Tuanjie Guo, Zhihao Yuan, Tao Wang, Jian Zhang, Heting Tang, Ning Zhang, Xiang Wang, Siteng Chen
Exploring useful prognostic markers and developing a robust prognostic model for patients with prostate cancer are crucial for clinical practice. We applied a deep learning algorithm to construct a prognostic model and proposed the deep learning-based ferroptosis score (DLFscore) for the prediction of prognosis and potential chemotherapy sensitivity in prostate cancer. Based on this prognostic model, there was a statistically significant difference in the disease-free survival probability between patients with high and low DLFscore in the The Cancer Genome Atlas (TCGA) cohort (P < 0.0001). In the validation cohort GSE116918, we also observed a consistent conclusion with the training set (P = 0.02). Additionally, functional enrichment analysis showed that DNA repair, RNA splicing signaling, organelle assembly, and regulation of centrosome cycle pathways might regulate prostate cancer through ferroptosis. Meanwhile, the prognostic model we constructed also had application value in predicting drug sensitivity. We predicted some potential drugs for the treatment of prostate cancer through AutoDock, which could potentially be used for prostate cancer treatment.
探索有用的预后标志物和发展一个强大的预后模型的前列腺癌患者是至关重要的临床实践。我们应用深度学习算法构建预后模型,并提出基于深度学习的铁下垂评分(DLFscore)来预测前列腺癌的预后和潜在的化疗敏感性。基于该预后模型,在the Cancer Genome Atlas (TCGA)队列中,高、低dlf评分患者的无病生存率差异有统计学意义(P P = 0.02)。此外,功能富集分析表明,DNA修复、RNA剪接信号、细胞器组装和中心体周期途径的调节可能通过铁下垂调节前列腺癌。同时,所构建的预后模型在预测药物敏感性方面也具有应用价值。我们通过AutoDock预测了一些治疗前列腺癌的潜在药物,这些药物有可能用于前列腺癌的治疗。
{"title":"Integrative analysis of ferroptosis regulators for clinical prognosis based on deep learning and potential chemotherapy sensitivity of prostate cancer.","authors":"Tuanjie Guo, Zhihao Yuan, Tao Wang, Jian Zhang, Heting Tang, Ning Zhang, Xiang Wang, Siteng Chen","doi":"10.1093/pcmedi/pbad001","DOIUrl":"https://doi.org/10.1093/pcmedi/pbad001","url":null,"abstract":"<p><p>Exploring useful prognostic markers and developing a robust prognostic model for patients with prostate cancer are crucial for clinical practice. We applied a deep learning algorithm to construct a prognostic model and proposed the deep learning-based ferroptosis score (DLF<sub>score</sub>) for the prediction of prognosis and potential chemotherapy sensitivity in prostate cancer. Based on this prognostic model, there was a statistically significant difference in the disease-free survival probability between patients with high and low DLF<sub>score</sub> in the The Cancer Genome Atlas (TCGA) cohort (<i>P</i> < 0.0001). In the validation cohort GSE116918, we also observed a consistent conclusion with the training set (<i>P</i> = 0.02). Additionally, functional enrichment analysis showed that DNA repair, RNA splicing signaling, organelle assembly, and regulation of centrosome cycle pathways might regulate prostate cancer through ferroptosis. Meanwhile, the prognostic model we constructed also had application value in predicting drug sensitivity. We predicted some potential drugs for the treatment of prostate cancer through AutoDock, which could potentially be used for prostate cancer treatment.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/10/40/pbad001.PMC9982702.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10848453","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}
Zijian Tian, Fei Chen, Jing Wang, Benrui Wu, Jian Shao, Ziqing Liu, Li Zheng, You Wang, Tao Xu, Kaixin Zhou
Abstract Background Chronic diseases are becoming a critical challenge to the aging Chinese population. Biobanks with extensive genomic and environmental data offer opportunities to elucidate the complex gene–environment interactions underlying their aetiology. Genome-wide genotyping array remains an efficient approach for large-scale genomic data collection. However, most commercial arrays have reduced performance for biobanking in the Chinese population. Materials and methods Deep whole-genome sequencing data from 2 641 Chinese individuals were used as a reference to develop the CAS array, a custom-designed genotyping array for precision medicine. Evaluation of the array was performed by comparing data from 384 individuals assayed both by the array and whole-genome sequencing. Validation of its mitochondrial copy number estimating capacity was conducted by examining its association with established covariates among 10 162 Chinese elderly. Results The CAS Array adopts the proven Axiom technology and is restricted to 652 429 single-nucleotide polymorphism (SNP) markers. Its call rate of 99.79% and concordance rate of 99.89% are both higher than for commercial arrays. Its imputation-based genome coverage reached 98.3% for common SNPs and 63.0% for low-frequency SNPs, both comparable to commercial arrays with larger SNP capacity. After validating its mitochondrial copy number estimates, we developed a publicly available software tool to facilitate the array utility. Conclusion Based on recent advances in genomic science, we designed and implemented a high-throughput and low-cost genotyping array. It is more cost-effective than commercial arrays for large-scale Chinese biobanking.
{"title":"CAS Array: design and assessment of a genotyping array for Chinese biobanking.","authors":"Zijian Tian, Fei Chen, Jing Wang, Benrui Wu, Jian Shao, Ziqing Liu, Li Zheng, You Wang, Tao Xu, Kaixin Zhou","doi":"10.1093/pcmedi/pbad002","DOIUrl":"https://doi.org/10.1093/pcmedi/pbad002","url":null,"abstract":"Abstract Background Chronic diseases are becoming a critical challenge to the aging Chinese population. Biobanks with extensive genomic and environmental data offer opportunities to elucidate the complex gene–environment interactions underlying their aetiology. Genome-wide genotyping array remains an efficient approach for large-scale genomic data collection. However, most commercial arrays have reduced performance for biobanking in the Chinese population. Materials and methods Deep whole-genome sequencing data from 2 641 Chinese individuals were used as a reference to develop the CAS array, a custom-designed genotyping array for precision medicine. Evaluation of the array was performed by comparing data from 384 individuals assayed both by the array and whole-genome sequencing. Validation of its mitochondrial copy number estimating capacity was conducted by examining its association with established covariates among 10 162 Chinese elderly. Results The CAS Array adopts the proven Axiom technology and is restricted to 652 429 single-nucleotide polymorphism (SNP) markers. Its call rate of 99.79% and concordance rate of 99.89% are both higher than for commercial arrays. Its imputation-based genome coverage reached 98.3% for common SNPs and 63.0% for low-frequency SNPs, both comparable to commercial arrays with larger SNP capacity. After validating its mitochondrial copy number estimates, we developed a publicly available software tool to facilitate the array utility. Conclusion Based on recent advances in genomic science, we designed and implemented a high-throughput and low-cost genotyping array. It is more cost-effective than commercial arrays for large-scale Chinese biobanking.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10031742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9192775","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}
Precision cardiology aims to implement personalized health care and precise medical decisions based on the specific characteristics of individuals. Metabolic remodeling plays a causal role in the pathogenesis of heart failure (HF). Changes in metabolic pathways such as substrate preference, high-energy phosphate metabolism and amino acid metabolism, are involved in pathological structural remodeling and functional impairment. These metabolic alterations are usually not restricted in the cardiac tissue, but also manifest in circulation. In clinical practice, blood sample is routinely used for HF screening. Metabolomics is an emerging omics technology that provides an efficient way to acquire dynamic metabolic profiles in circulation. An increasing number of metabolic biomarkers have been implicated in disease progression, making it possible to fight HF in a more effective and precise way. This review summarizes the modern analytical techniques in metabolomics as well as emerging circulating metabolites during the pathogenesis of HF, aiming to provide new insights into the prevention, diagnosis and treatment of HF in the era of precision medicine.
{"title":"Circulating metabolic signatures of heart failure in precision cardiology.","authors":"Huijing Xie, Bowen Zhang, Maodi Xie, Tao Li","doi":"10.1093/pcmedi/pbad005","DOIUrl":"https://doi.org/10.1093/pcmedi/pbad005","url":null,"abstract":"<p><p>Precision cardiology aims to implement personalized health care and precise medical decisions based on the specific characteristics of individuals. Metabolic remodeling plays a causal role in the pathogenesis of heart failure (HF). Changes in metabolic pathways such as substrate preference, high-energy phosphate metabolism and amino acid metabolism, are involved in pathological structural remodeling and functional impairment. These metabolic alterations are usually not restricted in the cardiac tissue, but also manifest in circulation. In clinical practice, blood sample is routinely used for HF screening. Metabolomics is an emerging omics technology that provides an efficient way to acquire dynamic metabolic profiles in circulation. An increasing number of metabolic biomarkers have been implicated in disease progression, making it possible to fight HF in a more effective and precise way. This review summarizes the modern analytical techniques in metabolomics as well as emerging circulating metabolites during the pathogenesis of HF, aiming to provide new insights into the prevention, diagnosis and treatment of HF in the era of precision medicine.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a1/7e/pbad005.PMC10068425.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9257804","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}
Chen Liang, Zixian Zhao, Sarah Liu, Ting Zhang, Wei Zuo
The integrity of the vaginal epithelium is crucial for women’s reproductive health and for providing protection against HIV and sexually transmitted infections. 1 The vagina is a tubular tract made of fibromuscular and elastic tissue that connects the cervix to the outer genitals. Its main function is to discharge uterine secretions. 2 The vaginal epithelium (VE) is a keratinized, stratified squamous epithelium consisting of three layers: the basal layer, the suprabasal layer, and the apical cornified layer. 3 Estrogens induce the proliferation of basal epithelial cells in the vagina. The suprabasal cells, which are no longer mitogenic, differentiate as they move up through the epithelium. The apical cells undergo keratinization, lose their nuclei and cytoplasm, and eventually shed from the surface. 4 With multiple sexually transmitted diseases posing a significant threat to human health, 5 it is increasingly important to understand how the vaginal epithelium regenerates to maintain homeostasis and how it differs from the neighboring cervical epithelium. In this study, we extracted vaginal tissue from five adult virgin mice and conducted single-cell RNA sequencing (scRNA-seq) on the vaginal epithelium. We obtained a total of 7823 cells and isolated and sequenced
{"title":"Single-cell transcriptome profiling of the vaginal epithelium reveals the heterogeneity of suprabasal cells.","authors":"Chen Liang, Zixian Zhao, Sarah Liu, Ting Zhang, Wei Zuo","doi":"10.1093/pcmedi/pbad006","DOIUrl":"https://doi.org/10.1093/pcmedi/pbad006","url":null,"abstract":"The integrity of the vaginal epithelium is crucial for women’s reproductive health and for providing protection against HIV and sexually transmitted infections. 1 The vagina is a tubular tract made of fibromuscular and elastic tissue that connects the cervix to the outer genitals. Its main function is to discharge uterine secretions. 2 The vaginal epithelium (VE) is a keratinized, stratified squamous epithelium consisting of three layers: the basal layer, the suprabasal layer, and the apical cornified layer. 3 Estrogens induce the proliferation of basal epithelial cells in the vagina. The suprabasal cells, which are no longer mitogenic, differentiate as they move up through the epithelium. The apical cells undergo keratinization, lose their nuclei and cytoplasm, and eventually shed from the surface. 4 With multiple sexually transmitted diseases posing a significant threat to human health, 5 it is increasingly important to understand how the vaginal epithelium regenerates to maintain homeostasis and how it differs from the neighboring cervical epithelium. In this study, we extracted vaginal tissue from five adult virgin mice and conducted single-cell RNA sequencing (scRNA-seq) on the vaginal epithelium. We obtained a total of 7823 cells and isolated and sequenced","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10065133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9595474","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}
A commentary on "Multi-omics single-cell data integration and regulatory inference with graph-linked embedding".
“多组学单细胞数据集成与图链接嵌入的调控推理”评论。
{"title":"GLUE multimodal single cell data.","authors":"Weizhong Li, Chaoyu Yan","doi":"10.1093/pcmedi/pbad007","DOIUrl":"https://doi.org/10.1093/pcmedi/pbad007","url":null,"abstract":"<p><p>A commentary on \"Multi-omics single-cell data integration and regulatory inference with graph-linked embedding\".</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9610067","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}
To investigate the role of patient-derived organoid (PDO) model in the precision medicine of advanced clear cell renal cell carcinoma (ccRCC), we retrospectively analyzed the clinical data of seven cases of ccRCC diagnosed by operation and pathology in Renji Hospital from September 2021 to September 2022. The seven patients were diagnosed with advanced ccRCC with or without remote metastasis. Cytoreductive and radical nephrectomy was performed respectively. To predict the response to immunotherapy and provide personalized medicine recommendation, a PDO model based on air-liquid interface system was established from the surgical resected tumor and subsequent drug screening was performed. Hematoxylin and eosin (H&E) staining and immunohistochemistry revealed that the PDO recapitulated the histological feature of parent tumor. Immunofluorescence staining identified that CD3+ T cells, SMA+ cancer associated fibroblasts, and CD31+ endothelial cells were preserved in PDO models. Fluorescence activated cell sorter (FACS) revealed an evidently increased ratio of CD8+/CD4+ T cells and apoptotic tumor cells in PDO treated with toripalimab than those treated with IgG4. The results showed that toripalimab is able to rescue the excessive death of CD8+ T cells by critically reversing the immune exhaustion state of ccRCC in PDO model. This research validated that PDO is a promising and faithful preclinical model for prediction of immunotherapy response in patients with ccRCC.
{"title":"Patient-derived organoids potentiate precision medicine in advanced clear cell renal cell carcinoma.","authors":"Yizheng Xue, Bingran Wang, Yiying Tao, Jun Xia, Kedi Yuan, Junhua Zheng, Wei Zhai, Wei Xue","doi":"10.1093/pcmedi/pbac028","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac028","url":null,"abstract":"<p><p>To investigate the role of patient-derived organoid (PDO) model in the precision medicine of advanced clear cell renal cell carcinoma (ccRCC), we retrospectively analyzed the clinical data of seven cases of ccRCC diagnosed by operation and pathology in Renji Hospital from September 2021 to September 2022. The seven patients were diagnosed with advanced ccRCC with or without remote metastasis. Cytoreductive and radical nephrectomy was performed respectively. To predict the response to immunotherapy and provide personalized medicine recommendation, a PDO model based on air-liquid interface system was established from the surgical resected tumor and subsequent drug screening was performed. Hematoxylin and eosin (H&E) staining and immunohistochemistry revealed that the PDO recapitulated the histological feature of parent tumor. Immunofluorescence staining identified that CD3<sup>+</sup> T cells, SMA<sup>+</sup> cancer associated fibroblasts, and CD31<sup>+</sup> endothelial cells were preserved in PDO models. Fluorescence activated cell sorter (FACS) revealed an evidently increased ratio of CD8<sup>+</sup>/CD4<sup>+</sup> T cells and apoptotic tumor cells in PDO treated with toripalimab than those treated with IgG4. The results showed that toripalimab is able to rescue the excessive death of CD8<sup>+</sup> T cells by critically reversing the immune exhaustion state of ccRCC in PDO model. This research validated that PDO is a promising and faithful preclinical model for prediction of immunotherapy response in patients with ccRCC.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10411140","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}
With the improved efficacy and accessibility of antiviral agents as well as the concerns about disease progression, there is a hot discussion on whether HBeAg-negative chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and positive HBV DNA should be treated. According to the international guidelines on the stages of the natural history of HBV infection, HBeAg-negative CHB patients with normal ALT and positive HBV DNA can be divided into two groups: one is the well-known "inactive carrier phase", which is defined as serum HBV DNA < 2000 IU/ml and no significant liver inflammation; and the other is the "indeterminate phase", which is defined as serum HBV DNA ≥ 2000 IU/mL regardless of the pathological changes in liver tissue, or HBV DNA < 2000 IU/mL but accompanied by significant pathological changes in the liver. In this minireview, we will expound the disease characteristics, disease progression, and clinical management status of these two groups. Based on the analysis, we propose that HBeAg-negative patients with normal ALT but detectable serum HBV DNA should be treated, regardless of their age, family history of hepatocellular carcinoma (HCC) or the severity of liver necroinflammation. Expanding the indications of antiviral therapy will help improve the survival and quality of life of patients by preventing disease progression, and consequently reduce the risk of HCC development.
随着抗病毒药物疗效和可及性的提高,以及对疾病进展的担忧,hbeag阴性、ALT正常、HBV DNA阳性的慢性乙型肝炎(CHB)患者是否应该接受治疗成为人们讨论的热点。根据国际上关于HBV感染自然史分期的指南,ALT正常、HBV DNA阳性的hbeag阴性CHB患者可分为两组:一组是众所周知的“非活性携带者期”,定义为血清HBV DNA
{"title":"Expanding antiviral therapy indications for HBeAg-negative chronic hepatitis B patients with normal ALT and positive HBV DNA.","authors":"Jing Zhou, Fada Wang, Lanqing Li, Enqiang Chen","doi":"10.1093/pcmedi/pbac030","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac030","url":null,"abstract":"<p><p>With the improved efficacy and accessibility of antiviral agents as well as the concerns about disease progression, there is a hot discussion on whether HBeAg-negative chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and positive HBV DNA should be treated. According to the international guidelines on the stages of the natural history of HBV infection, HBeAg-negative CHB patients with normal ALT and positive HBV DNA can be divided into two groups: one is the well-known \"inactive carrier phase\", which is defined as serum HBV DNA < 2000 IU/ml and no significant liver inflammation; and the other is the \"indeterminate phase\", which is defined as serum HBV DNA ≥ 2000 IU/mL regardless of the pathological changes in liver tissue, or HBV DNA < 2000 IU/mL but accompanied by significant pathological changes in the liver. In this minireview, we will expound the disease characteristics, disease progression, and clinical management status of these two groups. Based on the analysis, we propose that HBeAg-negative patients with normal ALT but detectable serum HBV DNA should be treated, regardless of their age, family history of hepatocellular carcinoma (HCC) or the severity of liver necroinflammation. Expanding the indications of antiviral therapy will help improve the survival and quality of life of patients by preventing disease progression, and consequently reduce the risk of HCC development.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f7/23/pbac030.PMC9745772.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10731592","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}
Lei Zhong, Zhipeng Zhao, Xuerun Peng, Jun Zou, Shengyong Yang
The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural proteins (nsp) (e.g. RdRp, Mpro, PLpro, helicase, nsp14, and nsp16), host proteases (e.g. TMPRSS2, cathepsin, and furin) and the pivotal proteins mediating endocytosis (e.g. PIKfyve), as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. Here we present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.
{"title":"Recent advances in small-molecular therapeutics for COVID-19.","authors":"Lei Zhong, Zhipeng Zhao, Xuerun Peng, Jun Zou, Shengyong Yang","doi":"10.1093/pcmedi/pbac024","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac024","url":null,"abstract":"<p><p>The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural proteins (nsp) (e.g. RdRp, M<sup>pro</sup>, PL<sup>pro</sup>, helicase, nsp14, and nsp16), host proteases (e.g. TMPRSS2, cathepsin, and furin) and the pivotal proteins mediating endocytosis (e.g. PIKfyve), as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. Here we present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cb/d0/pbac024.PMC9579963.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9181205","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}
The Enterobacterales are an order of Gram-negative bacteria comprising a few major human pathogens such as Escherichia coli and Klebsiella pneumoniae . However, carbapenem-resistant En-terobacterales (CRE) has risen as an urgent threat for human health, leading to high mortality with very limited antimicrobial options. The main mechanism mediating resistance to β - lactams including carbapenems in the Enterobacterales is production of β -lactamases, which are two categories of enzymes capable of hydrolyzing β -lactams: serine β -lactamases and metallo-β -lactamases (MBLs). Avibactam (AVI) is a non-β -lactam β - lactamase inhibitor able to inhibit almost all serine β -lactamases but not MBLs.AVI in combination with ceftazidime (CAZ) has been approved for treating infections caused by CRE but CAZ-AVI has no activities against those producing MBLs. Currently, no MBL inhibitors have been approved for clinical use. Aztreonam (ATM), a monobactam, is stable to the hydrolysis of MBLs,and AVI can protect ATM from the inactivation by serine β -lactamases. The ATM- AVIcombinationmaythereforebeaviablechoiceagainstCREpro-ducing
{"title":"Aztreonam-avibactam: an option against carbapenem-resistant Enterobacterales with emerging resistance.","authors":"Shikai Wu, Zhiyong Zong","doi":"10.1093/pcmedi/pbac029","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac029","url":null,"abstract":"The Enterobacterales are an order of Gram-negative bacteria comprising a few major human pathogens such as Escherichia coli and Klebsiella pneumoniae . However, carbapenem-resistant En-terobacterales (CRE) has risen as an urgent threat for human health, leading to high mortality with very limited antimicrobial options. The main mechanism mediating resistance to β - lactams including carbapenems in the Enterobacterales is production of β -lactamases, which are two categories of enzymes capable of hydrolyzing β -lactams: serine β -lactamases and metallo-β -lactamases (MBLs). Avibactam (AVI) is a non-β -lactam β - lactamase inhibitor able to inhibit almost all serine β -lactamases but not MBLs.AVI in combination with ceftazidime (CAZ) has been approved for treating infections caused by CRE but CAZ-AVI has no activities against those producing MBLs. Currently, no MBL inhibitors have been approved for clinical use. Aztreonam (ATM), a monobactam, is stable to the hydrolysis of MBLs,and AVI can protect ATM from the inactivation by serine β -lactamases. The ATM- AVIcombinationmaythereforebeaviablechoiceagainstCREpro-ducing","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9745765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10731595","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}
Pub Date : 2022-11-18eCollection Date: 2022-12-01DOI: 10.1093/pcmedi/pbac027
[This corrects the article DOI: 10.1093/pcmedi/pbac007.].
[这更正了文章DOI: 10.1093/pcmedi/pbac007.]。
{"title":"Correction to: Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells.","authors":"","doi":"10.1093/pcmedi/pbac027","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac027","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/pcmedi/pbac007.].</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2022-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40506854","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}