Synergistic Precision Therapeutic Effects of Combining Aspirin and Sorafenib for the ACSL4+GADD45B- Hepatocellular Carcinoma

( Hongping Xia ),( Kam M Hui ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Sorafenib is currently the only FDA-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. The aim of this study is to investigate the synergistic therapeutic effects and molecular mechanism of sorafenib and aspirin combination in HCC. Methods: Drug combination studies and their synergy quantification were performed using the combination index (CI) method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Results: Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro. Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Additionally, combining subclinical doses of sorafenib and aspirin yielded significant synergistically anti-tumor effect by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence have independently corroborated that HCC patients expressed ACSL4highGADD45Blow survived significantly worse than patients with ACSL4lowGADD45Bhigh, thus demonstrating the potential clinical value of designing targeted therapeutic strategies with aspirin and sorafenib for HCC patients expressed ACSL4highGADD45Blow. Conclusions: Sorafenib and aspirin have synergistic therapeutic effects on HCC cells through simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells and can provide potential clinical value in precision medicine for HCC.

Structural damage and force identification under moving load

Hongping Zhu,Ling Mao,Shun Weng,Yong Xia 국제구조공학회 2015 Structural Engineering and Mechanics, An Int'l Jou Vol.53 No.2

Structural damage and moving load identification are the two aspects of structural system identification. However, they universally coexist in the damaged structures subject to unknown moving load. This paper proposed a dynamic response sensitivity-based model updating method to simultaneously identify the structural damage and moving force. The moving force which is equivalent as the nodal force of the structure can be expressed as a series of orthogonal polynomial. Based on the system Markov parameters by the state space method, the dynamic response and the dynamic response derivatives with respect to the force parameters and elemental variations are analytically derived. Afterwards, the damage and force parameters are obtained by minimizing the difference between measured and analytical response in the sensitivity-based updating procedure. A numerical example for a simply supported beam under the moving load is employed to verify the accuracy of the proposed method.

Structural damage and force identification under moving load

Zhu, Hongping,Mao, Ling,Weng, Shun,Xia, Yong Techno-Press 2015 Structural Engineering and Mechanics, An Int'l Jou Vol.53 No.2

Structural damage and moving load identification are the two aspects of structural system identification. However, they universally coexist in the damaged structures subject to unknown moving load. This paper proposed a dynamic response sensitivity-based model updating method to simultaneously identify the structural damage and moving force. The moving force which is equivalent as the nodal force of the structure can be expressed as a series of orthogonal polynomial. Based on the system Markov parameters by the state space method, the dynamic response and the dynamic response derivatives with respect to the force parameters and elemental variations are analytically derived. Afterwards, the damage and force parameters are obtained by minimizing the difference between measured and analytical response in the sensitivity-based updating procedure. A numerical example for a simply supported beam under the moving load is employed to verify the accuracy of the proposed method.

pH-Sensitive Nanoformulated Triptolide as a Targeted Therapeutic Strategy for Hepatocellular Carcinoma

Ling, Daishun,Xia, Hongping,Park, Wooram,Hackett, Michael J.,Song, Changyeong,Na, Kun,Hui, Kam Man,Hyeon, Taeghwan American Chemical Society 2014 ACS NANO Vol.8 No.8

<P>Hepatocellular carcinoma (HCC) has one of the worst prognoses for survival as it is poorly responsive to both conventional chemotherapy and mechanism-directed therapy. This results from a lack of therapeutic concentration in the tumor tissue coupled with the highly toxic off-site effects exhibited by these compounds. Consequently, we believe the best packaging for holistic therapy for HCC will involve three components: a potent therapeutic, a rationally designed drug delivery vehicle to enrich the target site concentration of the drug, and a surface ligand that can enable a greater propensity to internalization by tumor cells compared to the parenchyma. We screened a library containing hundreds of compounds against a panel of HCC cells and found the natural product, triptolide, to be more effective than sorafenib, doxorubicin, and daunorubicin, which are the current standards of therapy. However, the potential clinical application of triptolide is limited due to its poor solubility and high toxicity. Consequently, we synthesized tumor pH-sensitive nanoformulated triptolide coated with folate for use in an HCC-subpopulation that overexpresses the folate receptor. Our results show triptolide itself can prevent disease progression, but at the cost of significant toxicity. Conversely, our pH-sensitive nanoformulated triptolide facilitates uptake into the tumor, and specifically tumor cells, leading to a further increase in efficacy while mitigating systemic toxicity.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2014/ancac3.2014.8.issue-8/nn502074x/production/images/medium/nn-2014-02074x_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/nn502074x'>ACS Electronic Supporting Info</A></P>

A New Iridoid Glycoside from the Rhizomes of Cyperus rotundus

Tianzhu Zhang,Lijun Xu,Hongping Xiao,Xia Zhou,Simin Mo,Shimin Cai,Zhongliu Zhou 대한화학회 2014 Bulletin of the Korean Chemical Society Vol.35 No.7

A New Iridoid Glycoside from the Rhizomes of Cyperus rotundus

Zhang, Tianzhu,Xu, Lijun,Xiao, Hongping,Zhou, Xia,Mo, Simin,Cai, Shimin,Zhou, Zhongliu Korean Chemical Society 2014 Bulletin of the Korean Chemical Society Vol.35 No.7

Prognostic Perspectives of STING and PD-L1 Expression and Correlation with the Prognosis of Epstein-Barr Virus-Associated Gastric Cancers

( Qi Sun ),( Yao Fu ),( Xiaobing Chen ),( Lin Li ),( Hongyan Wu ),( Yixuan Liu ),( Haojun Xu ),( Guoren Zhou ),( Xiangshan Fan ),( Hongping Xia ) 대한소화기기능성질환·운동학회 2022 Gut and Liver Vol.16 No.6

Background/Aims: Epstein-Barr virus-associated gastric cancers (EBVaGCs) have unique molecular and clinicopathological characteristics. The cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is recently recognized as the critical innate immunity against pathogens and tumors. STING is also a master regulator in the cancer-immunity cycle and targeting STING could synergize with existing immune-checkpoint therapies. However, the role of STING in GC, especially in EBVaGC, and its correlation with programmed death-ligand 1 (PD-L1) remain largely unclear. Methods: We collected 78 cases of EBVaGCs and 210 cases of EBV-negative GC (EBVnGC) from a total of 1,443 cases of GC analyzed by EBV-encoded small RNA in situ hybridization. We investigated STING and PD-L1 expression and their concomitant prognostic value in EBVaGCs and EBVnGCs using tissue microarray and immunohistochemistry. The effects of STING and PD-L1 expression on the overall survival of patients with EBVaGC or EBVnGC were assessed by univariate and multivariate analysis. Results: We found that both STING and PD-L1 exhibited significantly higher expression in the EBVaGCs than that in the EBVnGCs. The expression of STING was positively correlated with that of PD-L1 in EBVaGCs. Simultaneous negative expression of STING and PD-L1, and positive expression of STING were independent prognostic risk factors for EBVaGC and EBVnGC, respectively. Conclusions: This is the first prognostic retrospective study of STING and PD-L1 expression and the prognosis among EBVaGC and EBVnGC. The expression and prognostic value of STING and PD-L1 are different in the two types of GCs. STING and PD-L1 are promising prognostic biomarkers and therapeutic targets for EBVaGC and EBVnGC. (Gut Liver 2022;16:875-891)

Host Langerin (CD207) is a receptor for <i>Yersinia pestis</i> phagocytosis and promotes dissemination

Yang, Kun,Park, Chae G,Cheong, Cheolho,Bulgheresi, Silvia,Zhang, Shusheng,Zhang, Pei,He, Yingxia,Jiang, Lingyu,Huang, Hongping,Ding, Honghui,Wu, Yiping,Wang, Shaogang,Zhang, Lin,Li, Anyi,Xia, Lianxu,B Nature Publishing Group 2015 Immunology and Cell Biology Vol. No.

<P><I>Yersinia pestis</I> is a Gram‐negative bacterium that causes plague. After <I>Y. pestis</I> overcomes the skin barrier, it encounters antigen‐presenting cells (APCs), such as Langerhans and dendritic cells. They transport the bacteria from the skin to the lymph nodes. However, the molecular mechanisms involved in bacterial transmission are unclear. Langerhans cells (LCs) express Langerin (CD207), a calcium‐dependent (C‐type) lectin. Furthermore, <I>Y. pestis</I> possesses exposed core oligosaccharides. In this study, we show that <I>Y. pestis</I> invades LCs and Langerin‐expressing transfectants. However, when the bacterial core oligosaccharides are shielded or truncated, <I>Y. pestis</I> propensity to invade Langerhans and Langerin‐expressing cells decreases. Moreover, the interaction of <I>Y. pestis</I> with Langerin‐expressing transfectants is inhibited by purified Langerin, a DC‐SIGN (DC‐specific intercellular adhesion molecule 3 grabbing nonintegrin)‐like molecule, an anti‐CD207 antibody, purified core oligosaccharides and several oligosaccharides. Furthermore, covering core oligosaccharides reduces the mortality associated with murine infection by adversely affecting the transmission of <I>Y. pestis</I> to lymph nodes. These results demonstrate that direct interaction of core oligosaccharides with Langerin facilitates the invasion of LCs by <I>Y. pestis</I>. Therefore, Langerin‐mediated binding of <I>Y. pestis</I> to APCs may promote its dissemination and infection.</P>