BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency

Sun, Chaoyang,Yin, Jun,Fang, Yong,Chen, Jian,Jeong, Kang Jin,Chen, Xiaohua,Vellano, Christopher P.,Ju, Zhenlin,Zhao, Wei,Zhang, Dong,Lu, Yiling,Meric-Bernstam, Funda,Yap, Timothy A.,Hattersley, Mauree Cell Press 2018 CANCER CELL Vol. No.

<P><B>Summary</B></P> <P>Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in <I>BRCA1</I>, <I>BRCA2</I>, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of <I>BRCA1/2</I>, <I>TP53</I>, <I>RAS</I>, or <I>BRAF</I> mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple <I>in vivo</I> models.</P> <P><B>Highlights</B></P> <P> <UL> <LI> BRD4 inhibition decreases homologous recombination competency by decreasing CtIP </LI> <LI> PARP and BRD4 inhibitors demonstrate synergy in multiple cancer lineages </LI> <LI> CtIP rescues DNA end resection and HR defect caused by BRD4 inhibition </LI> <LI> BRD4 inhibition resensitizes cells with acquired PARPi resistance to PARPi </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in <i>RAS</i> mutant cancers

Sun, Chaoyang,Fang, Yong,Yin, Jun,Chen, Jian,Ju, Zhenlin,Zhang, Dong,Chen, Xiaohua,Vellano, Christopher P.,Jeong, Kang Jin,Ng, Patrick Kwok-Shing,Eterovic, Agda Karina B.,Bhola, Neil H.,Lu, Yiling,Wes American Association for the Advancement of Scienc 2017 Science translational medicine Vol.9 No.392

<P>Mutant <I>RAS</I> has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple <I>RAS</I> mutant tumor models across tumor lineages where <I>RAS</I> mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of <I>BRCA1/2</I> and <I>p53</I> mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in <I>RAS</I> mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor–induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant <I>RAS</I> to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in <I>RAS</I> mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with <I>RAS</I> mutant tumors where there are few effective therapeutic options.</P>

Chemical Structures of Piericidins Produced by a Marine Streptomyces sp.

Chien Fang PI,Min ah LEE,Fakir Shahidullah TAREQ,Hwa-Sun LEE,Jong Seok LEE,Yeon-Ju LEE,Hee Jae SHIN 한국생물공학회 2014 한국생물공학회 학술대회 Vol.2014 No.4

배려적 학교풍토와 전문적 교사협력이 교사 직무만족에 미치는 영향

방효비 ( Fang Xiao-fei ),박수정 ( Park Soo Jung ),박선주 ( Park Sun Ju ) 충남대학교 교육연구소 2017 교육연구논총 Vol.38 No.1

이 연구는 배려적 학교풍토와 전문적 교사협력이 교사 직무만족에 미치는 영향력을 분석하는 것을 목적으로 하였다. 이를 위하여 『2013년 OECD 교수학습국제조사(TALIS)』의 국내 177개 중학교 2,933명의 교사가 응답한 자료 중, 결측치를 제외한 2,597명의 자료를 분석에 사용하였다. 자료 분석은 SPSS 22.0 프로그램을 사용하였고, 상관관계분석, 다중회귀분석을 실시하였다. 또한 배경변인에 의한 영향력을 알아보기 위해 교사의 성별, 연령, 교직경력, 고용형태를 통제변인으로 투입하였다. 주요 연구 결과는 다음과 같다. 첫째, 배려적 학교풍토와 전문적 교사협력, 교사 직무만족 간 정적 상관관계가 나타났다. 둘째, 배려적 학교풍토와 전문적 교사협력 모두 직무만족에 유의한 정적 영향을 미쳤으며, 교사 직무만족의 하위요인인 직업 만족과 근무환경 만족에도 정적 영향을 미치는 것으로 나타났다. 이 연구를 통해 교사의 직무만족을 향상시키기 위해 배려적 학교풍토와 전문적 교사협력에 대한 관심이 좀 더 필요함을 실증적으로 확인하였다. The purpose of this study is to analyze the influence of the caring school climate and professional teacher collaboration on teachers` job satisfaction. For this purpose, 『OECD Teaching and Learning International Survey(TALIS) 2013』of 2,597 middle school teachers` responses in Korea were used in the analysis. Data analysis was performed using the SPSS 22.0 and correlation analysis, multiple regression analysis carried out. In order to examine the influences of the background variables, the teachers` gender, age, teaching career experience and employment type were used as the control variables. The main results were as follows. First, there was a positive correlation among caring school climate, professional teacher collaboration and teachers` job satisfaction. Second, both the caring school climate and professional teacher collaboration had a significant positive effect on job satisfaction and they also had a positive effect on profession satisfaction and working environment satisfaction which were the sub-factors of teachers` job satisfaction. As the result, this study empirically verified that more attention was needed on the caring school climate and the professional teacher collaboration in order to improve the teachers` job satisfaction.

Two New α-Pyrones from a Streptomyces sp. Associated with a Marine Starfish

Hwa-Sun LEE,Min Ah LEE,Fakir Shahidullah TAREQ,Cien Fang PI,Hyi-Seung LEE,Jong Seok LEE,Yeon-Ju LEE,Hee Jae SHIN 한국생물공학회 2014 한국생물공학회 학술대회 Vol.2014 No.4

Serum Uric Acid Relation for Hearing Threshold Shiftt

Hui-Fang Yang,Tung-Wei Kao,Tao-Chun Peng,Yu-Shan Sun,Fang-Yih Liaw,Chung-Ching Wang,Ju-Ting Hsueh,Wei-Liang Chen 대한이비인후과학회 2017 Clinical and Experimental Otorhinolaryngology Vol.10 No.2

Objectives. The effects of serum uric acid (UA) level on a variety of diseases were found from experimental and observational studies via oxidative stress and anti-oxidants. However, research on the association of UA and hearing thresholds is relatively sparse. We investigated this issue in the U.S. general population to evaluate the relationship of serum UA levels and pure tone threshold of hearing. Methods. Forty four thousand eighty four eligible participants aged 20 to 69 years who have serum UA data and received Audiometry Examination Component were enrolled from the National Health and Nutrition Examination Survey 1999–2004. Hearing thresholds (dB) as a pure tone average at low frequencies (0.5, 1, 2 kHz) and at high frequencies (3, 4, 6, and 8 kHz) were computed. Multivariate linear regression models and tertile-based analysis with an extended-model approach for covariates adjustment were used to assess the correlation between serum UA level and hearing thresholds. Results. In the adjusted mode of tertile-based analysis, the regression coefficients elucidated as the change of log-transformed mean hearing thresholds upon comparing participants in the highest tertile of serum UA to those in the lowest tertile were –0.067 (P=0.023) in high frequency and –0.058 (P=0.054) in low frequency. After adjusting for multiple pertinent covariates, inverse association between tertiles of serum UA and hearing thresholds remained essentially unchanged. The negative trends between serum UA and hearing thresholds were statistically significant (P for trends <0.05) in tertile-based multiple linear regressions. Conclusion. Individuals with elevated UA levels independently were found to be inversely associated with hearing thresholds for pure tone audiometry in a nationally representative sample of U.S. adults.

Overcoming 5-Fu Resistance of Colon Cells through Inhibition of Glut1 by the Specific Inhibitor WZB117

Liu, Wei,Fang, Yong,Wang, Xiao-Tong,Liu, Ju,Dan, Xing,Sun, Lu-Lu Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.17

Background: 5-Fluorouracil (5-FU) is the most commonly used drug in colon cancer therapy. However, despite impressive clinical responses initially, development of drug resistance to 5-Fu in human tumor cells is the primary cause of failure of chemotherapy. In this study, we established a 5-Fu-resistant human colon cancer cell line for comparative chemosensitivity studies. Materials and Methods: Real time PCR and Western blotting were used to determine gene expression levels. Cell viability was measured by MTT assay. Glucose uptake was assess using an Amplex Red Glucose/Glucose Oxidase assay kit. Results: We found that 5-Fu resistance was associated with the overexpression of Glut1 in colon cancer cells. 5-Fu treatment at low toxic concentration induced Glut1 expression. At the same time, upregulation of Glut1 was detected in 5-Fu resistant cells when compared with their parental cells. Importantly, inhibition of Glut1 by a specific inhibitor, WZB117, significantly increased the sensitivity of 5-Fu resistant cells to the drug. Conclusions: This study provides novel information for the future development of targeted therapies for the treatment of chemo-resistant colon cancer patients. In particular it demonstrated that Glut1 inhibitors such as WZB117 may be considered an additional treatment options for patients with 5-Fu resistant colon cancers.

Synthesis and Characterization of Magnetic Nanoparticles and Its Application in Lipase Immobilization

Xu, Jiakun,Ju, Caixia,Sheng, Jun,Wang, Fang,Zhang, Quan,Sun, Guolong,Sun, Mi Korean Chemical Society 2013 Bulletin of the Korean Chemical Society Vol.34 No.8

We demonstrate herein the synthesis and modification of magnetic nanoparticles and its use in the immobilization of the lipase. Magnetic $Fe_3O_4$ nanoparticles (MNPs) were prepared by simple co-precipitation method in aqueous medium and then subsequently modified with tetraethyl orthosilicate (TEOS) and 3-aminopropyl triethylenesilane (APTES). Silanization magnetic nanoparticles (SMNP) and amino magnetic nanomicrosphere (AMNP) were synthesized successfully. The morphology, structure, magnetic property and chemical composition of the synthetic MNP and its derivatives were characterized using transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) analysis, X-ray diffraction, superconducting quantum interference device (SQUID) and thermogravimetric analyses (TGA). All of these three nanoparticles exhibited good crystallization performance, apparent superparamagnetism, and the saturation magnetization of MNP, SMNP, AMNP were 47.9 emu/g, 33.0 emu/g and 19.5 emu/g, respectively. The amino content was 5.66%. The AMNP was used to immobilize lipase, and the maximum adsorption capacity of the protein was 26.3 mg/g. The maximum maintained activity (88 percent) was achieved while the amount of immobilized lipase was 23.7 mg $g^{-1}$. Immobilization of enzyme on the magnetic nanoparticles can facilitate the isolation of reaction products from reaction mixture and thus lowers the cost of enzyme application.

Synthesis and Characterization of Magnetic Nanoparticles and Its Application in Lipase Immobilization

Jiakun Xu,Caixia Ju,Jun Sheng,Fang Wang,Quan Zhang,Guolong Sun,Mi Sun 대한화학회 2013 Bulletin of the Korean Chemical Society Vol.34 No.8

We demonstrate herein the synthesis and modification of magnetic nanoparticles and its use in the immobilization of the lipase. Magnetic Fe3O4 nanoparticles (MNPs) were prepared by simple co-precipitation method in aqueous medium and then subsequently modified with tetraethyl orthosilicate (TEOS) and 3- aminopropyl triethylenesilane (APTES). Silanization magnetic nanoparticles (SMNP) and amino magnetic nanomicrosphere (AMNP) were synthesized successfully. The morphology, structure, magnetic property and chemical composition of the synthetic MNP and its derivatives were characterized using transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) analysis, X-ray diffraction, superconducting quantum interference device (SQUID) and thermogravimetric analyses (TGA). All of these three nanoparticles exhibited good crystallization performance, apparent superparamagnetism, and the saturation magnetization of MNP, SMNP, AMNP were 47.9 emu/g, 33.0 emu/g and 19.5 emu/g, respectively. The amino content was 5.66%. The AMNP was used to immobilize lipase, and the maximum adsorption capacity of the protein was 26.3 mg/g. The maximum maintained activity (88 percent) was achieved while the amount of immobilized lipase was 23.7 mg g−1. Immobilization of enzyme on the magnetic nanoparticles can facilitate the isolation of reaction products from reaction mixture and thus lowers the cost of enzyme application.

Drug-loaded microbubble delivery system to enhance PD-L1 blockade immunotherapy with remodeling immune microenvironment

Zheng Jun,Huang Ju,Zhang Liang,Wang Mengna,Xu Lihong,Dou Xiaoyun,Leng Xiaojing,Fang Mingxiao,Sun Yang,Wang Zhigang 한국생체재료학회 2023 생체재료학회지 Vol.27 No.00

Although programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy.Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models.The dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases.PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.