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.
通讯机构：
[Lili Chen] D;Department of public health laboratory sciences, College of Public Health, University of South China, Hengyang, China<&wdkj&>Key Laboratory of Hengyang for Health Hazard Factors Inspection and Quarantine, Hengyang, China
摘要：
Background: Chlamydia psittaci is a pathogen of birds that can cause zoonotic disease in mammals including pneumonia in humans. MicroRNAs (miRNAs) are a class of small non-coding RNA fragments with a length of about 22 nt, which play an important role in regulating gene expression after transcription. Chlamydia infection can cause changes in host cell miRNA expression, but the potential biological function of miRNAs in C. psittaci infection and pathogenesis is not well understood. Methods: Small RNA sequencing (sRNA-Seq) technology was used to characterise miRNA expression in human bronchial epithelial (HBE) cells after C. psittaci infection, and differentially expressed miRNAs were identified. Candidate target genes for these miRNAs were then functionally annotated by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The sRNA-Seq results were partially validated by quantitative real time polymerase chain reaction (qRT-PCR) and miRNA-target networks were constructed using visualization software. Results: We identified 151 differentially expressed miRNAs (46 known miRNAs and 105 novel miRNAs) in C. psittaci-infected HBE cells, of which 140 were upregulated and 11 were downregulated. Of these, 17 known miRNAs were significantly upregulated and two were downregulated using P < 0.05 and |log2FoldChange|>1.5 as threshold criteria. GO enrichment results showed that the predicted targets of these differentially expressed miRNAs were mainly involved in transcriptional regulation and ATP binding. KEGG pathway analysis suggested that the candidate target genes were involved in several important signaling pathways such as MAPK, ErbB, cGMP-PKG, cAMP, mTOR, GNRH, oxytocin, PI3K-Akt and AMPK, which are primarily related to biological processes such as transcription and signal transduction. The qRT-PCR results for miR-2116 & ndash;3p, miR-3195, miR663a, miR-10401 & ndash;5p, miR-124 & ndash;3p, miR-184, miR-744 & ndash;5p and hsa-miR-514b-5p were consistent with the sRNASeq data. Conclusions: A large amount of miRNA expression profile data relating to C. psittaci infection was obtained, which provides a useful experimental and theoretical basis for further understanding the pathogenic mechanisms of C. psittaci infection.
摘要：
Ibrutinib is a BTK-targeted irreversible inhibitor. In this study, we demonstrate that ibrutinib potently inhibits SRC activity in a non-covalent manner via mass spectrometry and crystallography. The S345C mutation renders SRC to bind covalently with ibrutinib, and restores the potency of ibrutinib against the gatekeeper mutant. The co-crystal structure of ibrutinib/SRC shows Ser345 of SRC did not form covalent bond with ibrutinib, leading to a decrease of potency and loss of the ability to overcome the gatekeeper mutation of SRC. The X-ray crystallographic studies also provide structural insight into why ibrutinib behaves differently against gatekeeper mutants of different kinases.
期刊：
Frontiers in Genetics,2020年10:501407 ISSN：1664-8021
通讯作者：
He, Xiu-Sheng;Liu, Wen;Ye, Feng
作者机构：
[He, Xiu-Sheng; Tang, Guo-Hui] Univ South China, Hunan Prov Key Lab Canc Cellular & Mol Pathol, Hengyang, Peoples R China.;[He, Xiu-Sheng; Tang, Guo-Hui] Univ South China, Canc Res Inst, Hengyang Med Coll, Hengyang, Peoples R China.;[Tang, Guo-Hui] Univ South China, Dept Anus & Bowels, Affiliated Nanhua Hosp, Hengyang, Peoples R China.;[Du, Jun; Ding, Jian-Cheng; Liu, Wen; Chen, Xue] Xiamen Univ, Fujian Prov Key Lab Innovat Drug Target Res, Sch Pharmaceut Sci, Xiamen, Peoples R China.;[Xia, Lu; Lian, Jia-Bian; Lin, Xiao-Ting; Ye, Feng] Xiamen Univ, Dept Med Oncol, Affiliated Hosp 1, Xiamen, Peoples R China.
通讯机构：
[He, Xiu-Sheng] U;[Liu, Wen; Ye, Feng] X;Univ South China, Hunan Prov Key Lab Canc Cellular & Mol Pathol, Hengyang, Peoples R China.;Univ South China, Canc Res Inst, Hengyang Med Coll, Hengyang, Peoples R China.;Xiamen Univ, Fujian Prov Key Lab Innovat Drug Target Res, Sch Pharmaceut Sci, Xiamen, Peoples R China.
关键词：
cell growth;colorectal cancer;long non-coding RNA;therapeutic target;unfolded protein response
摘要：
Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide, and is well known for its strong invasiveness, rapid recurrence, and poor prognosis. Long non-coding RNAs (lncRNAs) have been shown to be involved in the development of various types of cancers, including colorectal cancer. Here, through transcriptomic analysis and functional screening, we reported that lncRNA LUCRC (LncRNA Upregulated in Colorectal Cancer) is highly expressed in colorectal tumor samples and is required for colorectal cancer cell proliferation, migration, and invasion in cultured cells and tumorigenesis in xenografts. LUCRC was found to regulate target gene expression of unfolded protein response (UPR) in endoplasmic reticulum (ER), such as BIP. The clinical significance of LUCRC is underscored by the specific presence of LUCRC in blood plasma of patients with colorectal cancers. These findings revealed a critical regulator of colorectal cancer development, which might serve as a therapeutic target in colorectal cancer.
摘要：
Polycystic ovary syndrome (PCOS) is the most typical and common metabolic abnormalities in women of reproductive age. This study examined the protective effects of Dendrobium nobile Lindl. polysaccharides (DNLP) on ovarian follicular development in letrozole-induced PCOS rats and explored the underlying molecular mechanisms. The PCOS rats showed the increased body weight, serum testosterone and luteinizing hormone levels and insulin resistance. DNLP treatment reduced the body weight, serum testosterone level and insulin resistance, but failed to affect luteinizing hormone level in the PCOS rats. DNLP treatment recovered disrupted estrous cycle in the PCOS rats. DNLP treatment decreased antral follicles and increased the thickness of the granular cell layer. DNLP treatment increased the PCNA mRNA and protein expression levels in the PCOS ovarian tissues, and inhibited cell apoptosis in the PCOS ovarian tissues via regulating apoptosis-related proteins including Bax, Bcl-2 and caspase-3. In summary, this study demonstrated the protective effects of DNLP on the ovaries in the letrozole-induced PCOS rat model. DNLP exerted its protective effects via improving follicular development and inhibiting apoptosis of ovarian granular cells in PCOS rats. This study will provide experimental basis for the future clinical application of DNLP in the treatment of PCOS. (C) 2020 Published by Elsevier B.V.
关键词：
Breast cancer;CD73;HIF-1;Hypoxia;Therapeutic targets
摘要：
Intratumoral hypoxia has a significant impact on the development and progression of breast cancer (BC). Rather than exerting limited regional impact, hypoxia create an aggressive macroenvironment for BC. Hypoxia-inducible factors-1(HIF-1) is extensively induced under hypoxia condition of BC, activating the transcription of multiple oncogenes. Thereinto, CD73 is the one which could be secreted into the microenvironment and is in favor of the growth, metastasis, resistance to therapies, as well as the stemness maintenance of BC. In this review, we address the significance of hypoxia/HIF-1/CD73 axis for BC, and provide a novel perspective into BC therapeutic strategies.
作者机构：
[王贞; 陈熙; 曹文宇; 牛磊; 万炜; Zeng J.-Y.; 罗诗诗] Clinical Anatomy and Reproductive Medicine Application Institute, School of Medicine, University of South China, Hu'nan Hengyang, 421001, China;[徐杨] Department of Physiology, Institute of Neuroscience, Medical School, University of South China, Hu'nan Hengyang, 421001, China
通讯机构：
[Wan, W.] C;Clinical Anatomy and Reproductive Medicine Application Institute, China
期刊：
International Journal of Cancer,2019年144(3):651-664 ISSN：0020-7136
通讯作者：
Zu, Xuyu;Jiang, Yuyang
作者机构：
[Zhong, Jing; Zu, Xuyu; Cao, Renxian; Peng, Xiuda; Liu, Jianghua; Ding, Wenjun; Shen, Yingying] Univ South China, Inst Clin Med, Affiliated Hosp 1, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Wei] Tsinghua Univ, Sch Med, Dept Biol, Beijing, Peoples R China.;[Cao, Renxian; Liu, Jianghua] Univ South China, Affiliated Hosp 1, Dept Metab & Endocrinol, Hengyang, Hunan, Peoples R China.;[He, Jun] Univ South China, Affiliated Hosp 1, Dept Spine Surg, Hengyang, Hunan, Peoples R China.;[Chen, Xiguang] Univ South China, Affiliated Hosp 1, Dept Med Oncol, Hengyang, Hunan, Peoples R China.
通讯机构：
[Zu, Xuyu] U;[Jiang, Yuyang] T;Univ South China, Inst Clin Med, Affiliated Hosp 1, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.;Tsinghua Univ, Grad Sch Shenzhen, Guangdong Prov Key Lab Chem Biol, Lishui Rd, Shenzhen 518055, Peoples R China.
关键词：
*AXL;*DCC-2036;*MET;*PDX;*TNBC
摘要：
Triple-negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC-2036 inhibited the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC-2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC-2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC-2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt-NFkappaB signaling to exert its antitumor effect in TNBC. DCC-2036 also inhibited the growth and metastasis of xenografted MDA-MB-231 cells (AXL/MET-high TNBC cells) but not MDA-MB-468 cells (AXL-low TNBC cells) in NSG mice in vivo. Furthermore, DCC-2036 significantly inhibited tumor growth and invasion of AXL/MET-high TNBC PDX tumors but not AXL/MET-low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC-2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC-2036 even at a high dosage. Therefore, DCC-2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.
摘要：
Male fertility depends on the regulatory balance between germ cell self-renewal and differentiation, and the spatial and temporal patterns of this balance must be maintained throughout the life cycle. Retinoic acid and its receptors are important factors in spermatogenesis. Spermatogonia cells can self-proliferate and differentiate and have unique meiotic capabilities; they halve their genetic material and produce monomorphic sperm to pass genetic material to the next generation. A number of studies have found that the spermatogenesis process is halted in animals with vitamin A deficiency and that most germ cells are degraded, but they tend to recover after treatment with RA or vitamin A. This literature review discusses our understanding of how RA regulates sperm cell differentiation and meiosis and also reviews the functional information and details of RA.
摘要：
Chlamydia psittaciis a well known zoonotic pathogen that can lead to severe respiratory disease in poultry, pet birds and humans. Development of an effective and safe vaccine would be the most effective way to control C. psittaci infection. In this study, we used bacterial ghosts (BGs) as a delivery vehicle to evaluate the protective effects of major outer membrane protein (MOMP) and macrophage infectivity potentiator (MIP) DNA vaccines in mice. We found that MOMP/MIP DNA-loaded BGs elicited a better immune response than a naked DNA vaccine, giving increased IgG titers, lymphocyte proliferation responses and higher levels of IFN-gamma. After challenge infection, MOMP/MIP DNA-loaded BGs-immunized mice showed lower chlamydial load and inflammation pathology in lung tissues. In addition, we found that MOMP and MIP co-immunization or a heterologous prime-boost strategy could induce stronger immune responses and better protective efficacy against C. psittaci infection. Together, the above results suggest that BGs can act as an effective delivery vehicle for C. psittaci DNA vaccines, and co-immunization or heterologous prime-boost strategy can enhance protective efficacy against infection, thereby providing an alternative strategy for the design of vaccines against C. psittaci.
作者机构：
[乃爱桃; 艾小红] Department of Radiation Oncology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China;[王五洲; 陈熙; Wan W.; 曹文宇; 王逸轩] Clinical Anatomy & Reproductive Medicine Application Institute, Medical College, University of South China, Hengyang, 421001, China;[罗丹; 何洁] Department of Pathology, Medical College, University of South China, Hengyang, 421001, China;[万炜; 何淑雅] Department of Radiation Medicine, School of Public Health, University of South China, Hengyang, 421001, China;[徐杨] Department of Physiology, Medical College, University of South China, Hengyang, 421001, China
通讯机构：
[Xu, Y.; Ai, X.] D;Department of Physiology, China;Department of Radiation Oncology, China
关键词：
电离辐射;前额叶皮质区;NLRP3炎性小体;认知功能障碍
摘要：
探讨电离辐射诱导小鼠认知功能障碍的可能机制.20只雌性昆明小鼠随机分为对照组和辐照组,辐照组小鼠接受137Cs γ射线单次全身辐照至吸收剂量4 Gy.35 d后采用新旧事物识别实验检测小鼠认知功能;免疫组织化学法检测小鼠前额叶皮质区小胶质细胞标记物离子钙接头蛋白-1(IBA-1)的表达;蛋白质印迹法检测前额叶皮质区核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)、凋亡相关斑点样蛋白(ASC)、半胱氨酸天门冬氨酸蛋白酶-1(Caspase-1)、白细胞介素-1β(IL-1 β)和白细胞介素-18(IL-18)蛋白的表达变化;荧光定量PCR(RT-PCR)检测前额叶皮质IBA-1、NLRP3、ASC和Caspase-1 mRNA的表达情况.结果显示:与对照组相比,辐照组小鼠在新旧事物识别实验中对新事物的分辨率明显降低(38.39 ± 3.69 vs. 28.82 ± 2.08, p<0.05);前额叶皮质区IBA-1阳性细胞数(138.2 ± 3.7 vs. 159.6 ± 6.9, p<0.05)和mRNA表达(1.000 ± 0.031 vs. 1.173 ± 0.055, p<0.05)均显著上调;前额叶皮质区NLRP3、ASC、Caspase-1蛋白(1.000 ± 0.066 vs. 1.341 ± 0.119, p<0.05;1.000 ± 0.073 vs. 1.298 ± 0.083, p<0.05;1.000 ± 0.039 vs. 1.603 ± 0.159, p<0.01)及NLRP3、 ASC mRNA表达(1.000 ± 0.046 vs. 1.372 ± 0.071, p<0.01; 1.000 ± 0.068 vs. 1.225 ± 0.069, p<0.05)均明显上调;前额叶皮质区炎性细胞因子IL-1β和IL-18的表达(1.000 ± 0.033 vs. 1.167 ± 0.059, p<0.05;1.000 ± 0.196 vs. 1.614 ± 0.163, p<0.05)均明显上调.结果提示,电离辐射可能是通过激活前额叶皮质区小胶质细胞,活化NLRP3炎性小体,诱导炎症因子释放引起认知功能障碍的.
期刊：
CANCER MANAGEMENT AND RESEARCH,2019年11:179-190 ISSN：1179-1322
通讯作者：
Liao, Ning;Xie, Xiaoming
作者机构：
[Liao, Ning; Zhang, Guochun; Wang, Yulei; Chen, Bo] Guangdong Gen Hosp, Dept Breast Canc, Canc Ctr, 106 Zhongshan 2 Rd, Guangzhou 510080, Guangdong, Peoples R China.;[Liao, Ning; Zhang, Guochun; Wang, Yulei; Chen, Bo] Guangdong Acad Med Sci, 106 Zhongshan 2 Rd, Guangzhou 510080, Guangdong, Peoples R China.;[Tang, Hailin; Xie, Xiaoming] Sun Yat Sen Univ, Dept Breast Oncol, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med,Canc Ctr, 651 East Dongfeng Rd, Guangzhou 510060, Guangdong, Peoples R China.;[Chen, Xi] Univ South China, Hengyang Med Coll, Dept Anat, Hengyang, Peoples R China.
通讯机构：
[Liao, Ning] G;[Xie, Xiaoming] S;Guangdong Gen Hosp, Dept Breast Canc, Canc Ctr, 106 Zhongshan 2 Rd, Guangzhou 510080, Guangdong, Peoples R China.;Guangdong Acad Med Sci, 106 Zhongshan 2 Rd, Guangzhou 510080, Guangdong, Peoples R China.;Sun Yat Sen Univ, Dept Breast Oncol, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med,Canc Ctr, 651 East Dongfeng Rd, Guangzhou 510060, Guangdong, Peoples R China.
关键词：
HORMAD1;triple-negative breast cancer;non-triple-negative breast cancer;prognostic factor;transcriptome
摘要：
Transcriptomic analyses identify key differentially expressed genes and clinical outcomes between triple-negative and non-triple-negative breast cancer Bo Chen,1,* Hailin Tang,2,* Xi Chen,3,* Guochun Zhang,1 Yulei Wang,1 Xiaoming Xie,2 Ning Liao1 1Department of Breast Cancer, Cancer Center, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 2Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; 3Department of Anatomy, Hengyang Medical College, University of South China, Hengyang, China *These authors contributed equally to this work Purpose: There are significant differences in the biological behavior between triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC). In the present study, we identify key differential genes and clinical outcomes between TNBC and non-TNBC. Materials and methods: Transcriptomic analyses used GEO datasets (GSE76275), gene ontology, KEGG pathway analysis and cBioPortal. Quantitative RT-PCR analysis (qRT-PCR) was used to validate the differentially expressed genes. We used the KM Plotter Online Tool and 240 patients with TNBC tissue microarray to assay the prognostic value of HORMAD1. Results: The upregulated differentially expressed genes were enriched in transcription factor activity, sequence-specific DNA binding and nucleic acid binding transcription factor activity. Only 16 genes were upregulated when further screened for fold change >4-fold change. HORMAD1 and SOX8 exhibited high frequencies of change of greater than 10% (HORMAD1 was close to 20%). qRT-PCR results indicated that HORMAD1 and SOX8 mRNA levels were significantly upregulated in TNBC samples. In KM Plotter Online Tool, high HORMAD1 was associated with worse outcome. In our tissue microarray (including 240 TNBC tissues), IHC analysis revealed that 29.7% (55/240) of the tumor samples exhibited high HORMAD1 expression and 70.3% (185/240) of the tumor samples exhibited low HORMAD1 expression levels. Meanwhile, high HORMAD1 group has a bad prognosis. Conclusion: The status of transcriptional activation is an important difference between TNBC and non-TNBC. HORMAD1 is a key differential gene associated with poor outcome in TNBC. Epigenetic therapy and agents targeting cancer/testis antigens might potentially help to customize therapies of TNBC. Keywords: HORMAD1, triple-negative breast cancer, non-triple-negative breast cancer, prognostic factor, transcriptome
