L. Deng, K. Jin, Xianghong Zhou, Zilong Zhang, Liming Ge, X. Xiong, X. Su, Di Jin, Qiming Yuan, Chichen Zhang, Yifan Li, Haochen Zhao, Qiang Wei, L. Yang, S. Qiu
Abstract Background Diminished sensitivity towards chemotherapy remains the major impediment to the clinical treatment of bladder cancer. However, the critical elements in control of chemotherapy resistance remain obscure. Methods We adopted improved collagen gels and performed cytotoxicity analysis of doxorubicin (DOX) and mitomycin C (MMC) of bladder cancer cells in a 3D culture system. We then detected the expression of multidrug resistant gene ABCB1, dormancy-associated functional protein chicken ovalbumin upstream-transcription factor 1 (COUPTF1), cell proliferation marker Ki-67, and cellular senescence marker senescence-associated β-galactosidase (SA-β-Gal) in these cells. We further tested the effects of integrin blockade or protein kinase B (AKT) inhibitor on the senescent state of bladder cancer. Also, we examined the tumor growth and survival time of bladder cancer mouse models given the combination treatment of chemotherapeutic agents and integrin α2β1 ligand peptide TFA (TFA). Results Collagen gels played a repressive role in bladder cancer cell apoptosis induced by DOX and MMC. In mechanism, collagen activated the integrin β1/AKT cascade to drive bladder cancer cells into a premature senescence state via the p53/p21 pathway, thus attenuating chemotherapy-induced apoptosis. In addition, TFA had the ability to mediate the switch from senescence to apoptosis of bladder cancer cells in xenograft mice. Meanwhile, TFA combined with chemotherapeutic drugs produced a substantial suppression of tumor growth as well as an extension of survival time in vivo. Conclusions Based on our finding that integrin β1/AKT acted primarily to impart premature senescence to bladder cancer cells cultured in collagen gel, we suggest that integrin β1 might be a feasible target for bladder cancer eradication.
{"title":"Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells","authors":"L. Deng, K. Jin, Xianghong Zhou, Zilong Zhang, Liming Ge, X. Xiong, X. Su, Di Jin, Qiming Yuan, Chichen Zhang, Yifan Li, Haochen Zhao, Qiang Wei, L. Yang, S. Qiu","doi":"10.1093/pcmedi/pbac007","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac007","url":null,"abstract":"Abstract Background Diminished sensitivity towards chemotherapy remains the major impediment to the clinical treatment of bladder cancer. However, the critical elements in control of chemotherapy resistance remain obscure. Methods We adopted improved collagen gels and performed cytotoxicity analysis of doxorubicin (DOX) and mitomycin C (MMC) of bladder cancer cells in a 3D culture system. We then detected the expression of multidrug resistant gene ABCB1, dormancy-associated functional protein chicken ovalbumin upstream-transcription factor 1 (COUPTF1), cell proliferation marker Ki-67, and cellular senescence marker senescence-associated β-galactosidase (SA-β-Gal) in these cells. We further tested the effects of integrin blockade or protein kinase B (AKT) inhibitor on the senescent state of bladder cancer. Also, we examined the tumor growth and survival time of bladder cancer mouse models given the combination treatment of chemotherapeutic agents and integrin α2β1 ligand peptide TFA (TFA). Results Collagen gels played a repressive role in bladder cancer cell apoptosis induced by DOX and MMC. In mechanism, collagen activated the integrin β1/AKT cascade to drive bladder cancer cells into a premature senescence state via the p53/p21 pathway, thus attenuating chemotherapy-induced apoptosis. In addition, TFA had the ability to mediate the switch from senescence to apoptosis of bladder cancer cells in xenograft mice. Meanwhile, TFA combined with chemotherapeutic drugs produced a substantial suppression of tumor growth as well as an extension of survival time in vivo. Conclusions Based on our finding that integrin β1/AKT acted primarily to impart premature senescence to bladder cancer cells cultured in collagen gel, we suggest that integrin β1 might be a feasible target for bladder cancer eradication.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"1 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84023968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Precision medicine: a few thoughts from 2022","authors":"Sherman M. Weissman","doi":"10.1093/pcmedi/pbac003","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac003","url":null,"abstract":"","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"133 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90707884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
X. Gong, Yanan Li, Kaiying Yang, Siyuan Chen, Yi Ji
Abstract Infantile hepatic hemangiomas (IHHs) are common benign tumors seen in the liver of infants. IHHs are true infantile hemangiomas (IHs) and have phases of proliferation and involution parallel to those of cutaneous IHs. The definition and classification of IHH are still confusing in the literature. The mechanisms during the pathogenesis of IHH have yet to be discovered. The clinical manifestations of IHH are heterogeneous. Although most IHH lesions are asymptomatic, some lesions can lead to severe complications, such as hypothyroidism, consumptive coagulopathy, and high-output congestive cardiac failure. Consequently, some patients can possibly encounter a fatal clinical condition. The heterogeneity of the lesions and the occurrence of disease-related comorbidities can make the treatment of IHH challenging. Oral propranolol is emerging as an effective systemic approach to IHH with obvious responses in tumor remission and symptom regression. However, the precise clinical characteristics and treatment strategies for patients with severe IHH have not yet been well established. Here, we summarize the epidemiology, pathogenic mechanism, clinical manifestations, diagnosis, and treatment of IHH. Recent updates and future perspectives for IHH will also be elaborated.
{"title":"Infantile hepatic hemangiomas: looking backwards and forwards","authors":"X. Gong, Yanan Li, Kaiying Yang, Siyuan Chen, Yi Ji","doi":"10.1093/pcmedi/pbac006","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac006","url":null,"abstract":"Abstract Infantile hepatic hemangiomas (IHHs) are common benign tumors seen in the liver of infants. IHHs are true infantile hemangiomas (IHs) and have phases of proliferation and involution parallel to those of cutaneous IHs. The definition and classification of IHH are still confusing in the literature. The mechanisms during the pathogenesis of IHH have yet to be discovered. The clinical manifestations of IHH are heterogeneous. Although most IHH lesions are asymptomatic, some lesions can lead to severe complications, such as hypothyroidism, consumptive coagulopathy, and high-output congestive cardiac failure. Consequently, some patients can possibly encounter a fatal clinical condition. The heterogeneity of the lesions and the occurrence of disease-related comorbidities can make the treatment of IHH challenging. Oral propranolol is emerging as an effective systemic approach to IHH with obvious responses in tumor remission and symptom regression. However, the precise clinical characteristics and treatment strategies for patients with severe IHH have not yet been well established. Here, we summarize the epidemiology, pathogenic mechanism, clinical manifestations, diagnosis, and treatment of IHH. Recent updates and future perspectives for IHH will also be elaborated.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"12 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85246610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract In 2006, Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4, Sox2, Klf44, and c-Myc. Since then, the future clinical application of somatic cell reprogramming technology has become an attractive research topic in the field of regenerative medicine. Of note, considerable interest has been placed in circumventing ethical issues linked to embryonic stem cell research. However, tumorigenicity, immunogenicity, and heterogeneity may hamper attempts to deploy this technology therapeutically. This review highlights the progress aimed at reducing induced pluripotent stem cells tumorigenicity risk and how to assess the safety of induced pluripotent stem cells cell therapy products.
{"title":"Tumorigenicity risk of iPSCs in vivo: nip it in the bud","authors":"Chaoliang Zhong, Miao Liu, Xinghua Pan, Haiying Zhu","doi":"10.1093/pcmedi/pbac004","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac004","url":null,"abstract":"Abstract In 2006, Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4, Sox2, Klf44, and c-Myc. Since then, the future clinical application of somatic cell reprogramming technology has become an attractive research topic in the field of regenerative medicine. Of note, considerable interest has been placed in circumventing ethical issues linked to embryonic stem cell research. However, tumorigenicity, immunogenicity, and heterogeneity may hamper attempts to deploy this technology therapeutically. This review highlights the progress aimed at reducing induced pluripotent stem cells tumorigenicity risk and how to assess the safety of induced pluripotent stem cells cell therapy products.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"1 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76213327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Management of severe asthma: from stepwise approach to therapy to treatable traits?","authors":"Gang Wang, V. McDonald, P. Gibson","doi":"10.1093/pcmedi/pbab028","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab028","url":null,"abstract":"","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"30 1","pages":"293-296"},"PeriodicalIF":5.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89285774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenxin Luo, Zhoufeng Wang, Ting Zhang, Lan Yang, Jinghong Xian, Yalun Li, Weimin Li
Lung cancer, with non-small cell lung cancer (NSCLC) being the major type, is the second most common malignancy and the leading cause of cancer-related death globally. Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has been one of the greatest advances in recent years for the treatment of solid tumors including NSCLC. However, not all NSCLC patients experience an effective response to immunotherapy with the established selection criteria of programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB). Furthermore, a considerable proportion of patients experience unconventional responses, including pseudoprogression or hyperprogressive disease (HPD), immune-related toxicities, and primary or acquired resistance during the immunotherapy process. To better understand the immune response in NSCLC and provide reference for clinical decision-making, we herein review the rationale and recent advances in using immunotherapy to treat NSCLC. Moreover, we discuss the current challenges and future strategies of this approach to improve its efficacy and safety in treating NSCLC.
{"title":"Immunotherapy in non-small cell lung cancer: rationale, recent advances and future perspectives.","authors":"Wenxin Luo, Zhoufeng Wang, Ting Zhang, Lan Yang, Jinghong Xian, Yalun Li, Weimin Li","doi":"10.1093/pcmedi/pbab027","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab027","url":null,"abstract":"<p><p>Lung cancer, with non-small cell lung cancer (NSCLC) being the major type, is the second most common malignancy and the leading cause of cancer-related death globally. Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has been one of the greatest advances in recent years for the treatment of solid tumors including NSCLC. However, not all NSCLC patients experience an effective response to immunotherapy with the established selection criteria of programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB). Furthermore, a considerable proportion of patients experience unconventional responses, including pseudoprogression or hyperprogressive disease (HPD), immune-related toxicities, and primary or acquired resistance during the immunotherapy process. To better understand the immune response in NSCLC and provide reference for clinical decision-making, we herein review the rationale and recent advances in using immunotherapy to treat NSCLC. Moreover, we discuss the current challenges and future strategies of this approach to improve its efficacy and safety in treating NSCLC.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"4 4","pages":"258-270"},"PeriodicalIF":5.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10268801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chong Zhang, Jionghui Gu, Yangyang Zhu, Zheling Meng, Tong Tong, Dongyang Li, Zhenyu Liu, Yang Du, Kun Wang, Jie Tian
Abstract Medical imaging provides a comprehensive perspective and rich information for disease diagnosis. Combined with artificial intelligence technology, medical imaging can be further mined for detailed pathological information. Many studies have shown that the macroscopic imaging characteristics of tumors are closely related to microscopic gene, protein and molecular changes. In order to explore the function of artificial intelligence algorithms in in-depth analysis of medical imaging information, this paper reviews the articles published in recent years from three perspectives: medical imaging analysis method, clinical applications and the development of medical imaging in the direction of pathological molecular prediction. We believe that AI-aided medical imaging analysis will be extensively contributing to precise and efficient clinical decision.
{"title":"AI in spotting high-risk characteristics of medical imaging and molecular pathology","authors":"Chong Zhang, Jionghui Gu, Yangyang Zhu, Zheling Meng, Tong Tong, Dongyang Li, Zhenyu Liu, Yang Du, Kun Wang, Jie Tian","doi":"10.1093/pcmedi/pbab026","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab026","url":null,"abstract":"Abstract Medical imaging provides a comprehensive perspective and rich information for disease diagnosis. Combined with artificial intelligence technology, medical imaging can be further mined for detailed pathological information. Many studies have shown that the macroscopic imaging characteristics of tumors are closely related to microscopic gene, protein and molecular changes. In order to explore the function of artificial intelligence algorithms in in-depth analysis of medical imaging information, this paper reviews the articles published in recent years from three perspectives: medical imaging analysis method, clinical applications and the development of medical imaging in the direction of pathological molecular prediction. We believe that AI-aided medical imaging analysis will be extensively contributing to precise and efficient clinical decision.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"28 1","pages":"271 - 286"},"PeriodicalIF":5.3,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83416902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huimin Chen, Xiaohan Wu, Chunjin Xu, Jian Lin, Zhanju Liu
Abstract Neutrophils are considered as complex innate immune cells and play a critical role in maintaining intestinal mucosal homeostasis. They exert robust pro-inflammatory effects and recruit other immune cells in the acute phase of pathogen infection and intestinal inflammation, but paradoxically, they also limit exogenous microbial invasion and facilitate mucosal restoration. Hyperactivation or dysfunction of neutrophils results in abnormal immune responses, leading to multiple autoimmune and inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases (IBD). As a refractory intestinal inflammatory disease, the pathogenesis and progression of IBD are associated with complicated immune response processes in which neutrophils are profoundly involved. However, the consensus on potential roles of neutrophils in modulating pathogenic and repair processes of IBD remains not fully understood. Accumulated infiltrating neutrophils cross the epithelial barrier and contribute to microbial dysbiosis, aggravated intestinal architectural damage, compromised resolution of intestinal inflammation and increased risk of thrombosis during IBD. Paradoxically, activated neutrophils are also associated with effective elimination of invaded microbiota, promoted angiogenesis and tissue restoration of gut mucosa in IBD. Here, we discuss the beneficial and detrimental roles of neutrophils in the onset and resolution of intestinal mucosal inflammation, hoping to provide a precise overview of neutrophil functions in the pathogenesis of IBD.
{"title":"Dichotomous roles of neutrophils in modulating pathogenic and repair processes of inflammatory bowel diseases","authors":"Huimin Chen, Xiaohan Wu, Chunjin Xu, Jian Lin, Zhanju Liu","doi":"10.1093/pcmedi/pbab025","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab025","url":null,"abstract":"Abstract Neutrophils are considered as complex innate immune cells and play a critical role in maintaining intestinal mucosal homeostasis. They exert robust pro-inflammatory effects and recruit other immune cells in the acute phase of pathogen infection and intestinal inflammation, but paradoxically, they also limit exogenous microbial invasion and facilitate mucosal restoration. Hyperactivation or dysfunction of neutrophils results in abnormal immune responses, leading to multiple autoimmune and inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases (IBD). As a refractory intestinal inflammatory disease, the pathogenesis and progression of IBD are associated with complicated immune response processes in which neutrophils are profoundly involved. However, the consensus on potential roles of neutrophils in modulating pathogenic and repair processes of IBD remains not fully understood. Accumulated infiltrating neutrophils cross the epithelial barrier and contribute to microbial dysbiosis, aggravated intestinal architectural damage, compromised resolution of intestinal inflammation and increased risk of thrombosis during IBD. Paradoxically, activated neutrophils are also associated with effective elimination of invaded microbiota, promoted angiogenesis and tissue restoration of gut mucosa in IBD. Here, we discuss the beneficial and detrimental roles of neutrophils in the onset and resolution of intestinal mucosal inflammation, hoping to provide a precise overview of neutrophil functions in the pathogenesis of IBD.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"29 1","pages":"246 - 257"},"PeriodicalIF":5.3,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81886816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mandy M Liu, Tiantian Liu, S. Yeung, Zhijun Wang, B. Andresen, C. Parsa, R. Orlando, Bingsen Zhou, Wei Wu, Xia Li, Yilong Zhang, Charles Wang, Ying Huang
Abstract The medicinal mushroom Ganoderma lucidum (GL, Reishi or Lingzhi) exhibits an inhibitory effect on cancers. However, the underlying mechanism of the antitumor activity of GL is not fully understood. In this study, we characterized the gene networks regulated by a commercial product of GL containing a mixture of spores and fruiting bodies namely “GLSF”, in colorectal carcinoma. We found that in vitro co-administration of GLSF extract at non-toxic concentrations significantly potentiated growth inhibition and apoptosis induced by paclitaxel in CT26 and HCT-15 cells. GLSF inhibited NF-κB promoter activity in HEK-293 cells but did not affect the function of P-glycoprotein in K562/DOX cells. Furthermore, we found that when mice were fed a modified diet containing GLSF for 1 month prior to the CT26 tumor cell inoculation, GLSF alone or combined with Nab-paclitaxel markedly suppressed tumor growth and induced apoptosis. RNA-seq analysis of tumor tissues derived from GLSF-treated mice identified 53 differentially expressed genes compared to normal tissues. Many of the GLSF-down-regulated genes were involved in NF-κB-regulated inflammation pathways, such as IL-1β, IL-11 and Cox-2. Pathway enrichment analysis suggested that several inflammatory pathways involving leukocyte migration and adhesion were most affected by the treatment. Upstream analysis predicted activation of multiple tumor suppressors such as α-catenin and TP53 and inhibition of critical inflammatory mediators. “Cancer” was the major significantly inhibited biological effect of GLSF treatment. These results demonstrate that GLSF can improve the therapeutic outcome for colorectal cancer through a mechanism involving suppression of NF-κB-regulated inflammation and carcinogenesis.
{"title":"Inhibitory activity of medicinal mushroom Ganoderma lucidum on colorectal cancer by attenuating inflammation","authors":"Mandy M Liu, Tiantian Liu, S. Yeung, Zhijun Wang, B. Andresen, C. Parsa, R. Orlando, Bingsen Zhou, Wei Wu, Xia Li, Yilong Zhang, Charles Wang, Ying Huang","doi":"10.1093/pcmedi/pbab023","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab023","url":null,"abstract":"Abstract The medicinal mushroom Ganoderma lucidum (GL, Reishi or Lingzhi) exhibits an inhibitory effect on cancers. However, the underlying mechanism of the antitumor activity of GL is not fully understood. In this study, we characterized the gene networks regulated by a commercial product of GL containing a mixture of spores and fruiting bodies namely “GLSF”, in colorectal carcinoma. We found that in vitro co-administration of GLSF extract at non-toxic concentrations significantly potentiated growth inhibition and apoptosis induced by paclitaxel in CT26 and HCT-15 cells. GLSF inhibited NF-κB promoter activity in HEK-293 cells but did not affect the function of P-glycoprotein in K562/DOX cells. Furthermore, we found that when mice were fed a modified diet containing GLSF for 1 month prior to the CT26 tumor cell inoculation, GLSF alone or combined with Nab-paclitaxel markedly suppressed tumor growth and induced apoptosis. RNA-seq analysis of tumor tissues derived from GLSF-treated mice identified 53 differentially expressed genes compared to normal tissues. Many of the GLSF-down-regulated genes were involved in NF-κB-regulated inflammation pathways, such as IL-1β, IL-11 and Cox-2. Pathway enrichment analysis suggested that several inflammatory pathways involving leukocyte migration and adhesion were most affected by the treatment. Upstream analysis predicted activation of multiple tumor suppressors such as α-catenin and TP53 and inhibition of critical inflammatory mediators. “Cancer” was the major significantly inhibited biological effect of GLSF treatment. These results demonstrate that GLSF can improve the therapeutic outcome for colorectal cancer through a mechanism involving suppression of NF-κB-regulated inflammation and carcinogenesis.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"139 1","pages":"231 - 245"},"PeriodicalIF":5.3,"publicationDate":"2021-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73265350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Somatic gene therapy remains technically challenging, especially in the central nervous system (CNS). Efficiency of gene delivery, efficacy in recipient cells, and proportion of cells required for overall benefit are the key points needed to be considered in any therapeutic approach. Recent efforts have demonstrated the efficacy of RNA-guided nucleases such as CRISPR/Cas9 in correcting point mutations or removing dominant mutations. Here we used viral delivered Cas9 plasmid and two guide RNAs to remove a recessive insertional mutation, vibrator (vb), in the mouse brain. The vb mice expressed ∼20% of normal levels of phosphatidylinositol transfer protein, α (PITPα) RNA and protein due to an endogenous retrovirus inserted in intron 4, resulting in early-onset tremor, degeneration of brainstem and spinal cord neurons, and juvenile death. The in situ CRISPR/Cas9 viral treatment effectively delayed neurodegeneration, attenuated tremor, and bypassed juvenile death. Our studies demonstrate the potential of CRISPR/Cas9-mediated gene therapy for insertional mutations in the postnatal brain.
{"title":"CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model","authors":"Xin Fu, Jie Zhu, Yaou Duan, P. Lu, Kang Zhang","doi":"10.1093/pcmedi/pbab021","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab021","url":null,"abstract":"Abstract Somatic gene therapy remains technically challenging, especially in the central nervous system (CNS). Efficiency of gene delivery, efficacy in recipient cells, and proportion of cells required for overall benefit are the key points needed to be considered in any therapeutic approach. Recent efforts have demonstrated the efficacy of RNA-guided nucleases such as CRISPR/Cas9 in correcting point mutations or removing dominant mutations. Here we used viral delivered Cas9 plasmid and two guide RNAs to remove a recessive insertional mutation, vibrator (vb), in the mouse brain. The vb mice expressed ∼20% of normal levels of phosphatidylinositol transfer protein, α (PITPα) RNA and protein due to an endogenous retrovirus inserted in intron 4, resulting in early-onset tremor, degeneration of brainstem and spinal cord neurons, and juvenile death. The in situ CRISPR/Cas9 viral treatment effectively delayed neurodegeneration, attenuated tremor, and bypassed juvenile death. Our studies demonstrate the potential of CRISPR/Cas9-mediated gene therapy for insertional mutations in the postnatal brain.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"34 1","pages":"168 - 175"},"PeriodicalIF":5.3,"publicationDate":"2021-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89723565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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