Precision Clinical Medicine最新文献

{"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":null,"pages":null},"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}

{"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":null,"pages":null},"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}

{"title":"CXCL13 expression in mouse 4T1 breast cancer microenvironment elicits antitumor immune response by regulating immune cell infiltration.","authors":"Qizhi Ma, Yue Chen, Qing Qin, Fuchun Guo, Yong-Sheng Wang, Dan Li","doi":"10.1093/pcmedi/pbab020","DOIUrl":"10.1093/pcmedi/pbab020","url":null,"abstract":"<p><p>Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide. Previous studies have reported contradictory performance of chemokine CXC motif ligand 13 (CXCL13) in breast cancer. In this study, The Cancer Genome Atlas database analysis revealed that CXCL13 was overexpressed in various human cancers including breast carcinoma, and associated with good clinical prognosis in breast cancer. Flow cytometry detection also found upregulated intracellular CXCL13 expression in human breast cancer cell lines. To explore the possible role of CXCL13 in the breast cancer microenvironment, mouse triple negative breast cancer (TNBC) was lentivirally transfected to stably overexpress mouse CXCL13 (4T1-CXCL13). Both parental 4T1 and 4T1-CXCL13 strains showed no <i>in vitro</i> or <i>in vivo</i> endogenous cell surface CXCR5 expression. In immune-competent BALB/c mice, the <i>in vivo</i> tumor growth of 4T1-CXCL13 was significantly inhibited and even completely eradicated, accompanied with increased infiltrations of CD4⁺, CD8⁺ T lymphocytes and CD11b⁺CD11c⁺ DCs. Further investigations showed that CXCL13 expression in the 4T1 tumor microenvironment elicited long-term antitumor immune memory, and rejection of distal parental tumor. The antitumor activity of CXCL13 was remarkedly impaired in BALB/cA-nu nude mice, or in BALB/c mice with CD8⁺ T lymphocyte or NK cell depletion. Our investigation indicated that CXCL13 expression in TNBC triggered effective antitumor immunity by chemoattracting immune cell infiltrations and could be considered as a novel prognostic marker for TNBC.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2021-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80050118","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}

{"title":"Identification and characteristic analysis of enhancers across 13 major cancer types.","authors":"Mingming Qian, Wenzhu Wang, Yana Zhang, Yi Zhao, Huige Quan, Yuting Chen, Xinyue Dai, Zhiyun Guo","doi":"10.1093/pcmedi/pbab019","DOIUrl":"10.1093/pcmedi/pbab019","url":null,"abstract":"<p><p>Enhancers are often mutated and dysregulated in various diseases such as cancer. By integrating the function annotation of the mammalian genome (FANTOM) enhancers expression profiles and RNA-seq data from The Cancer Genome Atlas (TCGA) of 13 cancers and their corresponding <i>para</i>-cancerous tissues, we systematically identified a total of 4702 significantly differentially expressed (DE) enhancers. Furthermore, a total of 1036 DE genes regulated by DE enhancers were identified. It was found that in these 13 cancers, most (61.13%) enhancers were ubiquitously expressed, whereas DE enhancers were more likely to be tissue-specific expressed, and the DE genes regulated by DE enhancers were significantly enriched in cancer-related pathways. Finally, it was manifested that 74 single nucleotide polymorphisms (SNPs) were located in 37 DE enhancers, and these SNPs affected the gain and loss of functional transcription factor binding sites of 758 transcription factors, which were shown to be highly correlated with tumorigenesis and development.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2021-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74331974","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}

{"title":"The SARS-CoV-2 spike L452R-E484Q variant in the Indian B.1.617 strain showed significant reduction in the neutralization activity of immune sera.","authors":"Gen Li, Zhongcheng Zhou, Peng Du, Meixing Yu, Ning Li, Xinxin Xiong, Hong Huang, Zhihai Liu, Qinjin Dai, Jie Zhu, Chengbin Guo, Shanyun Wu, Daniel T Baptista-Hon, Man Miao, Lam Wai Ming, Yong Wu, Fanxin Zeng, Charlotte L Zhang, Edward D Zhang, Haifeng Song, Jianghai Liu, Johnson Yiu-Nam Lau, Andy P Xiang, Kang Zhang","doi":"10.1093/pcmedi/pbab016","DOIUrl":"10.1093/pcmedi/pbab016","url":null,"abstract":"<p><p>To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1 (dominant variant identified in the current India outbreak) on the infectivity and neutralization activities of the immune sera, L452R and E484Q (L452R-E484Q variant), pseudotyped virus was constructed (with the D614G background). The impact on binding with the neutralizing antibodies was also assessed with an ELISA assay. Pseudotyped virus carrying a L452R-E484Q variant showed a comparable infectivity compared with D614G. However, there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant receptor binding domain (RBD) protein, convalescent patients, and healthy vaccinees vaccinated with an mRNA vaccine. In addition, there was a reduction in binding of L452R-E484Q-D614G protein to the antibodies of the immune sera from vaccinated non-human primates. These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2. Reduced neutralization activities against the L452R-E484Q variant will have an impact on health authority planning and implications for the vaccination strategy/new vaccine development.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2021-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80865481","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}

{"title":"A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification.","authors":"Hongna Sun, Xiaofen Li, Shuang Dai, Xudong Shen, Meng Qiu","doi":"10.1093/pcmedi/pbab017","DOIUrl":"10.1093/pcmedi/pbab017","url":null,"abstract":"<p><p>Gallbladder cancer (GBC) is a highly invasive disease and the most prevalent malignancy of the biliary system. Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis. Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades. Recently, several targeted therapies have been investigated in advanced biliary tract cancer (BTC) including inhibitors of genes or pathways such as <i>FGFR2</i> fusions or rearrangements, <i>IDH1</i> mutations, and <i>NTRK</i> gene fusions. Also, several clinical studies involving molecular stratification have been performed in defined patient groups, for example, <i>BRAF V600E</i> and <i>HER2</i>. Mesenchymal epithelial transition<i>(MET)</i>encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene. Targeting the <i>MET</i> signaling pathway is an effective strategy in numerous cancer types. However, the poor efficacy of <i>MET</i> inhibitors has been demonstrated in several phase II studies, but currently no reports have explained the potential mechanisms of resistance to <i>MET</i> inhibitors in BTC. In this article, we report a case of metastatic GBC with <i>MET</i> amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy. After the patient had progressed and discontinued crizotinib, cabozantinib was introduced. Analysis of circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) indicated a loss of <i>MET</i> amplification status. To our knowledge, this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-<i>MET</i> treatment in GBC.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2021-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81731880","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}

{"title":"Understanding the predictive value and methods of risk assessment based on coronary computed tomographic angiography in populations with coronary artery disease: a review.","authors":"Yiming Li, Kaiyu Jia, Yuheng Jia, Yong Yang, Yijun Yao, Mao Chen, Yong Peng","doi":"10.1093/pcmedi/pbab018","DOIUrl":"10.1093/pcmedi/pbab018","url":null,"abstract":"<p><p>Risk assessment in coronary artery disease plays an essential role in the early identification of high-risk patients. However, conventional invasive imaging procedures all require long intraprocedural times and high costs. The rapid development of coronary computed tomographic angiography (CCTA) and related image processing technology has facilitated the formulation of noninvasive approaches to perform comprehensive evaluations. Evidence has shown that CCTA has outstanding performance in identifying the degree of stenosis, plaque features, and functional reserve. Moreover, advancements in radiomics and machine learning allow more comprehensive interpretations of CCTA images. This paper reviews conventional as well as novel diagnostic and risk assessment tools based on CCTA.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2021-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81112087","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}

{"title":"Improving T cell therapy: in vivo CRISPR-Cas9 screens tell us how to do","authors":"Tao Yin","doi":"10.1093/pcmedi/pbab015","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab015","url":null,"abstract":"Editor’s note A commentary on “In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer”.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2021-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75198038","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":"Applications and challenges of CRISPR-Cas gene-editing to disease treatment in clinics.","authors":"Wenyi Liu, Luoxi Li, Jianxin Jiang, Min Wu, Ping Lin","doi":"10.1093/pcmedi/pbab014","DOIUrl":"10.1093/pcmedi/pbab014","url":null,"abstract":"<p><p>Clustered regularly interspaced short palindromic repeats (CRISPR)-associated systems (Cas) are efficient tools for targeting specific genes for laboratory research, agricultural engineering, biotechnology, and human disease treatment. Cas9, by far the most extensively used gene-editing nuclease, has shown great promise for the treatment of hereditary diseases, viral infection, cancers, and so on. Recent reports have revealed that some other types of CRISPR-Cas systems may also have surprising potential to join the fray as gene-editing tools for various applications. Despite the rapid progress in basic research and clinical tests, some underlying problems present continuous, significant challenges, such as editing efficiency, relative difficulty in delivery, off-target effects, immunogenicity, etc. This article summarizes the applications of CRISPR-Cas from bench to bedside and highlights the current obstacles that may limit the usage of CRISPR-Cas systems as gene-editing toolkits in precision medicine and offer some viewpoints that may help to tackle these challenges and facilitate technical development. CRISPR-Cas systems, as a powerful gene-editing approach, will offer great hopes in clinical treatments for many individuals with currently incurable diseases.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2021-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39431646","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}

{"title":"COVID-19 has triggered a new century of vaccination and infection control for the benefit of all mankind","authors":"B. Marshall","doi":"10.1093/pcmedi/pbab010","DOIUrl":"https://doi.org/10.1093/pcmedi/pbab010","url":null,"abstract":"Modern safe vaccinations were pioneered in 1796 by Edward Jenner in England, when he noticed that milkmaids had beautiful complexions, clear of the blemishes from smallpox scars. This was attributed to their exposure to ‘cowpox’ in localised blisters, which seemed to protect them from the more severe and often fatal ‘smallpox’. In the twentieth century, the importance of immunity was emphasised by the very first Nobel Prize in Medicine, awarded to Emil Adolf von Bering who recognised the therapeutic role of antibodies in blood,1 using plasma from a recovered human (or horse) to protect and treat diphtheria, and eventually inventing the diphtheria vaccine in 1907. The first vaccines were simply made, being denatured protein extracts of live cultured bacteria, so there was no danger of causing the disease from the vaccination. Diphtheria-Pertussis-Tetanus (DPT) vaccine has long been available and is given to infants, making these three dreaded diseases of children uncommon in Western countries. My first personal experience with vaccination was as a 6-year-old (school grade 1) with my mother and 3-yearold brother attending the town hall in Kalgoorlie, Western Australia, for a mass polio vaccination administering the Salk vaccine. I remember that the vaccine was in a 50 ml multiple use bottle containing an estimated 25 dosages of 2 ml. The hall was pandemonium, with lines of people and numerous crying children. Hygiene in the stuffy, packed hall was less than ideal, the multiuse needles simply being soaked in alcohol for sterilisation between patients, becoming blunt and unsafe for use. But there had been at least a 12-month delay before the Salk vaccine could be used in Australia, as one of the early batches from Cutter Labs USA was withdrawn. The virus antigen made from cultured polio virus had not been sterilised adequately in 1955, resulting in more than 250 cases of actual polio in the USA. This caused the FDA to go on high alert, insisting on more stringent manufacturing and quality control procedures, followed by large-scale phase 1, 2 and 3 testing for all new vaccines. The concept is that, because vaccines are given to healthy people, a one-in-a-million incidence of severe side effects (or death) may be too much, even when preventing a dangerous disease such as polio or more recently COVID-19. Attenuated live polio vaccine replaced the Salk injected vaccine after 1960. Under the umbrella of the school vaccination programme, I received the new format whereby a drop of the pink vaccine was placed on a sugar cube and then eaten. The success of the new Sabin vaccine was its simplicity and oral format. After all, polio is an enterovirus, and I suppose family members could be infected with the live vaccine strain if schoolchildren experienced a very mild gastrointestinal illness at home. The live vaccination trivalent Sabin strain could cause overt polio in very few cases so that, as the actual wild-strain polio became extremely rare, vaccinations","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87347898","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}