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.

Efficacy and Safety of 12 Weeks of Daclatasvir, Asunaprevir Plus Ribavirin for the Treatment of HCV Genotype 1b Infection without Baseline NS5A Resistance-Associated Variants (DARING)-Interim Report

( Ming-lung Yu ),( Chao-hung Hung ),( Yi-hsiang Huang ),( Cheng-yuan Peng ),( Chun-yen Lin ),( Pin-nan Cheng ),( Rong-nan Chien ),( Shih-jer Hsu ),( Chen-hua Liu ),( Jee-fu Huang ),( Chung-feng Huang 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The current study aims to elucidate the treatment efficacy (defined as undetectable HCV RNA throughout 12 weeks of post-treatment follow-up, SVR12) and safety DCV/ASV plus ribavirin for 12 weeks in HCV-1b patients without NS5A RAS. Methods: This is a single-arm, open-label phase 2 study. Seventy directly acting antivirals (DAA)-naïve HCV-1b patients without L31/Y93 RAS are planned to receive daclatasvir (60 mg/ day) and asunaprevir (100 mg twice daily) plus weight-based ribavirin (1000-1200 mg/day) for 12 weeks. After treatment they were followed up for 12 weeks. Results: As of 31 Oct 2017, 58 eligible patients are allocated to treatment, with a mean age of 59.3 years and female predominance (67.2%, 39/58). The mean HCV RNA was 5.87+0.77 log10 IU/mL; 23 patients (39.7 %) had significant hepatic fibrosis (>F2). In the modified intention-to-treat analysis, the rate of undetectable HCV at week 1, week 2, week 4, week 8 and endof- treatment was 25 % (14/56), 84.8 % (39/46), 100 % (46/46), 100 % (38/38) and 100 % (27/27), respectively. Undetectable HCV RNA were observed in all of the patients with HCV RNA assessable 4 weeks (SVR4, 18/18) and 12 weeks (SVR12, 12/12) post treatment. None of the 18 patients who completed the 12-week treatment experienced relapse during post-treatment follow-up. The most common adverse event was fatigue (78.3 %), followed by pruritus (65.2 %) and dizziness (52.2 %), of which were considered as ribavirin related. None of the participating subjects withdrew treatment or follow-up throughout the trial peroid. Three serious adverse events were reported which included urosepsis, appendicitis and left ureteral stone. All were unrelated to the investigating drugs. Conclusions: 12 weeks of DCV/ASV plus ribavirin was highly effective and safe in HCV-1b patients without NS5A RAS in the interim analysis. The satisfactory results would be anticipated in the full patient set.

Submicron-Size Patterning on the Sapphire Substrate Prepared by Nanosphere Lithography and Nanoimprint Lithography Techniques

Chun-Ming Chang,Ming-Hua Shiao,Donyau Chiang,Chin-Tien Yang,Mao-Jung Huang,Wen-Jeng Hsueh 대한금속·재료학회 2013 METALS AND MATERIALS International Vol.19 No.4

In this paper, we demonstrate and compare the formation of ordered etching masks for submicron-size patterned sapphire substrates through use of the nanosphere lithography and nanoimprint lithography methods. The metal honeycomb network structure and the polymer pillar protrusion structure were obtained from these two methods. Subsequently, the inductively-coupled-plasma reactive ion etching technique was applied to etch the sapphire substrates, and the etchant mixture gases of boron trichloride and argon with the flow rate ratio of 1 to 6 were introduced into the etchant chamber. Two types of submicron -pattern structures were obtained on the sapphire substrate surface after the etching processes were completed. One type of sapphire substrate was the submicron hole array structure and another type was the submicron cone array structure. The working pressure had a considerable effect on the shape geometry and etching rate, and the possible mechanism is discussed.

Predictors of Positive Bone Metastasis in Newly Diagnosed Prostate Cancer Patients

Chien, Tsu-Ming,Lu, Yen-Man,Geng, Jiun-Hung,Huang, Tsung-Yi,Ke, Hung-Lung,Huang, Chun-Nung,Li, Ching-Chia,Chou, Yii-Her,Wu, Wen-Jeng,Huang, Shu-Pin Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.3

Background: The prevalence of prostate cancer (PCa) has been increasing in recent years. Treatment strategies are largely based on the results of bone scan screening. Therefore, our aim was to investigate predictors of positive bone metastasis in newly diagnosed PCa patients. Materials and Methods: After extensive review, 336 consecutive patients newly diagnosed with PCa between April 2010 and November 2013 at our institution were enlisted in the study. Patients were divided into two groups according to bone scan results. Univariate analyses (Chi-square test for discrete variables and independent t-test for continuous variables) were applied to determine the potentially significant risk factors associated with distant bone metastasis. Binary logistic regression analyses were used to further investigate the influence of these factors on bone metastasis. Results: The patient mean age was $71.9{\pm}8.6years$ (range: 48 to 94 years). The mean prostate specific antigen (PSA) level and biopsy Gleason score were $260.2{\pm}1107.8ng/mL$ and $7.4{\pm}1.5$, respectively. The body mass index (BMI) for the series was $24.5{\pm}3.4kg/m^2$. Sixty-four patients (19.0%) had a positive bone scan result. Patients with positive bone scan results had a significantly lower BMI ($23.3{\pm}3.5$ vs. $24.8{\pm}3.3$; p=0.003), a higher Gleason score ($8.5{\pm}1.1$ vs. $7.1{\pm}1.5$; p < 0.001), and a higher PSA level ($1071.3{\pm}2337.1$ vs. $69.4{\pm}235.5$; p < 0.001) than those without bone metastasis. Multivariate logistic regression analysis employing the above independent predictors demonstrated that a Gleason score of ${\geq}7$, clinical stage ${\geq}T3$, $BMI{\leq}22kg/m^2$, and an initial PSA level of ${\geq}20ng/mL$ were all independent predictors of bone metastasis. Conclusions: A bone scan might be necessary in newly diagnosed PCa patients with any of the following criteria: clinical stage T3 or higher, a Gleason score of 7 or higher, BMI equal to or less than 22, and a PSA level of 20 or higher.

Thalidomide Combined with Chemotherapy in Treating Patients with Advanced Colorectal Cancer

Huang, Xin-En,Yan, Xiao-Chun,Wang, Lin,Ji, Zhu-Qing,Li, Li,Liu, Meng-Yan,Qian, Ting,Shen, Hui-Ling,Gu, Han-Gang,Liu, Yong,Gu, Ming,Deng, Li-Chun Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.17

Objective: To assess the safety and effectiveness of thalidomide (produced by CHANGZHOU PHARMACEUTICAL FACTORY CO.LTD) combined with chemotherapy in treating patients with advanced colorectal cancer. Method: A consecutive cohort of pretreated patients with advanced colorectal cancer were treated with thalidomide combined with chemotherapy. And chemotherapy for patients with advanced colorectal cancer were administered according to the condition of patients. Thalidomide was orally administered at a dosage of 50mg/day to 150mg/day before sleeping for at least 14 days. After at least 14 days of treatment, safety and side effects were evaluated. Results: There were 12 female and 3 male patients with advanced cancer recruited into this study, including 9 patients with colon, 6 patients with rectal cancer. The median age of patients was 57(41-82) years. Partial response was observed in 2 patients (2/15), and stable disease in 3 patients(3/15). Incidences of Grade 1 to 2 myelosuppression was observed in 1/15 patients, and Grade 1 to 2 elevation of hepatic enzyme was recorded in 1/15 patients. Adverse effects on the gastrointestinal tract were documented in 1/15 patients, and were Grade 1. No Grade 3-4 toxicities were diagnosed. No treatment related death was found. Conclusions: Thalidomide combined with chemotherapy was safe and mildly effective in treating patients with advanced colorectal cancer. However, further study should be conducted to clarify the effectiveness of this combination.

Privet golden leaves adapt unexpectedly well to light changes

Ming Yuan,Bo Huang,Li-Hua Dong,Qiao-Hong Han,Yong Yang,Chun-Bang Ding,Chao Hu,Yang-Er Chen,Zhong-Wei Zhang,Shu Yuan 한국원예학회 2020 Horticulture, Environment, and Biotechnology Vol.61 No.4

Golden-leaf privet ( Ligustrum × vicaryi ) is widely used as a horticultural shrub because of its upper golden leaves, butits lower leaves are green. However, the putative mechanisms of its upper golden leaves and the leaf color changes inresponse to light shifts have not been well studied so far. Here, chlorophylls (Chl), carotenoids, and Chl precursors from bothgolden and green leaves grown in full sunlight (approximately 1200 μmol photons m −2 s −1 at noon) or low-light conditions(180 μmol m −2 s −1 ) were determined spectrophotometrically. In addition, their gas exchange parameters and Chl fl uorescencewere measured in situ. Metabolic fl ux analysis of chlorophyll intermediates indicated that the conversion of prochlorophyllideto chlorophyllide was signifi cantly blocked in golden leaves when compared with green leaves. Green leaves showed higherphotosynthetic capacity in low light than golden leaves, but golden leaves presented unexpectedly stronger photosyntheticcapacity and lower reactive oxygen species accumulation under the high-light condition. Furthermore, golden leaves showeda higher level of nonphotochemical quenching (NPQ) after the light-to-dark shift and presented a stronger adaptive abilityto a broad range of light environments. Higher NPQ values and less oxidative damage in golden leaves may be correlatedwith their higher carotenoid levels. The results imply that lower chlorophyll levels and higher carotenoid levels in canopyleaves may help privet plants acclimate better to illumination changes. This study demonstrates the key role of irradiance ingenerating the two types of Ligustrum × vicaryi leaves and sheds a light on cultivation of other ornamental foliage plants.

Microstructures, Mechanical Properties, and Fracture Behaviors of Metal-Injection Molded 17-4PH Stainless Steel

Ming-Wei Wu,Zeng-Kai Huang,Chun-Feng Tseng,Kuen-Shyang Hwang 대한금속·재료학회 2015 METALS AND MATERIALS International Vol.21 No.3

Metal injection molding (MIM) is a versatile technique for economically manufacturing various metal parts with complicated shapes and excellent properties. The objective of this study was to clarify the effects of powder type (water-atomized and gas-atomized powders) and various heat treatments (sintering, solutioning, H900, and H1100) on the microstructures, mechanical properties, and fracture behaviors of MIM 17- 4PH stainless steels. The results showed that better mechanical properties of MIM 17-4PH can be achieved with gas-atomized powder than with water-atomized powder due mainly to the lower silicon and oxygen contents and fewer SiO2 inclusions in the steels. The presence of 10 vol% δ ferrite does not impair the UTS or elongation of MIM 17-4PH stainless steels. The δ ferrite did not fracture, even though the neighboring martensitic matrix was severely cracked. Moreover, H900 treatment produces the highest hardness and UTS, along with moderate elongation. H1100 treatment produces the best elongation, along with moderate hardness and UTS.

Design of a hydraulic anti-lock braking system (ABS) for a motorcycle

Chun-Kuei Huang,Ming-Chang Shih 대한기계학회 2010 JOURNAL OF MECHANICAL SCIENCE AND TECHNOLOGY Vol.24 No.5

This work presents a hydraulic anti-lock braking system (ABS) for a motorcycle. The ABS has a hydraulic modulator and an intelligent controller. The hydraulic modulator is analyzed, and then equipped on a scooter for road tests. The intelligent controller controls the hydraulic modulator by estimated vehicle velocity to calculate the slip ratio of the wheels in real time. The performance of the hydraulic modulator and intelligent controller are assessed by the hardware-in-the-loop (HIL) simulations and road tests. In HIL simulation, the ABS is tested for different initial braking velocities on roads with different adhesive coefficients. Furthermore, both HIL simulations and road tests are conducted on a one-phase pavement road and three-phase pavement road.

CAPTIVE BREEDING AND EARLY DEVELOPMENT OF THE RINGED PIPEFISH Dunckerocampus dactyliophorus (SYNGNATHIDAE)

Ming-Yih Leu,Chun-Yu Huang,Cheng-Hao Tang,Pei-Jie Meng 한국수산과학회 양식분과 2015 한국수산과학회 양식분과 학술대회 Vol.2015 No.5

Dielectric properties of Mg0.95Ni0.05TiO3 ceramic modified by Nd0.5Na0.5TiO3 at microwave frequencies

Chun-Hsu Shen,Cheng-Liang Huang,Chuan-Feng Shih,Chih-Ming Huang 한국물리학회 2009 Current Applied Physics Vol.9 No.5

The effect of Nd0.5Na0.5TiO3 addition on the microwave dielectric properties of Mg0.95Ni0.05TiO3 ceramics was investigated. The Nd0.5Na0.5TiO3 content plays a significant role in improving the dielectric properties. Microwave dielectric measurements show an increase in the dielectric constant (εr) and temperature coefficient of the resonant frequency (τf) and a decrease in the quality factor (Q × f value) with increasing Nd0.5Na0.5TiO3 content. By properly adjusting the Nd0.5Na0.5TiO3 content, a zero τf value can also be obtained, which make Mg0.95Ni0.05TiO3 a promising material in wireless systems. At 1300 ℃, the 0.81Mg0.95Ni0.05TiO3–0.19Nd0.5Na0.5TiO3 ceramics possess excellent microwave dielectric properties: a dielectric constant (εr) of 25.61, a Q × f value of 69,100 GHz, and a τf value of -6 ppm/℃. The effect of Nd0.5Na0.5TiO3 addition on the microwave dielectric properties of Mg0.95Ni0.05TiO3 ceramics was investigated. The Nd0.5Na0.5TiO3 content plays a significant role in improving the dielectric properties. Microwave dielectric measurements show an increase in the dielectric constant (εr) and temperature coefficient of the resonant frequency (τf) and a decrease in the quality factor (Q × f value) with increasing Nd0.5Na0.5TiO3 content. By properly adjusting the Nd0.5Na0.5TiO3 content, a zero τf value can also be obtained, which make Mg0.95Ni0.05TiO3 a promising material in wireless systems. At 1300 ℃, the 0.81Mg0.95Ni0.05TiO3–0.19Nd0.5Na0.5TiO3 ceramics possess excellent microwave dielectric properties: a dielectric constant (εr) of 25.61, a Q × f value of 69,100 GHz, and a τf value of -6 ppm/℃.