摘要:
Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.
作者机构:
[Li, Tony W. H.; Lu, Shelly C.; Wang, Jiaohong; Fan, Wei; Li, Yuan; Seki, Ekihiro; Zhang, Jing; Xiong, Ting; Tu, Jian; Lu, Liqing; Yang, Heping; Peng, Hui] Cedars Sinai Med Ctr, Div Digest & Liver Dis, Los Angeles, CA 90048 USA.;[Li, Yuan; Liu, Ting] Cent South Univ, Xiangya Hosp, Dept Gastroenterol, 78 Xiangya Rd, Changsha 410083, Hunan, Peoples R China.;[Xiong, Ting; Lu, Liqing; Chen, Yongheng; Liu, Ting] Cent South Univ, Xiangya Hosp, Chinese Minist Hlth, Key Lab Canc Prote, Changsha, Peoples R China.;[Tu, Jian] Univ South China, Inst Pharm & Pharmacol, Hengyang, Peoples R China.;[Zhang, Jing] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Oncol, Wuhan, Peoples R China.
通讯机构:
[Liu, Ting; Lu, Shelly C.; Yang, Heping] C;Cent South Univ, Xiangya Hosp, Dept Gastroenterol, 78 Xiangya Rd, Changsha 410083, Hunan, Peoples R China.;Cedars Sinai Med Ctr, Dept Med, Div Digest & Liver Dis, Davis Bldg,Room 2097,8700 Beverly Blvd, Los Angeles, CA 90048 USA.;Cedars Sinai Med Ctr, Dept Med, Div Digest & Liver Dis, Davis Bldg,Room 2094B,8700 Beverly Blvd, Los Angeles, CA 90048 USA.
作者机构:
[Tian, Xiao-Ting; Ba, Hui-Xue; Cao, Yuan-Yuan; Li, Xiao-Hui] Cent South Univ, Xiangya Sch Pharmaceut Sci, Dept Pharmacol, Changsha 410013, Peoples R China.;[Li, Ke] Hunan Acad Tradit Chinese Med, Changsha 410013, Hunan, Peoples R China.;[Li, Ying] Cent South Univ, Xiangya Hosp 3, Dept Hlth Management, Changsha, Peoples R China.;[Li, Xiao-Hui] Hunan Key Lab Bioanal Complex Matrix Samples, Changsha, Peoples R China.;[Wang, Aiping] Univ South China, Nanhua Affiliated Hosp, Inst Clin Res, Hengyang, Peoples R China.
通讯机构:
[Ke Li] H;[Xiao-Hui Li] D;Hunan Academy of Traditional Chinese Medicine, Hunan, China<&wdkj&>Department of Pharmacology, Xiangya School of Pharmaceutical Science, Central South University, Changsha, China<&wdkj&>Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, China
期刊:
Life Sciences,2019年228(4):167-175 ISSN:0024-3205
通讯作者:
Li, Yukun;Wu, Daichao
作者机构:
[Li, Yan] Cent S Univ, Sch Basic Med Sci, Inst Reprod & Stem Cell Engn, Changsha 410013, Hunan, Peoples R China.;[Li, Yan] Reprod & Genet Hosp Citic Xiangya, Changsha 410078, Hunan, Peoples R China.;[Chen, Changye; Luo, Guifang; Ma, Yan] Univ South China, Affiliated Hosp 1, Dept Gynecol, Hengyang 421001, Peoples R China.;[Xiao, Jiao] Univ South China, Affiliated Nanhua Hosp, Dept Endocrinol, Hengyang 421002, Peoples R China.;[Li, Yukun] Univ South China, Canc Res Inst, Coll Hunan Prov, Key Lab Tumor Cellular & Mol Pathol, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Li, Yukun; Wu, Daichao] U;Univ South China, Canc Res Inst, Coll Hunan Prov, Key Lab Tumor Cellular & Mol Pathol, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Dept Histol & Embryol, Clin Anat & Reprod Med Applicat Inst, Hengyang 421001, Hunan, Peoples R China.
关键词:
AGEs;IR;IVF;PCOS;UPR;therapy
摘要:
Polycystic ovary syndrome (PCOS), a multisystem disease, is a major reason for female infertility around the world. It is no longer considered simply as a disease of ovary. Now researchers growing awareness of the multisystem features of this disease. PCOS has a higher relationship with metabolic disturbance and hypothalamic-pituitary-ovarian axis (HPOA) function disorders. This syndrome results in hyperandrogenemia (HA), hyperinsulinemia/insulin resistance (IR), increased estrone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) ratio imbalance, infertility, cardiovascular diseases, endometrial dysfunction, obesity, and including a litany of other health issues. Furthermore, PCOS has been garnered in recent times. Interventions like metformin, orlistat, hormonal contraceptives, GLP1 agonists, and VitD have been applied to ameliorate or reverse the pathological characterization of PCOS. Moreover, drug-combined therapy of PCOS is superior to single drug administration. This review will focus on the recent progress in pathogenesis and therapy of PCOS.
作者机构:
[Li, Tao; Chen, Zhongqing; Xu, Wei] Southern Med Univ, Sch Clin Med 1, Nanfang Hosp, Dept Crit Care Med, Guangzhou 510515, Guangdong, Peoples R China.;[Li, Tao; Li, Yunfeng; Dai, Xingui] Univ South China, Peoples Hosp Chenzhou 1, Dept Crit Care Med, Inst Translat Med, Chenzhou 423000, Peoples R China.;[Liu, Youtan; Liu, Ruimeng] Southern Med Univ, Shenzhen Hosp, Dept Anesthesiol, Shenzhen 518110, Peoples R China.;[Gao, Youguang] Fujian Med Univ, Affiliated Hosp 1, Dept Anesthesiol, Sch Clin Med 1, Fuzhou 350005, Fujian, Peoples R China.
通讯机构:
[Chen, Zhongqing] S;[Li, Yunfeng] U;Southern Med Univ, Sch Clin Med 1, Nanfang Hosp, Dept Crit Care Med, Guangzhou 510515, Guangdong, Peoples R China.;Univ South China, Peoples Hosp Chenzhou 1, Dept Crit Care Med, Inst Translat Med, Chenzhou 423000, Peoples R China.
摘要:
Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury. To establish the ARDS model, C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) in vivo and Beas-2B cells were exposured to 0.5 mM LPS in vitro. Our results indicate that PD facilitates Parkin translocation to mitochondria and promotes mitophagy in ARDS-challenged mice and LPS-treated Beas-2B cells. However, PD-induced mitophagy was suppressed in Parkin-/- mice and Parkin siRNA transfected cells, indicating that PD activates Parkin-dependent mitophagy. Furthermore, the protective effects of PD against LPS-induced mitochondria-dependent apoptosis and lung injury were suppressed when Parkin was depleted both in vivo and in vitro. The inhibition of mitophagy with mitophagy inhibitor mitochondrial division inhibitor-1 in vivo and silencing of autophagy-related gene 7 in vitro also blocked the protective effects mediated by PD. Our data suggest that Parkin-dependent mitophagy induced by PD provides protection against mitochondria-dependent apoptosis in ARDS.
期刊:
American Journal of Human Genetics,2019年105(1):166-176 ISSN:0002-9297
通讯作者:
Shen, Lu;Jin, Peng
作者机构:
[Tian, Yun; Sun, Qi-Ying; Yi, Fang; Tang, Bei-Sha; Zhou, Ya-Fang; Xu, Hong-Wei] Cent S Univ, Xiangya Hosp, Dept Geriatr, Changsha 410008, Hunan, Peoples R China.;[Zeng, Sheng; Jiao, Bin; Liu, Zhen; Chen, Zhao; Jiang, Hong; Zhou, Chao-Jun; Yan, Xin-Xiang; Hou, Xuan; Guo, Ji-Feng; Tang, Bei-Sha; Long, Hong-Yu; Wang, Jun-Ling; Shen, Lu] Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China.;[Tian, Yun; Tang, Bei-Sha; Shen, Lu] Cent S Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha 410008, Hunan, Peoples R China.;[Xia, Kun; Hu, Zheng-Mao; Huang, Wen; Duan, Ran-Hui] Cent S Univ, Sch Life Sci, Ctr Med Genet, Changsha 410008, Hunan, Peoples R China.;[Kong, Ha Eun; Li, Yujing; Shafik, Andrew Mark; Allen, Emily G.; Jin, Peng] Emory Univ, Sch Med, Dept Human Genet, Whitehead Res Bldg,Room 305A,615 Michael St, Atlanta, GA 30322 USA.
通讯机构:
[Shen, Lu] C;[Jin, Peng] E;Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China.;Cent S Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha 410008, Hunan, Peoples R China.;Emory Univ, Sch Med, Dept Human Genet, Whitehead Res Bldg,Room 305A,615 Michael St, Atlanta, GA 30322 USA.
摘要:
Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.
摘要:
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA/DNA special binding protein that participates in regulating the expression of related genes, transcription, RNA alternative splicing, translation, posttranslational modification, cell signal transduction, cell movement, interacts with ncRNAs, and induces angiogenesis. Moreover, several cellular functions forcefully indicated that hnRNP K participates in tumorigenesis. Numerous studies indicated hnRNP K is aberrantly elevated in multiple tumors. In addition, hnRNP K abnormal accumulation in cytoplasmic is also associated with poor prognosis. This suggests that hnRNP K may play a role in the development and progression of tumors. However, related studies demonstrated that hnRNP K acts as a tumor suppressor to suppress tumor formation. Therefore, this paper aims to explore the role of hnRNPK in tumors.
作者机构:
[Li, Junyu] Canc Hosp Jiangxi Prov, Dept Radiotherapy, Nanchang 330029, Jiangxi, Peoples R China.;[Li, Yuehua; Wu, Xiaoping] Univ South China, Affiliated Hosp 1, Dept Med Oncol, Hengyang 421001, Hunan, Peoples R China.;[Li, Ying] Hubei Canc Hosp, Dept Radiat Oncol, 116 Zhuodaoquan South Rd, Wuhan 430079, Hubei, Peoples R China.
通讯机构:
[Li, Ying] H;Hubei Canc Hosp, Dept Radiat Oncol, 116 Zhuodaoquan South Rd, Wuhan 430079, Hubei, Peoples R China.
关键词:
biomarker;head and neck squamous cell carcinoma;long non-coding RNA;signature;survival
摘要:
Long non-coding RNAs (lncRNAs) are frequently dysregulated in cancer and their aberrant expression has been associated with cancer diagnosis and prognosis, which suggests that they may be promising molecular biomarkers. However, understanding of the expression pattern of lncRNAs and their prognostic roles in head and neck squamous cell carcinoma (HNSCC) is relatively limited. In the current study, the prognostic value of lncRNA expression profiles in predicting the OS of patients with HNSCC was investigated by integrating clinical and profiling data from The Cancer Genome Atlas. A total of ten lncRNAs closely associated with the prognosis of patients with HNSCC were identified and may serve as novel biomarkers. This 10-lncRNA signature was used to classify patients into 2 groups with significantly different overall survival (OS) times (median OS time, 1.65 vs. 13.04 years; P<0.0001). This lncRNA signature was validated in an independent testing cohort. The results of multivariable Cox regression and stratification analyses revealed that the prognostic value of the 10-lncRNA signature was independent of other clinical and pathological factors for the survival of patients with HNSCC. Functional analysis demonstrated that lncRNA expression-based risk scoring may reflect the basic status of the immune response in the tumor microenvironment. The presented study demonstrated the value of a lncRNA signature as a potential biomarker to improve the clinical prognosis of patients with HNSCC.