SPECT/CT Imaging of the Novel HER2-targeted Peptide Probe 99mTc-HYNIC-H6F in Breast Cancer Mouse Models

展开

作者:Liqiang Li, Yue Wu, Zihua Wang, Bing Jia, Zhiyuan Hu, Chengyan Dong, Fan Wang

Journal of Nuclear Medicine 卷:58 期:8 页:821  发表年份:2017

摘要:Objectives: Overexpression of human epidermal growth factor receptor 2 (HER2) plays important roles in tumorigenesis and tumor progression in breast cancer. Nuclear imaging of HER2 expression in tumors might detect all HER2-positive tumors throughout the body and guide HER2-targeted therapies for patients. We therefore aimed to develop a HER2-targeted peptide probe for breast cancer imaging. A novel single-photon emission computed tomography (SPECT) imaging probe, 99mTc-HYNIC-H6F, was prepared and then evaluated in breast cancer animal models. Methods: The HER2-targeted peptide H6F (YLFFVFER) was conjugated with the bifunctional chelator hydrazinonicotinamide (HYNIC). 99mTc-HYNIC-H6F was prepared, and the in vivo characteristics of 99mTc-HYNIC-H6F were investigated in MDA-MB-453 (HER2-positive) and MDA-MB-231 (HER2- negative) models using small-animal SPECT/computed tomography (CT). Moreover, to investigate the specificity of the H6F peptide toward HER2 and the potential applications in monitoring therapies involving trastuzumab, unlabeled H6F and trastuzumab were employed as blocking agents in cell competition studies and SPECT imaging. Results: A standard tricine/trisodium triphenylphosphine-3,3’,3’’-trisulfonate (TPPTS) labeling procedure demonstrated that the radiochemical purity was greater than 95%. 99mTc-HYNIC-H6F displayed excellent HER2 binding specificity both in vitro and in vivo. SPECT/CT imaging revealed that the MDA-MB-453 tumors were clearly visualized (3.58 ± 0.01 %ID/g at 30 min p.i.), whereas the signals in HER2-negative MDA-MB-231 tumors were much lower (0.73 ± 0.22 %ID/g at 30 min p.i.). Tumor uptake of MDA-MB-453 was blocked by the co-injection of excess H6F but not by excess trastuzumab. Conclusion: The 99mTc-HYNIC-H6F peptide probe specifically accumulates in HER2-positive tumors and is therefore a promising probe for the diagnosis of HER2-positive cancers. Because 99mTc-HYNIC H6F and trastuzumab target different regions of the HER2 receptor, this radiotracer also has great potential for monitoring the therapeutical efficacy of trastuzumab by rechecking the expression level of HER2 without blocking effect during therapy.

全文网址:http://jnm.snmjournals.org/cgi/pmidlookup?view=long&pmid=28104744

Radiolabeled novel mAb 4G1 for immunoSPECT imaging of EGFRvIII expression in preclinical glioblastoma xenografts

展开

作者:Xujie Liu, Chengyan Dong, Jiyun Shi, Teng Ma, Zhongxia Jin, Bing Jia, Zhaofei Liu, Li Shen, Fan Wang

Oncotarget 卷:8 期:4 页:6364  发表年份:2017

摘要:Epidermal growth factor receptor mutant III (EGFRvIII) is exclusively expressed in tumors, such as glioblastoma, breast cancer and hepatocellular carcinoma, but never in normal organs. Increasing evidence suggests that EGFRvIII has clinical significance in glioblastoma prognosis due to its enhanced tumorigenicity and chemo/radio resistance, thus the development of an imaging approach to early detect EGFRvIII expression with high specificity is urgently needed. To illustrate this point, we developed a novel anti-EGFRvIII monoclonal antibody 4G1 through mouse immunization, cell fusion and hybridoma screening and then confirmed its specificity and affinity by a serial of assays. Following biodistribution and small animal single-photon emission computed tomography (SPECT/CT) imaging of 125I-4G1 in EGFRvIII positive/negative tumor-bearing mice were performed and evaluated to verify the tumor accumulation of this radiotracer. The biodistribution indicated that 125I-4G1 showed prominent tumor accumulation at 24 h post-injection, which reached maximums of 11.20 ± 0.75% ID/g and 13.98 ± 0.57% ID/g in F98npEGFRvIII and U87vIII xenografts, respectively. In contrast, 125I-4G1 had lower tumor accumulation in F98npEGFR and U87MG xenografts. Small animal SPECT/CT imaging revealed that 125I-4G1 had a higher tumor uptake in EGFRvIII-positive tumors than that in EGFRvIII-negative tumors. This study demonstrates that radiolabeled 4G1 can serve as a valid probe for the imaging of EGFRvIII expression, and would be valuable into the clinical translation for the diagnosis, prognosis, guiding therapy, and therapeutic efficacy evaluation of tumors.

全文网址:http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=14088&pubmed-linkout=1 PDF下载

Hyaluronic Acid-Coated Silver Nanoparticles As a Nanoplatform for in Vivo Imaging Applications

展开

作者:Xin Zhang,† Meinan Yao,† Muhua Chen,† Liqiang Li,† Chengyan Dong,‡ Yi Hou,§ Huiyun Zhao,†,⊥ Bing Jia,*,†,⊥ and Fan Wang*,†,‡

ACS Appl. Mater. Interfaces 卷:0 期:8 页:25650  发表年份:2016

摘要:An efficient chemical reduction protocol has been developed for the synthesis of hyaluronic acid-coated silver nanoparticles (HA-Ag NPs) that are spherical, ultrasmall and monodisperse. The as-synthesized HA-Ag NPs not only exhibited excellent long-term stability and low cytotoxicity but also could be used as a nanoplatform for X-ray computed tomography (CT) and single-photon emission computed tomography (SPECT) imaging after being radiolabeled with 99mTc.

全文网址:http://pubs.acs.org/doi/pdf/10.1021/acsami.6b08166 PDF下载

Sperm tsRNAs and acquired metabolic disorders

展开

作者:Menghong Yan and Qiwei Zhai

Journal of Endocrinology 卷:230 期:3 页:F13-F18  发表年份:2016

摘要:Many findings support the hypothesis that metabolic changes associated withenvironmental factors can be transmitted from father to offspring. The molecular mechanisms underlying the intergenerational transmission of metabolic changes remain to be fully explored. These acquired metabolic disorders in offspring may be partially explained by some potential epigenetic information carriers such as DNA methylation, histone modification and small non-coding RNAs. Recent evidence shows that spermtRNA-derived small RNAs (tsRNAs) as a type of paternal epigenetic information carrier may mediate intergenerational inheritance. In this review, we provide current knowledge of a father’s influence on metabolic disorders in subsequent generations and discuss the roles of sperm tsRNAs and their modifications in paternal epigenetic information transmission.

PDF下载

Down-regulation of Risa improves insulin sensitivity by enhancing autophagy

展开

作者:Yuangao Wang,* Yanan Hu,* Chenxia Sun,* Shu Zhuo,* Zhishui He,* Hui Wang,* Menghong Yan,* Jun Liu,* Yi Luan,* Changgui Dai,* Yonggang Yang,* Rui Huang,* Ben Zhou,* Fang Zhang,* and Qiwei Zhai*,†,1

The FASEB Journal 卷:30 期:9 页:3133-3145  发表年份:2016

摘要:It has been reported that some smal lnoncoding RNAs are involved in the regulationof insulin sensitivity.However, whether long noncoding RNAs also participate in the regulation of insulin sensitivity is still largely unknown. We identified and characterized a long noncoding RNA, regulator of insulin sensitivity and autophagy(Risa), which is a poly(A)+ cytoplasmic RNA. Overexpression of Risa in mouse primary hepatocytes or C2C12 myotubes attenuated insulin-stimulated phosphorylation of insulin receptor, Akt, and Gsk3b, and knockdown of Risa alleviated insulin resistance. Further studies showed that overexpression of Risa in hepatocytes or myotubes decreased autophagy, and knockdown of Risa up-regulated autophagy. Moreover, knockdown of Atg7 or -5 significantly inhibited the effect of knockdown of Risa on insulin resistance, suggesting that knockdown of Risa alleviated insulin resistance via enhancing autophagy. In addition, tail vein injection of adenovirus to knock down Risa enhanced insulin sensitivity and hepatic autophagy in both C57BL/6 and ob/ob mice. Taken together, the data demonstrate that Risa regulates insulin sensitivity by affecting autophagy and suggest that Risa is a potential target for treating insulin-resistance–related diseases.—Wang, Y., Hu, Y., Sun, C., Zhuo, S., He, Z.,Wang, H., Yan,M., Liu,J., Luan, Y., Dai, C., Yang, Y., Huang, R., Zhou, B., Zhang, F., Zhai, Q. Down-regulation of Risa improves insulin sensitivity by enhancing autophagy.FASEB J. 30, 3133–3145 (2016). www.fasebj.org

PDF下载

Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1 dependent manner.

展开

作者:Man, Na(#),Tan, Yurong,Sun, Xiao-Jian,Liu, Fan,Cheng, Guoyan,Greenblatt, Sarah,Martinez, Camilo,Karl, Daniel L,Ando, Koji,Sun, Ming,Hou, Dan,Chen, Bingyi,Xu, Mingjiang,Yang, Feng-Chun,Chen, Zhu,Chen, Saijuan,Nimer, Stephen D,Wang, Lan(*)

Blood 卷:129 期:20 页:2782-2792  发表年份:2017

摘要:AML1-ETO (AE), a fusion oncoprotein, generated by the t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3 compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML. We report here that loss of Caspase-3 triggers a conserved, adaptive mechanism, namely autophagy (or macroautophagy), that acts to limit AE9a-driven leukemia. Furthermore, we identify ULK1 as a novel substrate of Caspase-3 and show that upregulation of ULK1 drives autophagy initiation in leukemia cells and that inhibition of ULK1 can rescue the phenotype induced by Caspase-3 deletion in vitro and in vivo Collectively, these data highlight Caspase-3 as an important regulator of autophagy in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of...

全文网址:http://www.bloodjournal.org/content/129/20/2782.long?sso-checked=true PDF下载

Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin.

展开

作者:Man, Na;Sun, Xiao-Jian;Tan, Yurong等

Blood 卷:127 期:19 页:2322-2326  发表年份:2016

摘要:Inhibitor of DNA binding 1 (Id1) functions as an E protein inhibitor, and overexpression of Id1 is seen in acute myeloid leukemia (AML) patients. To define the effects of Id1 on leukemogenesis, we expressed MLL-AF9 in fetal liver (FL) cells or bone marrow (BM) cells isolated from wild-type, Id1(-/-), p21(-/-), or Id1(-/-)p21(-/-) mice, and transplanted them into syngeneic recipient mice. We found that although mice receiving MLL-AF9-transduced FL or BM cells develop AML, loss of Id1 significantly prolonged the median survival of mice receiving FL cells but accelerated leukemogenesis in recipients of BM cells. Deletion of Cdkn1a (p21), an Id1 target gene, can rescue the effect of Id1 loss in both models, suggesting that Cdkn1a is a critical target of Id1 in leukemogenesis. It has been suggested that the FL transplant model mimics human fetal-origin (infant) MLL fusion protein (FP)-driven leukemia, whereas the BM transplantation model resembles postnatal MLL leukemia; in fact, the analysis of clinical samples from patients with MLL-FP(+) leukemia showed that Id1 expression is elevated in the former and reduced in the latter type of MLL-FP(+) AML. Our findings suggest that Id1 could be a potential therapeutic target for infant MLL-AF9-driven ...

全文网址:http://www.bloodjournal.org/content/127/19/2322.long?sso-checked=true

Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock

展开

作者:Fabin Dang*, Xiujie Sun*

Nature Communications 卷:8 期:31 页:2041-1723  发表年份:2016

摘要:

Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism

展开

作者:Fabin Dang

Scientific Reports 卷:11 期:15 页:6:36926  发表年份:2016

摘要:

表面活性蛋白的不同结构和功能

展开

作者:Marieke Schor, et al

Trends in Biochemical Sciences 卷:41 期:7 页:610-620  发表年份:2016

摘要:Surface tension at liquid–air interfaces is a major barrier that needs to be surmounted by a wide range of organisms; surfactant and interfacially active proteins have evolved for this purpose. Although these proteins are essential for a variety of biological processes, our understanding of how they elicit their function has been limited. However, with the recent determination of high-resolution 3D structures of several examples, we have gained insight into the distinct shapes and mechanisms that have evolved to confer interfacial activity. It is now a matter of harnessing this information, and these systems, for biotechnological purposes.

全文网址:http://www.sciencedirect.com/science/article/pii/S0968000416300275 PDF下载