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":"5 4","pages":"pbac030"},"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":"5 4","pages":"pbac024"},"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":"5 4","pages":"pbac029"},"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}
Yanqi He, Calvin Wei, Zhifu Sun, Julie M Cunningham, Liang Wang, Zong Wei, Ping Yang
the epige-netic biomarkers under investigation. We here report a study that identified aberrantly methylated genes between current and former smokers among SCLC patients, revealing a set of candidate biomarkers in peripheral blood DNA for better stratifying patients with high risk.
{"title":"Genome-wide methylation profiling reveals differentially methylated genes in blood DNA of small-cell lung cancer patients.","authors":"Yanqi He, Calvin Wei, Zhifu Sun, Julie M Cunningham, Liang Wang, Zong Wei, Ping Yang","doi":"10.1093/pcmedi/pbac017","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac017","url":null,"abstract":"the epige-netic biomarkers under investigation. We here report a study that identified aberrantly methylated genes between current and former smokers among SCLC patients, revealing a set of candidate biomarkers in peripheral blood DNA for better stratifying patients with high risk.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"5 3","pages":"pbac017"},"PeriodicalIF":5.3,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10400146","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}
Can Hou, Huazhen Yang, Yuanyuan Qu, Wenwen Chen, Yu Zeng, Yao Hu, K M Venkat Narayan, Huan Song, Dong Li
Background: Although cumulating evidence has suggested that early-onset type 2 diabetes mellitus (T2DM) conferred on patients a broader tendency for complications beyond vascular ones, a comprehensive analysis of patterns of complications across all relevant systems is currently lacking.
Method: We prospectively studied 1 777 early-onset (age at diagnosis ≤ 45 years) and 35 889 late-onset (>45 years) T2DM patients with matched unexposed individuals from the UK Biobank. Diabetes-specific and -related complications were examined using phenome-wide association analysis, with patterns identified by comorbidity network analysis. We also evaluated the effect of lifestyle modifications and glycemic control on complication development.
Results: The median follow-up times for early-onset and late-onset T2DM patients were 17.83 and 9.39 years, respectively. Compared to late-onset T2DM patients, patients with early-onset T2DM faced a significantly higher relative risk of developing subsequent complications that primarily affected sense organs [hazard ratio (HR) 3.46 vs. 1.72], the endocrine/metabolic system (HR 3.08 vs. 2.01), and the neurological system (HR 2.70 vs. 1.81). Despite large similarities in comorbidity patterns, a more complex and well-connected network was observed for early-onset T2DM. Furthermore, while patients with early-onset T2DM got fewer benefits (12.67% reduction in pooled HR for all studied complications) through fair glycemic control (median HbA1c ≤ 53 mmol/mol) compared to late-onset T2DM patients (18.01% reduction), they seemed to benefit more from favorable lifestyles, including weight control, healthy diet, and adequate physical activity.
Conclusions: Our analyses reveal that early-onset T2DM is an aggressive disease resulting in more complex complication networks than late-onset T2DM. Aggressive glucose-lowering intervention, complemented by lifestyle modifications, are feasible strategies for controlling early-onset T2DM-related complications.
背景:尽管越来越多的证据表明，早发型2型糖尿病(T2DM)使患者更容易出现血管以外的并发症，但目前缺乏对所有相关系统并发症模式的全面分析。方法:我们前瞻性地研究了1777例早发性(诊断时年龄≤45岁)和35889例晚发性(>45岁)T2DM患者与来自UK Biobank的匹配的未暴露个体。使用全现象关联分析检查糖尿病特异性和相关并发症，并通过合并症网络分析确定模式。我们还评估了生活方式改变和血糖控制对并发症发展的影响。结果:早发性和晚发性T2DM患者的中位随访时间分别为17.83年和9.39年。与迟发性T2DM患者相比，早发性T2DM患者发生主要影响感觉器官、内分泌/代谢系统(HR 3.08 vs. 2.01)和神经系统(HR 2.70 vs. 1.81)的后续并发症的相对风险明显更高。尽管合并症模式有很大的相似之处，但在早发型T2DM中观察到一个更复杂且连接良好的网络。此外，虽然与迟发性T2DM患者相比，早发性T2DM患者通过合理控制血糖(中位HbA1c≤53 mmol/mol)获得的益处(所有研究并发症的总HR降低12.67%)较少(降低18.01%)，但他们似乎从良好的生活方式中获益更多，包括体重控制、健康饮食和充足的体育活动。结论:我们的分析表明，早发性T2DM是一种侵袭性疾病，其并发症网络比晚发性T2DM更复杂。积极的降糖干预，辅以生活方式的改变，是控制早发性t2dm相关并发症的可行策略。
{"title":"Health consequences of early-onset compared with late-onset type 2 diabetes mellitus.","authors":"Can Hou, Huazhen Yang, Yuanyuan Qu, Wenwen Chen, Yu Zeng, Yao Hu, K M Venkat Narayan, Huan Song, Dong Li","doi":"10.1093/pcmedi/pbac015","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac015","url":null,"abstract":"<p><strong>Background: </strong>Although cumulating evidence has suggested that early-onset type 2 diabetes mellitus (T2DM) conferred on patients a broader tendency for complications beyond vascular ones, a comprehensive analysis of patterns of complications across all relevant systems is currently lacking.</p><p><strong>Method: </strong>We prospectively studied 1 777 early-onset (age at diagnosis ≤ 45 years) and 35 889 late-onset (>45 years) T2DM patients with matched unexposed individuals from the UK Biobank. Diabetes-specific and -related complications were examined using phenome-wide association analysis, with patterns identified by comorbidity network analysis. We also evaluated the effect of lifestyle modifications and glycemic control on complication development.</p><p><strong>Results: </strong>The median follow-up times for early-onset and late-onset T2DM patients were 17.83 and 9.39 years, respectively. Compared to late-onset T2DM patients, patients with early-onset T2DM faced a significantly higher relative risk of developing subsequent complications that primarily affected sense organs [hazard ratio (HR) 3.46 vs. 1.72], the endocrine/metabolic system (HR 3.08 vs. 2.01), and the neurological system (HR 2.70 vs. 1.81). Despite large similarities in comorbidity patterns, a more complex and well-connected network was observed for early-onset T2DM. Furthermore, while patients with early-onset T2DM got fewer benefits (12.67% reduction in pooled HR for all studied complications) through fair glycemic control (median HbA<sub>1c</sub> ≤ 53 mmol/mol) compared to late-onset T2DM patients (18.01% reduction), they seemed to benefit more from favorable lifestyles, including weight control, healthy diet, and adequate physical activity.</p><p><strong>Conclusions: </strong>Our analyses reveal that early-onset T2DM is an aggressive disease resulting in more complex complication networks than late-onset T2DM. Aggressive glucose-lowering intervention, complemented by lifestyle modifications, are feasible strategies for controlling early-onset T2DM-related complications.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"5 2","pages":"pbac015"},"PeriodicalIF":5.3,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d3/f1/pbac015.PMC9239845.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9859060","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}
Minglei Yang, Chenghao Lin, Yanni Wang, Kang Chen, Yutong Han, Haiyue Zhang, Weizhong Li
Abstract Background Evidence has suggested that cytokine storms may be associated with T cell exhaustion (TEX) in COVID-19. However, the interaction mechanism between cytokine storms and TEX remains unclear. Methods With the aim of dissecting the molecular relationship of cytokine storms and TEX through single-cell RNA sequencing data analysis, we identified 14 cell types from bronchoalveolar lavage fluid of COVID-19 patients and healthy people. We observed a novel subset of severely exhausted CD8 T cells (Exh T_CD8) that co-expressed multiple inhibitory receptors, and two macrophage subclasses that were the main source of cytokine storms in bronchoalveolar. Results Correlation analysis between cytokine storm level and TEX level suggested that cytokine storms likely promoted TEX in severe COVID-19. Cell–cell communication analysis indicated that cytokines (e.g. CXCL10, CXCL11, CXCL2, CCL2, and CCL3) released by macrophages acted as ligands and significantly interacted with inhibitory receptors (e.g. CXCR3, DPP4, CCR1, CCR2, and CCR5) expressed by Exh T_CD8. These interactions formed the cytokine–receptor axes, which were also verified to be significantly correlated with cytokine storms and TEX in lung squamous cell carcinoma. Conclusions Cytokine storms may promote TEX through cytokine-receptor axes and be associated with poor prognosis in COVID-19. Blocking cytokine-receptor axes may reverse TEX. Our finding provides novel insights into TEX in COVID-19 and new clues for cytokine-targeted immunotherapy development.
{"title":"Cytokine storm promoting T cell exhaustion in severe COVID-19 revealed by single cell sequencing data analysis","authors":"Minglei Yang, Chenghao Lin, Yanni Wang, Kang Chen, Yutong Han, Haiyue Zhang, Weizhong Li","doi":"10.1093/pcmedi/pbac014","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac014","url":null,"abstract":"Abstract Background Evidence has suggested that cytokine storms may be associated with T cell exhaustion (TEX) in COVID-19. However, the interaction mechanism between cytokine storms and TEX remains unclear. Methods With the aim of dissecting the molecular relationship of cytokine storms and TEX through single-cell RNA sequencing data analysis, we identified 14 cell types from bronchoalveolar lavage fluid of COVID-19 patients and healthy people. We observed a novel subset of severely exhausted CD8 T cells (Exh T_CD8) that co-expressed multiple inhibitory receptors, and two macrophage subclasses that were the main source of cytokine storms in bronchoalveolar. Results Correlation analysis between cytokine storm level and TEX level suggested that cytokine storms likely promoted TEX in severe COVID-19. Cell–cell communication analysis indicated that cytokines (e.g. CXCL10, CXCL11, CXCL2, CCL2, and CCL3) released by macrophages acted as ligands and significantly interacted with inhibitory receptors (e.g. CXCR3, DPP4, CCR1, CCR2, and CCR5) expressed by Exh T_CD8. These interactions formed the cytokine–receptor axes, which were also verified to be significantly correlated with cytokine storms and TEX in lung squamous cell carcinoma. Conclusions Cytokine storms may promote TEX through cytokine-receptor axes and be associated with poor prognosis in COVID-19. Blocking cytokine-receptor axes may reverse TEX. Our finding provides novel insights into TEX in COVID-19 and new clues for cytokine-targeted immunotherapy development.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"56 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76283422","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}
Pub Date : 2022-05-10eCollection Date: 2022-06-01DOI: 10.1093/pcmedi/pbac013
Xiaolei Liu, Jirong Yue
Sarcopenia is an aging-related disease characterized by progressive muscle mass loss, decreasing muscle strength, and physiological muscle function decline. It is associated with multiple adverse outcomes, including falls, fractures, physical disability, and death. The new code in ICD-10-CM (M62.84) in 2016 signifies its being recognized as a disease and drawing attention to the condition in this ever-aging society. The prevalence of sarcopenia in the elderly is ∼6.8%–25.7% for Asia1 and, in particular, 8.9%–38.8% for China.2 The mechanism of sarcopenia is complex and includes hormonal changes, nutritional deficiencies, chronic inflammation, neuromuscular function decline, and decreased physical activity. While no specific drugs have been approved to treat sarcopenia, ten pharmacological interventions have been identified to ameliorate the condition in the elderly, including growth hormone, growth hormone-releasing hormone, vitamin D, dehydroepiandrosterone, combined estrogen– progesterone, testosterone-growth hormone, pioglitazone, testosterone, insulin-like growth factor-1, and angiotensin-converting enzyme inhibitors.3 Possible drugs for sarcopenia are under development (Table 1).4 As a result, understanding the mechanisms of sarcopenia is critical for drug development. The treatment of sarcopenia currently focuses on nutrition and exercise interventions. However, the clinical evidence is very limited and many questions still remain unanswered. For example, how can the safety and compliance of exercise interventions be ensured according to stress adaptability? Besides, a large percentage of sarcopenic patients cannot live up to recommended degrees of both nutritional food intake and physical activity, resulting in numerous problems. Therefore, for elderly patients with sarcopenia with different conditions, individualized intervention and management strategies are urgently needed according to the patient’s metabolic and digestive functions. Food components with anti-inflammatory properties, such as probiotics and traditional Chinese medicine prescriptions, should be considered for intervention. Sarcopenia is associated with different genotypes. For example, in sarcopenia patients, the X allele of the alpha-actinin-3 (ACTN3) genotype was found to be more associated with decreased thigh muscle volume compared with the RR allele of the ACTN3 genotype.5 In addition, angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. Specifically, the I allele of ACE genotype is associated with endurance-orientated events, while the D allele is associated with strengthand power-orientated performance.6 Another gene associated with sarcopenia is vitamin D receptor (VDR), and FF carriers have double the risk of having sarcopenia compared with carriers of the f allele.7 Other genetic variations associated with sarcopenia include the tumo
{"title":"Precision intervention for sarcopenia.","authors":"Xiaolei Liu, Jirong Yue","doi":"10.1093/pcmedi/pbac013","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac013","url":null,"abstract":"Sarcopenia is an aging-related disease characterized by progressive muscle mass loss, decreasing muscle strength, and physiological muscle function decline. It is associated with multiple adverse outcomes, including falls, fractures, physical disability, and death. The new code in ICD-10-CM (M62.84) in 2016 signifies its being recognized as a disease and drawing attention to the condition in this ever-aging society. The prevalence of sarcopenia in the elderly is ∼6.8%–25.7% for Asia1 and, in particular, 8.9%–38.8% for China.2 The mechanism of sarcopenia is complex and includes hormonal changes, nutritional deficiencies, chronic inflammation, neuromuscular function decline, and decreased physical activity. While no specific drugs have been approved to treat sarcopenia, ten pharmacological interventions have been identified to ameliorate the condition in the elderly, including growth hormone, growth hormone-releasing hormone, vitamin D, dehydroepiandrosterone, combined estrogen– progesterone, testosterone-growth hormone, pioglitazone, testosterone, insulin-like growth factor-1, and angiotensin-converting enzyme inhibitors.3 Possible drugs for sarcopenia are under development (Table 1).4 As a result, understanding the mechanisms of sarcopenia is critical for drug development. The treatment of sarcopenia currently focuses on nutrition and exercise interventions. However, the clinical evidence is very limited and many questions still remain unanswered. For example, how can the safety and compliance of exercise interventions be ensured according to stress adaptability? Besides, a large percentage of sarcopenic patients cannot live up to recommended degrees of both nutritional food intake and physical activity, resulting in numerous problems. Therefore, for elderly patients with sarcopenia with different conditions, individualized intervention and management strategies are urgently needed according to the patient’s metabolic and digestive functions. Food components with anti-inflammatory properties, such as probiotics and traditional Chinese medicine prescriptions, should be considered for intervention. Sarcopenia is associated with different genotypes. For example, in sarcopenia patients, the X allele of the alpha-actinin-3 (ACTN3) genotype was found to be more associated with decreased thigh muscle volume compared with the RR allele of the ACTN3 genotype.5 In addition, angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. Specifically, the I allele of ACE genotype is associated with endurance-orientated events, while the D allele is associated with strengthand power-orientated performance.6 Another gene associated with sarcopenia is vitamin D receptor (VDR), and FF carriers have double the risk of having sarcopenia compared with carriers of the f allele.7 Other genetic variations associated with sarcopenia include the tumo","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"5 2","pages":"pbac013"},"PeriodicalIF":5.3,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9172647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427466","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}
Ang Li, Bicheng Ye, Fangnan Lin, Yi-lin Wang, Xiaye Miao, Yanfang Jiang
Abstract Background The immune response in the tumor microenvironment (TME) plays a crucial role in cancer progression and recurrence. We aimed to develop an immune-related gene (IRG) signature to improve prognostic predictive power and reveal the immune infiltration characteristics of pancreatic ductal adenocarcinoma (PDAC). Methods The Cancer Genome Atlas (TCGA) PDAC was used to construct a prognostic model as a training cohort. The International Cancer Genome Consortium (ICGC) and the Gene Expression Omnibus (GEO) databases were set as validation datasets. Prognostic genes were screened by using univariate Cox regression. Then, a novel optimal prognostic model was developed by using least absolute shrinkage and selection operator (LASSO) Cox regression. Cell type identification by estimating the relative subsets of RNA transcripts (CIBERSORT) and estimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) algorithms were used to characterize tumor immune infiltrating patterns. The tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict immunotherapy responsiveness. Results A prognostic signature based on five IRGs (MET, ERAP2, IL20RB, EREG, and SHC2) was constructed in TCGA-PDAC and comprehensively validated in ICGC and GEO cohorts. Multivariate Cox regression analysis demonstrated that this signature had an independent prognostic value. The area under the curve (AUC) values of the receiver operating characteristic (ROC) curve at 1, 3, and 5 years of survival were 0.724, 0.702, and 0.776, respectively. We further demonstrated that our signature has better prognostic performance than recently published ones and is superior to traditional clinical factors such as grade and tumor node metastasis classification (TNM) stage in predicting survival. Moreover, we found higher abundance of CD8+ T cells and lower M2-like macrophages in the low-risk group of TCGA-PDAC, and predicted a higher proportion of immunotherapeutic responders in the low-risk group. Conclusions We constructed an optimal prognostic model which had independent prognostic value and was comprehensively validated in external PDAC databases. Additionally, this five-genes signature could predict immune infiltration characteristics. Moreover, the signature helped stratify PDAC patients who might be more responsive to immunotherapy.
{"title":"A novel immunogenomic signature to predict prognosis and reveal immune infiltration characteristics in pancreatic ductal adenocarcinoma","authors":"Ang Li, Bicheng Ye, Fangnan Lin, Yi-lin Wang, Xiaye Miao, Yanfang Jiang","doi":"10.1093/pcmedi/pbac010","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac010","url":null,"abstract":"Abstract Background The immune response in the tumor microenvironment (TME) plays a crucial role in cancer progression and recurrence. We aimed to develop an immune-related gene (IRG) signature to improve prognostic predictive power and reveal the immune infiltration characteristics of pancreatic ductal adenocarcinoma (PDAC). Methods The Cancer Genome Atlas (TCGA) PDAC was used to construct a prognostic model as a training cohort. The International Cancer Genome Consortium (ICGC) and the Gene Expression Omnibus (GEO) databases were set as validation datasets. Prognostic genes were screened by using univariate Cox regression. Then, a novel optimal prognostic model was developed by using least absolute shrinkage and selection operator (LASSO) Cox regression. Cell type identification by estimating the relative subsets of RNA transcripts (CIBERSORT) and estimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) algorithms were used to characterize tumor immune infiltrating patterns. The tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict immunotherapy responsiveness. Results A prognostic signature based on five IRGs (MET, ERAP2, IL20RB, EREG, and SHC2) was constructed in TCGA-PDAC and comprehensively validated in ICGC and GEO cohorts. Multivariate Cox regression analysis demonstrated that this signature had an independent prognostic value. The area under the curve (AUC) values of the receiver operating characteristic (ROC) curve at 1, 3, and 5 years of survival were 0.724, 0.702, and 0.776, respectively. We further demonstrated that our signature has better prognostic performance than recently published ones and is superior to traditional clinical factors such as grade and tumor node metastasis classification (TNM) stage in predicting survival. Moreover, we found higher abundance of CD8+ T cells and lower M2-like macrophages in the low-risk group of TCGA-PDAC, and predicted a higher proportion of immunotherapeutic responders in the low-risk group. Conclusions We constructed an optimal prognostic model which had independent prognostic value and was comprehensively validated in external PDAC databases. Additionally, this five-genes signature could predict immune infiltration characteristics. Moreover, the signature helped stratify PDAC patients who might be more responsive to immunotherapy.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"36 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79301441","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}
C. Tan, Mingming Yang, Zhisheng You, Hu Chen, Yan Zhang
Abstract Low-dose computed tomography (LDCT) denoising is an indispensable procedure in the medical imaging field, which not only improves image quality, but can mitigate the potential hazard to patients caused by routine doses. Despite the improvement in performance of the cycle-consistent generative adversarial network (CycleGAN) due to the well-paired CT images shortage, there is still a need to further reduce image noise while retaining detailed features. Inspired by the residual encoder–decoder convolutional neural network (RED-CNN) and U-Net, we propose a novel unsupervised model using CycleGAN for LDCT imaging, which injects a two-sided network into selective kernel networks (SK-NET) to adaptively select features, and uses the patchGAN discriminator to generate CT images with more detail maintenance, aided by added perceptual loss. Based on patch-based training, the experimental results demonstrated that the proposed SKFCycleGAN outperforms competing methods in both a clinical dataset and the Mayo dataset. The main advantages of our method lie in noise suppression and edge preservation.
{"title":"A selective kernel-based cycle-consistent generative adversarial network for unpaired low-dose CT denoising","authors":"C. Tan, Mingming Yang, Zhisheng You, Hu Chen, Yan Zhang","doi":"10.1093/pcmedi/pbac011","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac011","url":null,"abstract":"Abstract Low-dose computed tomography (LDCT) denoising is an indispensable procedure in the medical imaging field, which not only improves image quality, but can mitigate the potential hazard to patients caused by routine doses. Despite the improvement in performance of the cycle-consistent generative adversarial network (CycleGAN) due to the well-paired CT images shortage, there is still a need to further reduce image noise while retaining detailed features. Inspired by the residual encoder–decoder convolutional neural network (RED-CNN) and U-Net, we propose a novel unsupervised model using CycleGAN for LDCT imaging, which injects a two-sided network into selective kernel networks (SK-NET) to adaptively select features, and uses the patchGAN discriminator to generate CT images with more detail maintenance, aided by added perceptual loss. Based on patch-based training, the experimental results demonstrated that the proposed SKFCycleGAN outperforms competing methods in both a clinical dataset and the Mayo dataset. The main advantages of our method lie in noise suppression and edge preservation.","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"7 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82715383","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}
Jixiang Zhang, Xuemei Jia, Yuanmei Guo, Haotian Jiang, Jia-yuan Hu, Siwei Wang, Binglu Huang, Wenhao Su, Jun Liu, Xiaoli Wang, W. Dong
ABSTRACT Background Individualization using different volumes of polyethylene glycol is widely regarded as the optimal solution for bowel preparation, while the patient-directed regimen we propose may serve as a reliable individual solution. This study aimed to assess the efficacy, safety, and satisfaction of bowel preparation with a patient-directed regimen. Methods Patients in the fixed-volume group ingested the same amount of PEG, while those in patient-directed group ingested different amount according to stool consistency or stool water content. Results After filtering by exclusion criteria, 428 individuals in the fixed-volume group and 103 in the patient-directed group were successfully enrolled and analyzed. Eighty-three (80.6%) individuals in the patient-directed group had a reduced polyethylene glycol volume. There was no significant difference in the bowel preparation efficacy between the two groups (90.0% vs. 90.3%, χ² = 0.01; p = 0.918). Patients in the patient-directed group complained of fewer adverse effects (53.0% vs. 36.9%, χ² = 8.655; p = 0.003), especially vomiting (13.6% vs. 1.0%, χ² = 13.304; p < 0.001). Regarding comfort during bowel preparation, the degree of comfort was not significantly different between groups. Furthermore, the willingness rate for further colonoscopy in the patient-directed group was significantly higher than that in the fixed-volume group (90.3% vs. 77.1%, χ² = 8.912; p < 0.05). Multivariable logistic regression analysis showed that the body mass index served as an independent factor impacting quality of bowel preparation with the patient-directed regimen (OR 1.16, 95% CI 1.00–1.34; p = 0.043). Conclusions Without decreasing the bowel preparation efficacy, the patient-directed regimen increased the safety and satisfaction of bowel preparation and is expected to be a regular and individual solution for bowel preparation. Individuals with a lower body mass index are more likely to undertake this new regimen. Trial registration number ChiCTR1900022072 at ChiClinicalTrials.gov
背景:个体化使用不同体积的聚乙二醇被广泛认为是肠道准备的最佳解决方案，而我们提出的以患者为导向的方案可能是可靠的个体化解决方案。本研究旨在评估以患者为导向的肠准备方案的有效性、安全性和满意度。方法固定体积组患者摄入相同量的聚乙二醇，而患者定向组患者根据粪便稠度或粪便含水量摄入不同量的聚乙二醇。结果通过排除标准筛选后，固定容量组428例，患者导向组103例成功入组分析。在患者导向组中，83人(80.6%)的聚乙二醇体积减少。两组患者的肠道准备效果差异无统计学意义(90.0% vs 90.3%， χ²= 0.01;P = 0.918)。患者导向组患者抱怨不良反应较少(53.0% vs 36.9%， χ²= 8.655;P = 0.003)，尤其是呕吐(13.6% vs. 1.0%， χ²= 13.304;P < 0.001)。在肠准备过程中的舒适度方面，各组之间的舒适度无显著差异。此外，患者指导组进一步结肠镜检查的意愿率显著高于固定容积组(90.3% vs 77.1%， χ²= 8.912;P < 0.05)。多变量logistic回归分析显示，体重指数是影响患者指导方案肠道准备质量的独立因素(OR 1.16, 95% CI 1.00-1.34;P = 0.043)。结论患者导向方案在不降低肠准备效果的前提下，提高了肠准备的安全性和满意度，有望成为一种常规的个体化肠准备方案。身体质量指数较低的人更有可能采用这种新疗法。试验注册号ChiCTR1900022072，登录chicclinicaltrials .gov
{"title":"Patient-directed vs. fixed-volume PEG for colonoscopy preparation: a randomized controlled trial","authors":"Jixiang Zhang, Xuemei Jia, Yuanmei Guo, Haotian Jiang, Jia-yuan Hu, Siwei Wang, Binglu Huang, Wenhao Su, Jun Liu, Xiaoli Wang, W. Dong","doi":"10.1093/pcmedi/pbac009","DOIUrl":"https://doi.org/10.1093/pcmedi/pbac009","url":null,"abstract":"ABSTRACT Background Individualization using different volumes of polyethylene glycol is widely regarded as the optimal solution for bowel preparation, while the patient-directed regimen we propose may serve as a reliable individual solution. This study aimed to assess the efficacy, safety, and satisfaction of bowel preparation with a patient-directed regimen. Methods Patients in the fixed-volume group ingested the same amount of PEG, while those in patient-directed group ingested different amount according to stool consistency or stool water content. Results After filtering by exclusion criteria, 428 individuals in the fixed-volume group and 103 in the patient-directed group were successfully enrolled and analyzed. Eighty-three (80.6%) individuals in the patient-directed group had a reduced polyethylene glycol volume. There was no significant difference in the bowel preparation efficacy between the two groups (90.0% vs. 90.3%, χ² = 0.01; p = 0.918). Patients in the patient-directed group complained of fewer adverse effects (53.0% vs. 36.9%, χ² = 8.655; p = 0.003), especially vomiting (13.6% vs. 1.0%, χ² = 13.304; p < 0.001). Regarding comfort during bowel preparation, the degree of comfort was not significantly different between groups. Furthermore, the willingness rate for further colonoscopy in the patient-directed group was significantly higher than that in the fixed-volume group (90.3% vs. 77.1%, χ² = 8.912; p < 0.05). Multivariable logistic regression analysis showed that the body mass index served as an independent factor impacting quality of bowel preparation with the patient-directed regimen (OR 1.16, 95% CI 1.00–1.34; p = 0.043). Conclusions Without decreasing the bowel preparation efficacy, the patient-directed regimen increased the safety and satisfaction of bowel preparation and is expected to be a regular and individual solution for bowel preparation. Individuals with a lower body mass index are more likely to undertake this new regimen. Trial registration number ChiCTR1900022072 at ChiClinicalTrials.gov","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":"43 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2022-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73240318","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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