The PLC risk for the PLA group was significantly higher within the first year after PLA diagnosis (hazard ratio: 35.4) as compared with the control group and became insignificant (hazard ratio: 2.0, 95% confidence interval = 0.8-4.9) more than one year after PLA diagnosis. Conclusions: Patients with PLA have a higher rate of PLC than matched controls, especially within the first year after the diagnosis of PLA, suggesting PLA is a warning sign for PLC.