Pub Date : 2019-06-01DOI: 10.1097/JBR.0000000000000031
Xiaolong Fu, R. Chai
Autophagy, a ubiquitous cellular biological behavior that features a lysosome-dependent degradation pathway, is an important mechanism for cellular self-protection in eukaryotes. Autophagy plays essential roles in cell survival, renewal, material reuse and the maintenance of homeostasis. This paper reviews recent advances in understanding the physiological function of autophagy and its possible roles in auditory diseases. We focused our review on original publications on animal models, drug models, and molecular mechanisms of hearing impairment involved in the dysregulation of autophagy. As research on the mechanisms of autophagy has deepened, it has become obvious that autophagy plays essential roles not only in cell survival, but the occurrence and development of a variety of auditory-related disorder, including aminoglycoside-induced hearing loss, age-related hearing loss, and noise-induced hearing loss. While clinical treatment of such conditions via regulation of the development of autophagy is a novel idea, more time is needed to fully elucidate the specific regulatory pathways and modes of autophagy in auditory diseases. The continued study of the mechanisms and regulation of autophagy in auditory diseases will be of great significance for the future treatment and prevention of these conditions. Key words: autophagosome; autophagy; hearing loss; lysosome; microtubule-associated proteins light chain 3; mTOR; rapamycin; stress; treatment
{"title":"Regulation of autophagy: a promising therapeutic target for the treatment of hearing loss","authors":"Xiaolong Fu, R. Chai","doi":"10.1097/JBR.0000000000000031","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000031","url":null,"abstract":"Autophagy, a ubiquitous cellular biological behavior that features a lysosome-dependent degradation pathway, is an important mechanism for cellular self-protection in eukaryotes. Autophagy plays essential roles in cell survival, renewal, material reuse and the maintenance of homeostasis. This paper reviews recent advances in understanding the physiological function of autophagy and its possible roles in auditory diseases. We focused our review on original publications on animal models, drug models, and molecular mechanisms of hearing impairment involved in the dysregulation of autophagy. As research on the mechanisms of autophagy has deepened, it has become obvious that autophagy plays essential roles not only in cell survival, but the occurrence and development of a variety of auditory-related disorder, including aminoglycoside-induced hearing loss, age-related hearing loss, and noise-induced hearing loss. While clinical treatment of such conditions via regulation of the development of autophagy is a novel idea, more time is needed to fully elucidate the specific regulatory pathways and modes of autophagy in auditory diseases. The continued study of the mechanisms and regulation of autophagy in auditory diseases will be of great significance for the future treatment and prevention of these conditions. \u0000 \u0000 \u0000Key words: \u0000autophagosome; autophagy; hearing loss; lysosome; microtubule-associated proteins light chain 3; mTOR; rapamycin; stress; treatment","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123147010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-06-01DOI: 10.1097/JBR.0000000000000037
X. Xiong, Kai Xu, Sen Chen, Le Xie, Yu Sun, W. Kong
The pathogenic factors of deafness are complex; more than 50% of cases are caused by genetic factors. Between 75% and 80% of cases of hereditary hearing impairment are autosomal recessive, 15% to 25% are autosomal dominant, and 1% to 2% are mitochondrial or X-linked. Cochlea implantation is the main method for treating severe and extremely severe bilateral sensorineural deafness and it is widely used in clinical treatment. As clinical cases of cochlea implantation accumulate, differences in the efficacy of implantation in individuals are emerging and attracting attention. In addition to residual hearing level, implantation age, and other factors, gene mutation is an important factor influencing postoperative rehabilitation in patients. With continuous progress in genetic testing technology for deafness, genetic diagnosis has become an important tool in preoperative evaluation and postoperative effect prediction in patients undergoing cochlear implantation. This article reviews the current status and future development of cochlear implantation in the treatment of hereditary deafness resulting from mutations in common deafness-causing genes. Key words: cochlear implant; effectiveness; gene mutation; GJB2 gene; hereditary deafness; mitochondrial 12S rRNA gene; OTOF gene; PJVK gene; SLC26A4 gene; Usher syndrome
{"title":"Advances in cochlear implantation for hereditary deafness caused by common mutations in deafness genes","authors":"X. Xiong, Kai Xu, Sen Chen, Le Xie, Yu Sun, W. Kong","doi":"10.1097/JBR.0000000000000037","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000037","url":null,"abstract":"The pathogenic factors of deafness are complex; more than 50% of cases are caused by genetic factors. Between 75% and 80% of cases of hereditary hearing impairment are autosomal recessive, 15% to 25% are autosomal dominant, and 1% to 2% are mitochondrial or X-linked. Cochlea implantation is the main method for treating severe and extremely severe bilateral sensorineural deafness and it is widely used in clinical treatment. As clinical cases of cochlea implantation accumulate, differences in the efficacy of implantation in individuals are emerging and attracting attention. In addition to residual hearing level, implantation age, and other factors, gene mutation is an important factor influencing postoperative rehabilitation in patients. With continuous progress in genetic testing technology for deafness, genetic diagnosis has become an important tool in preoperative evaluation and postoperative effect prediction in patients undergoing cochlear implantation. This article reviews the current status and future development of cochlear implantation in the treatment of hereditary deafness resulting from mutations in common deafness-causing genes. \u0000 \u0000 \u0000Key words: \u0000cochlear implant; effectiveness; gene mutation; GJB2 gene; hereditary deafness; mitochondrial 12S rRNA gene; OTOF gene; PJVK gene; SLC26A4 gene; Usher syndrome","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126960757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-06-01DOI: 10.1097/JBR.0000000000000038
Weijian Zhang, H. Xiong, Jiaqi Pang, L. Lai, Zhongwu Su, Han-qing Lin, Bingquan Jian, Haidi Yang, Yiqing Zheng
Cisplatin (CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy. Thus far, effective approaches for attenuating hearing loss are unavailable in clinical practice. Mitochondrial biogenesis acts as a master element of mitochondrial health and is necessary for mitochondrial quality control. The current study examined whether mitochondrial biogenesis is involved in CDDP-induced ototoxicity. Herein, we showed that CDDP damaged mitochondrial function and caused death of House Ear Institute- Organ of Corti 1 (HEI-OC1) cells by impairing mitochondrial biogenesis. Moreover, overexpression of peroxisome proliferator-activated receptor-γ coactivator-1α, a key factor in mitochondrial biogenesis, promoted mitochondrial biogenesis in HEI-OC1 cells and protected them against CDDP-induced cytotoxicity. These findings suggest that mitochondrial biogenesis is involved in the pathology of CDDP cytotoxicity of HEI-OC1 cells, and activation of peroxisome proliferator-activated receptor-γ coactivator-1α can be considered a potential therapeutic strategy to attenuate CDDP-mediated ototoxicity. Key words: PGC-1α; cisplatin; mitochondrial biogenesis; survival; cell death; ZLN005; therapy; HEI-OC1 cells
{"title":"PGC-1α overexpression promotes mitochondrial biogenesis to protect auditory cells against cisplatin-induced cytotoxicity","authors":"Weijian Zhang, H. Xiong, Jiaqi Pang, L. Lai, Zhongwu Su, Han-qing Lin, Bingquan Jian, Haidi Yang, Yiqing Zheng","doi":"10.1097/JBR.0000000000000038","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000038","url":null,"abstract":"Cisplatin (CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy. Thus far, effective approaches for attenuating hearing loss are unavailable in clinical practice. Mitochondrial biogenesis acts as a master element of mitochondrial health and is necessary for mitochondrial quality control. The current study examined whether mitochondrial biogenesis is involved in CDDP-induced ototoxicity. Herein, we showed that CDDP damaged mitochondrial function and caused death of House Ear Institute- Organ of Corti 1 (HEI-OC1) cells by impairing mitochondrial biogenesis. Moreover, overexpression of peroxisome proliferator-activated receptor-γ coactivator-1α, a key factor in mitochondrial biogenesis, promoted mitochondrial biogenesis in HEI-OC1 cells and protected them against CDDP-induced cytotoxicity. These findings suggest that mitochondrial biogenesis is involved in the pathology of CDDP cytotoxicity of HEI-OC1 cells, and activation of peroxisome proliferator-activated receptor-γ coactivator-1α can be considered a potential therapeutic strategy to attenuate CDDP-mediated ototoxicity. \u0000 \u0000 \u0000Key words: \u0000PGC-1α; cisplatin; mitochondrial biogenesis; survival; cell death; ZLN005; therapy; HEI-OC1 cells","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130755479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-06-01DOI: 10.1097/JBR.0000000000000034
G. Ni, Jia Pang, Q. Zheng, Zihao Xu, B. Liu, Haiyu Zhang, Dong Ming
The cochlea plays an important role in the mammalian auditory system. Sound-induced cell motion in the cochlea is transformed into electrical signals that are then sent to primary auditory neurons. The most significant feature of the cochlea is the active and nonlinear amplification of faint sounds. This active process cannot be explained via a simple hydromechanical representation of the cochlea, that is, a macromechanic explanation. Although the mechanisms of this amplification are not well understood, cochlear micromechanical behavior is thought to play a significant role. The measurement of in vivo cochlea micromechanical responses is challenging and restricted by technical limitations. Modeling the micromechanics of the cochlea, however, can facilitate the interpretation of experimental observations. In this paper, we reviewed studies in which researchers modeled the cochlear micromechanics, and we discussed various modeling hypotheses, outcomes, and expectations. Key words: auditory; cochlea; cochlear amplifier; cochlear micromechanics; cochlear macromechanics; cochlear models; modeling hypothesis; model validation
{"title":"Modeling cochlear micromechanics: hypotheses and models","authors":"G. Ni, Jia Pang, Q. Zheng, Zihao Xu, B. Liu, Haiyu Zhang, Dong Ming","doi":"10.1097/JBR.0000000000000034","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000034","url":null,"abstract":"The cochlea plays an important role in the mammalian auditory system. Sound-induced cell motion in the cochlea is transformed into electrical signals that are then sent to primary auditory neurons. The most significant feature of the cochlea is the active and nonlinear amplification of faint sounds. This active process cannot be explained via a simple hydromechanical representation of the cochlea, that is, a macromechanic explanation. Although the mechanisms of this amplification are not well understood, cochlear micromechanical behavior is thought to play a significant role. The measurement of in vivo cochlea micromechanical responses is challenging and restricted by technical limitations. Modeling the micromechanics of the cochlea, however, can facilitate the interpretation of experimental observations. In this paper, we reviewed studies in which researchers modeled the cochlear micromechanics, and we discussed various modeling hypotheses, outcomes, and expectations. \u0000 \u0000 \u0000Key words: \u0000auditory; cochlea; cochlear amplifier; cochlear micromechanics; cochlear macromechanics; cochlear models; modeling hypothesis; model validation","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115379431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-06-01DOI: 10.1097/JBR.0000000000000036
Jun Lv, He Li, Xianmin Wu, Xiaoyun Chen, Yideng Huang
In this retrospective study, we evaluated the preoperative and intraoperative findings and functional results of revision surgery after canal wall down mastoidectomy. We reviewed 34 patients (14 men, 20 women; age, 17–68 years) who underwent revision canal wall down mastoidectomy from March 2006 to March 2017 in the Department of Otology of the First Affiliated Hospital, Wenzhou Medical University, China. This study was approved by the Ethics Committee of the First Affiliated Hospital, Wenzhou Medical University, China (approval No. 2008-05-02A11) on May 2, 2008. The possible reasons for previous surgical failures were confirmed by the operative findings and included a narrow auditory meatus orifice (100%), recurrent or residual cholesteatoma (82%), high facial ridge (94%), residual air cells (47%), and labyrinthine fistula (12%). The mean time until achievement of dry ear after surgery was 5.8 ± 2.4 weeks. After a mean 6-month follow-up, the mean postoperative air–bone gap decreased from 33.8 ± 4.8 to 17.1 ± 5.1 dB in 30 patients who underwent mastoidectomy with simultaneous tympanoplasty. However, no significant postoperative hearing change had occurred in the other 4 patients with eustachian tube occlusion. All patients were followed up for >24 months with a disease-free dry ear and stable hearing results. The main reasons for lack of dry ears after mastoidectomy were a narrow auditory meatus orifice, recurrent or residual cholesteatoma, high facial ridge, and residual air cells. Early dry ear and hearing promotion are obtainable in most patients using revision canal wall down mastoidectomy. Key words: canal wall down mastoidectomy; cholesteatoma; dry ear; hearing results; mastoid obliteration; otitis media; revision surgery; tympanoplasty
{"title":"Functional results of revision canal wall down mastoidectomy","authors":"Jun Lv, He Li, Xianmin Wu, Xiaoyun Chen, Yideng Huang","doi":"10.1097/JBR.0000000000000036","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000036","url":null,"abstract":"In this retrospective study, we evaluated the preoperative and intraoperative findings and functional results of revision surgery after canal wall down mastoidectomy. We reviewed 34 patients (14 men, 20 women; age, 17–68 years) who underwent revision canal wall down mastoidectomy from March 2006 to March 2017 in the Department of Otology of the First Affiliated Hospital, Wenzhou Medical University, China. This study was approved by the Ethics Committee of the First Affiliated Hospital, Wenzhou Medical University, China (approval No. 2008-05-02A11) on May 2, 2008. The possible reasons for previous surgical failures were confirmed by the operative findings and included a narrow auditory meatus orifice (100%), recurrent or residual cholesteatoma (82%), high facial ridge (94%), residual air cells (47%), and labyrinthine fistula (12%). The mean time until achievement of dry ear after surgery was 5.8 ± 2.4 weeks. After a mean 6-month follow-up, the mean postoperative air–bone gap decreased from 33.8 ± 4.8 to 17.1 ± 5.1 dB in 30 patients who underwent mastoidectomy with simultaneous tympanoplasty. However, no significant postoperative hearing change had occurred in the other 4 patients with eustachian tube occlusion. All patients were followed up for >24 months with a disease-free dry ear and stable hearing results. The main reasons for lack of dry ears after mastoidectomy were a narrow auditory meatus orifice, recurrent or residual cholesteatoma, high facial ridge, and residual air cells. Early dry ear and hearing promotion are obtainable in most patients using revision canal wall down mastoidectomy. \u0000 \u0000 \u0000Key words: \u0000canal wall down mastoidectomy; cholesteatoma; dry ear; hearing results; mastoid obliteration; otitis media; revision surgery; tympanoplasty","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114484060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-01DOI: 10.1097/JBR.0000000000000027
Na Yin, Ting Chu, Yin Peng, Yuanchun Yao, Jingjing Li, B. Xiang, Bo Yang, T. Johnston, Maosheng Yang
Abstract Traditional methods of inducing hyperlipidemia in animal models are either costly (genetic manipulation) or it is difficult to control for the effects of other variables. For example, during high-fat feeding, the amount of high-fat diet intake per animal cannot be precisely controlled. The aim of this study was to develop an experimental model of fatty organ degeneration induced by poloxamer 407 (P-407). The study was conducted in 2-month-old, male Sprague-Dawley rats that were administered intraperitoneally with either 10% (w/w) P-407 (1 g/kg) or saline (10 mL/kg) for 4 months. Their lipid profile, organ degeneration due to fat deposition, and body mass were assessed. Intraperitoneal administration of P-407 resulted in significant increases in plasma triglycerides (P ⩽ 0.001), total cholesterol (P < 0.001), high-density lipoprotein-cholesterol (P ⩽ 0.001), and low-density lipoprotein (P < 0.001) cholesterol. In contrast to the control group, fatty tissue degeneration was observed in the liver, spleen, and kidneys of P-407-treated rats. Positive correlations between fatty tissue degeneration, and the atherogenic index of plasma (P < 0.001) and the ratio of total cholesterol to high-density-lipoprotein (P < 0.001) were identified. In addition, treatment with P-407 for 3 to 4 months caused a significant reduction in body mass relative to controls (P < 0.001). Thus, this study describes the development of a cost-effective experimental rat model of organ degeneration, characterized by fat accumulation in the liver, spleen, and kidneys, which could be used for the study of steatosis and related diseases arising from sustained untreated dyslipidemia. Furthermore, both the atherogenic index of plasma and the ratio of total cholesterol to high-density lipoprotein-cholesterol can be used to predict the risk of fatty tissue degeneration in this model. The study was approval of the University of Jishou Biomedical Research Ethics Committee, China.
{"title":"A novel rat model of fatty organ degeneration induced by poloxamer 407","authors":"Na Yin, Ting Chu, Yin Peng, Yuanchun Yao, Jingjing Li, B. Xiang, Bo Yang, T. Johnston, Maosheng Yang","doi":"10.1097/JBR.0000000000000027","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000027","url":null,"abstract":"Abstract Traditional methods of inducing hyperlipidemia in animal models are either costly (genetic manipulation) or it is difficult to control for the effects of other variables. For example, during high-fat feeding, the amount of high-fat diet intake per animal cannot be precisely controlled. The aim of this study was to develop an experimental model of fatty organ degeneration induced by poloxamer 407 (P-407). The study was conducted in 2-month-old, male Sprague-Dawley rats that were administered intraperitoneally with either 10% (w/w) P-407 (1 g/kg) or saline (10 mL/kg) for 4 months. Their lipid profile, organ degeneration due to fat deposition, and body mass were assessed. Intraperitoneal administration of P-407 resulted in significant increases in plasma triglycerides (P ⩽ 0.001), total cholesterol (P < 0.001), high-density lipoprotein-cholesterol (P ⩽ 0.001), and low-density lipoprotein (P < 0.001) cholesterol. In contrast to the control group, fatty tissue degeneration was observed in the liver, spleen, and kidneys of P-407-treated rats. Positive correlations between fatty tissue degeneration, and the atherogenic index of plasma (P < 0.001) and the ratio of total cholesterol to high-density-lipoprotein (P < 0.001) were identified. In addition, treatment with P-407 for 3 to 4 months caused a significant reduction in body mass relative to controls (P < 0.001). Thus, this study describes the development of a cost-effective experimental rat model of organ degeneration, characterized by fat accumulation in the liver, spleen, and kidneys, which could be used for the study of steatosis and related diseases arising from sustained untreated dyslipidemia. Furthermore, both the atherogenic index of plasma and the ratio of total cholesterol to high-density lipoprotein-cholesterol can be used to predict the risk of fatty tissue degeneration in this model. The study was approval of the University of Jishou Biomedical Research Ethics Committee, China.","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115593189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-01DOI: 10.1097/jbr.0000000000000030
Qiaoyan Liu, Yikang Li, Xiong Ma, R. Tang
{"title":"Epigenetics of autoimmune liver diseases: current progress and future directions","authors":"Qiaoyan Liu, Yikang Li, Xiong Ma, R. Tang","doi":"10.1097/jbr.0000000000000030","DOIUrl":"https://doi.org/10.1097/jbr.0000000000000030","url":null,"abstract":"","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131441491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-01DOI: 10.1097/JBR.0000000000000028
X. Meng, Wenyan Wang, Jiaqi Liu, Shan Zheng, Changyuan Guo, Jie Wang, Z. Xing, Menglu Zhang, K. Feng, X. Wang, Xiang Wang
Abstract Breast cancer is one of the most common malignant tumors in women all over the world. Metastasis represents a major adverse progression of breast cancer, resulting in poor survival duration. Axillary lymph node metastasis is often the first step of systemic metastasis process of breast cancer. However, the mechanism of lymph node metastasis and the genomic signatures of primary breast tumors and lymph node metastasis are still under exploration. Whole exome sequencing was applied to primary breast cancer, axillary metastatic lymph nodes, and white blood cells from 10 Chinese women patients in our study. Single nucleotide variants (SNVs) and copy-number variants (CNVs) were compared between primary tumors and lymph nodes for individual patients. There are somatic SNVs (average 5.58 ± 2.56 per megabase) in primary breast cancers and somatic SNVs (average 5.46 ± 2.66 per megabase) in axillary metastatic lymph nodes were identified, which is corresponding to a semblable mutation burden in two malignant sites (P = 0.81). No difference was found in CNVs (P = 0.33). In primary breast cancer, somatic SNVs (48.12 ± 13.80%) and CNVs (61.72 ± 35.00%) were overlapping with somatic SNVs (49.43 ± 12.30%) and CNVs (72.01 ± 24.31%) in axillary metastatic lymph nodes. Nine genes were screened for significant specific mutations in primary tumors, and 15 genes were significantly mutated in metastatic lymph nodes. Using MutSigCV screening, it was found that HRNR and AHNAK2 are lymph node metastasis-specific genes. In our study, primary breast tumors are directly related to axillary lymph node metastases together and there are most SNVs and CNVs which were overlapping in primary and metastatic sites. These variants which are overlapping is closely related to the metastatic process of tumor invasion with early genetic variability. This is the first time to prove the concept of polyclonal metastatic model and in this model more than one clone migrates establish the metastases to axillary lymph nodes. This study was approved by the institutional review board (IRB) of the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, China (approval No. NCC2016G-030) on March 3, 2016.
{"title":"Genomic mutation signatures in primary breast cancer and their axillary metastatic lymph nodes","authors":"X. Meng, Wenyan Wang, Jiaqi Liu, Shan Zheng, Changyuan Guo, Jie Wang, Z. Xing, Menglu Zhang, K. Feng, X. Wang, Xiang Wang","doi":"10.1097/JBR.0000000000000028","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000028","url":null,"abstract":"Abstract Breast cancer is one of the most common malignant tumors in women all over the world. Metastasis represents a major adverse progression of breast cancer, resulting in poor survival duration. Axillary lymph node metastasis is often the first step of systemic metastasis process of breast cancer. However, the mechanism of lymph node metastasis and the genomic signatures of primary breast tumors and lymph node metastasis are still under exploration. Whole exome sequencing was applied to primary breast cancer, axillary metastatic lymph nodes, and white blood cells from 10 Chinese women patients in our study. Single nucleotide variants (SNVs) and copy-number variants (CNVs) were compared between primary tumors and lymph nodes for individual patients. There are somatic SNVs (average 5.58 ± 2.56 per megabase) in primary breast cancers and somatic SNVs (average 5.46 ± 2.66 per megabase) in axillary metastatic lymph nodes were identified, which is corresponding to a semblable mutation burden in two malignant sites (P = 0.81). No difference was found in CNVs (P = 0.33). In primary breast cancer, somatic SNVs (48.12 ± 13.80%) and CNVs (61.72 ± 35.00%) were overlapping with somatic SNVs (49.43 ± 12.30%) and CNVs (72.01 ± 24.31%) in axillary metastatic lymph nodes. Nine genes were screened for significant specific mutations in primary tumors, and 15 genes were significantly mutated in metastatic lymph nodes. Using MutSigCV screening, it was found that HRNR and AHNAK2 are lymph node metastasis-specific genes. In our study, primary breast tumors are directly related to axillary lymph node metastases together and there are most SNVs and CNVs which were overlapping in primary and metastatic sites. These variants which are overlapping is closely related to the metastatic process of tumor invasion with early genetic variability. This is the first time to prove the concept of polyclonal metastatic model and in this model more than one clone migrates establish the metastases to axillary lymph nodes. This study was approved by the institutional review board (IRB) of the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, China (approval No. NCC2016G-030) on March 3, 2016.","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123605513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-01DOI: 10.1097/JBR.0000000000000025
X. Yin, Yun-Long Wang, S. Bai, W. Feng, Lili Feng, Wan-Wen Zhao, M. Wei, Xiaoling Pang, Shuai Liu, Haiyang Chen, Fang He, Yikan Cheng, Jun-xiang Yin, Da-Lu Zhang, Jian Zheng, Lei Wang, Xinjuan Fan, X. Wan
Abstract Programmed death ligand-1 (PD-L1) is involved in inhibiting of T lymphocyte proliferation, producing cytokine, cytolytic activity, and suppressing of the immune response. Genes with molecular alterations involved in DNA mismatch repair promote cancer initiation and tumor progression. Clinical studies show that colorectal cancer (CRC) patients harboring microsatellite instability (MSI) have a higher anti-programmed cell death protein 1/PD-L1 immunotherapy response ratio compared with microsatellite stable subgroup patients. The underlying mechanism has however remained unclear. Here, we found that compared with microsatellite stable samples, PD-L1 was glycosylated and highly expressed both in MSI CRC cell lines and tissue samples. Specifically, PD-L1 was N-glycosylated at its N35, N192, N200, and N219 sites, and the four glycosylation sites were all responsible for PD-L1 degradation. Additionally, non-glycosylated PD-L1 underwent rapid degradation compared with glycosylated PD-L1 through the 26S proteasome pathway. The faster degradation of the non-glycosylated PD-L1 was ascribed to its binding to glycogen synthase kinase 3&bgr; via ubiquitination. This degradation phenotype was, however, not observed for glycosylated PD-L1. Significantly, glycosylated PD-L1 was up-regulated by activated epidermal growth factor receptor in MSI CRC cells. Together, our results indicate that epidermal growth factor receptor stabilized PD-L1 via glycosylation in MSI CRC cells, uncovering a novel role of PD-L1 in MSI CRC immunosuppression and disease progression. The study was approved by the Clinical Ethics Review Committee at the Six Affiliated Hospital of Sun Yat-sen University, China (Approval No. 2019ZSLYEC-005).
程序性死亡配体-1 (Programmed death ligand-1, PD-L1)参与抑制T淋巴细胞增殖、产生细胞因子、细胞溶解活性和抑制免疫反应。参与DNA错配修复的分子改变基因促进癌症的发生和肿瘤的进展。临床研究表明，微卫星不稳定性(microsatellite instability, MSI)的结直肠癌(CRC)患者的抗程序性细胞死亡蛋白1/PD-L1免疫治疗应答率高于微卫星稳定亚组患者。然而，潜在的机制仍不清楚。在这里，我们发现与微卫星稳定样本相比，PD-L1在MSI CRC细胞系和组织样本中都被糖基化并高度表达。具体来说，PD-L1在N35、N192、N200和N219位点被n糖基化，这四个糖基化位点都与PD-L1的降解有关。此外，与糖基化PD-L1相比，非糖基化PD-L1通过26S蛋白酶体途径快速降解。非糖基化PD-L1的快速降解归因于其与糖原合成酶激酶3的结合;通过泛素化。然而，糖基化的PD-L1没有观察到这种降解表型。值得注意的是，活化的表皮生长因子受体在MSI结直肠癌细胞中上调了糖基化的PD-L1。总之，我们的研究结果表明，表皮生长因子受体通过糖基化稳定了MSI CRC细胞中的PD-L1，揭示了PD-L1在MSI CRC免疫抑制和疾病进展中的新作用。本研究已获得中国中山大学附属第六医院临床伦理审查委员会批准(批准号:2019ZSLYEC-005)。
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Pub Date : 2019-03-01DOI: 10.1097/JBR.0000000000000024
Li Yu, R. Zhao, Xufeng Han, J. Shou, Liangkun You, Hanliang Jiang, Xiaoyun Zhou, Zhen Liu, H. Pan, W. Han
Abstract Whether regional lymph node involvement exerts significant effect on the prognosis still remains obscure for pancreatic neuroendocrine tumors. To clarify this association and identify predictors for lymph node involvement, we studied the data of patients aged >18 years with regional lymph node involvement histologically confirmed pancreatic neuroendocrine tumors from 2004 to 2014 in the Surveillance, Epidemiology, and End Results database (http://seer.cancer.gov/about). We evaluated Lymph node involvement as a prognostic factor by Cox regression. We reduced 9 variables of demographic and tumor characteristics to 5 potential predictors using least absolute shrinkage and selection operator (LASSO) regression model. We further constructed a lymph node involvement model by logistic regression. The model was verified by the verification set, and the visual expression of the model was realized by a nomogram. A total of 1545 cases of pancreatic neuroendocrine tumors were included in our study. Lymph node positivity was significantly associated with disease-specific survival (P < 0.001). Younger patients (P < 0.05), patients with tumors in the pancreatic head (P < 0.05), patients at high American Joint Committee on Cancer T stage (P < 0.001), and patients of an undifferentiated status (P < 0.05) showed a significantly higher possibility of developing lymph node involvement. The reliability of this model was verified by cross-validation between the training and testing set, and we obtained good discrimination and calibration power. This model also showed great performance in C-index and area under receiver operating characteristic curve. Lymph node positivity was an important negative prognostic predictor for pancreatic neuroendocrine tumor. We developed a lymph node involvement model based on the predictors including age, marital status, primary site, T status, and tumor grade.
{"title":"Lymph node involvement in pancreatic neuroendocrine tumors: significance as a predictor of survival","authors":"Li Yu, R. Zhao, Xufeng Han, J. Shou, Liangkun You, Hanliang Jiang, Xiaoyun Zhou, Zhen Liu, H. Pan, W. Han","doi":"10.1097/JBR.0000000000000024","DOIUrl":"https://doi.org/10.1097/JBR.0000000000000024","url":null,"abstract":"Abstract Whether regional lymph node involvement exerts significant effect on the prognosis still remains obscure for pancreatic neuroendocrine tumors. To clarify this association and identify predictors for lymph node involvement, we studied the data of patients aged >18 years with regional lymph node involvement histologically confirmed pancreatic neuroendocrine tumors from 2004 to 2014 in the Surveillance, Epidemiology, and End Results database (http://seer.cancer.gov/about). We evaluated Lymph node involvement as a prognostic factor by Cox regression. We reduced 9 variables of demographic and tumor characteristics to 5 potential predictors using least absolute shrinkage and selection operator (LASSO) regression model. We further constructed a lymph node involvement model by logistic regression. The model was verified by the verification set, and the visual expression of the model was realized by a nomogram. A total of 1545 cases of pancreatic neuroendocrine tumors were included in our study. Lymph node positivity was significantly associated with disease-specific survival (P < 0.001). Younger patients (P < 0.05), patients with tumors in the pancreatic head (P < 0.05), patients at high American Joint Committee on Cancer T stage (P < 0.001), and patients of an undifferentiated status (P < 0.05) showed a significantly higher possibility of developing lymph node involvement. The reliability of this model was verified by cross-validation between the training and testing set, and we obtained good discrimination and calibration power. This model also showed great performance in C-index and area under receiver operating characteristic curve. Lymph node positivity was an important negative prognostic predictor for pancreatic neuroendocrine tumor. We developed a lymph node involvement model based on the predictors including age, marital status, primary site, T status, and tumor grade.","PeriodicalId":150904,"journal":{"name":"Journal of Bio-X Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114432635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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