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Integrative analysis of ferroptosis regulators for clinical prognosis based on deep learning and potential chemotherapy sensitivity of prostate cancer. 基于深度学习和前列腺癌潜在化疗敏感性的铁下垂调节因子对临床预后的综合分析。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-03-01 DOI: 10.1093/pcmedi/pbad001
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。
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引用次数: 1
Circulating metabolic signatures of heart failure in precision cardiology. 精准心脏病学中心力衰竭的循环代谢特征。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-03-01 DOI: 10.1093/pcmedi/pbad005
Huijing Xie, Bowen Zhang, Maodi Xie, Tao Li

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.

精准心脏病学旨在根据个体的具体特征实施个性化的医疗保健和精准的医疗决策。代谢重塑在心力衰竭(HF)的发病机制中起因果作用。代谢途径的改变,如底物偏好、高能磷酸盐代谢和氨基酸代谢,涉及病理性结构重塑和功能损伤。这些代谢改变通常不局限于心脏组织,但也表现在循环中。在临床实践中,血液样本常规用于心衰筛查。代谢组学是一种新兴的组学技术,它提供了一种获取循环中动态代谢谱的有效方法。越来越多的代谢生物标志物与疾病进展有关,使得以更有效和精确的方式对抗HF成为可能。本文综述了代谢组学的现代分析技术以及心衰发病过程中出现的循环代谢物,旨在为精准医学时代心衰的预防、诊断和治疗提供新的见解。
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引用次数: 1
Single-cell transcriptome profiling of the vaginal epithelium reveals the heterogeneity of suprabasal cells. 阴道上皮的单细胞转录组分析揭示了基底上细胞的异质性。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-03-01 DOI: 10.1093/pcmedi/pbad006
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
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引用次数: 0
GLUE multimodal single cell data. GLUE多模态单细胞数据。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-03-01 DOI: 10.1093/pcmedi/pbad007
Weizhong Li, Chaoyu Yan

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。
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引用次数: 0
Patient-derived organoids potentiate precision medicine in advanced clear cell renal cell carcinoma. 患者来源的类器官增强了晚期透明细胞肾细胞癌的精准治疗。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2022-12-01 DOI: 10.1093/pcmedi/pbac028
Yizheng Xue, Bingran Wang, Yiying Tao, Jun Xia, Kedi Yuan, Junhua Zheng, Wei Zhai, Wei Xue

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.

为探讨患者源性类器官(PDO)模型在晚期透明细胞肾细胞癌(ccRCC)精准医学中的作用,我们回顾性分析仁集医院2021年9月至2022年9月经手术病理诊断的7例ccRCC的临床资料。7例患者被诊断为晚期ccRCC,伴有或不伴有远处转移。分别行细胞减缩和根治性肾切除术。为了预测对免疫治疗的反应,提供个性化的药物推荐,我们从手术切除的肿瘤中建立了基于气液界面系统的PDO模型,并进行了后续的药物筛选。苏木精和伊红(H&E)染色和免疫组化显示PDO重现了母肿瘤的组织学特征。免疫荧光染色发现,PDO模型中保留了CD3+ T细胞、SMA+癌相关成纤维细胞和CD31+内皮细胞。荧光活化细胞分选(FACS)结果显示,与IgG4组相比,托利莫单抗组PDO中CD8+/CD4+ T细胞和凋亡肿瘤细胞比例明显升高。结果表明,托利哌单抗能够通过严重逆转PDO模型ccRCC的免疫衰竭状态来挽救CD8+ T细胞的过度死亡。本研究验证了PDO是预测ccRCC患者免疫治疗反应的一个有希望和可靠的临床前模型。
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引用次数: 3
Expanding antiviral therapy indications for HBeAg-negative chronic hepatitis B patients with normal ALT and positive HBV DNA. 扩大丙肝抗原阴性慢性乙型肝炎患者ALT正常和HBV DNA阳性的抗病毒治疗适应症。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2022-12-01 DOI: 10.1093/pcmedi/pbac030
Jing Zhou, Fada Wang, Lanqing Li, Enqiang Chen

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
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引用次数: 3
Recent advances in small-molecular therapeutics for COVID-19. 新冠肺炎小分子治疗的最新进展。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2022-12-01 DOI: 10.1093/pcmedi/pbac024
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.

2019冠状病毒病大流行对全球卫生构成根本性挑战。自SARS-CoV-2爆发以来,人们在确定抗病毒策略和开发治疗药物方面做出了巨大努力。开发小分子抗sars - cov -2药物有不同的策略,包括针对冠状病毒结构蛋白(如刺突蛋白)、非结构蛋白(如RdRp、Mpro、PLpro、解旋酶、nsp14和nsp16)、宿主蛋白酶(如TMPRSS2、组织蛋白酶和furin)和介导内吞作用的关键蛋白(如PIKfyve),以及开发内核体酸化剂和免疫反应调节剂。法匹拉韦和氯喹是在此次疫情早期发现的抗sars - cov -2药物,并根据这些策略重新用于COVID-19临床治疗。然而,它们的功效是有争议的。目前,三种小分子抗sars - cov -2药物remdesivir、molnupiravir和Paxlovid (PF-07321332 +利托那韦)由于在III期试验中疗效显著,已在许多国家获得紧急使用授权或批准用于COVID-19治疗。与此同时,大量有前景的抗sars - cov -2候选药物已进入临床评估阶段。这些药物的开发为我们最终战胜COVID-19带来了希望。在这篇文章中,我们根据靶标分类对小分子抗sars - cov -2药物的最新进展进行了全面的综述。在这里,我们介绍了所有已批准的药物和针对每个靶点的大多数重要候选药物,并讨论了抗sars - cov -2药物未来研发的挑战和前景。
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引用次数: 9
Aztreonam-avibactam: an option against carbapenem-resistant Enterobacterales with emerging resistance. Aztreonam-avibactam:一种针对碳青霉烯耐药肠杆菌的选择。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2022-12-01 DOI: 10.1093/pcmedi/pbac029
Shikai Wu, Zhiyong Zong
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
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引用次数: 0
Genome-wide methylation profiling reveals differentially methylated genes in blood DNA of small-cell lung cancer patients. 全基因组甲基化分析揭示了小细胞肺癌患者血液DNA中的差异甲基化基因。
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2022-09-01 DOI: 10.1093/pcmedi/pbac017
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.
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引用次数: 2
Health consequences of early-onset compared with late-onset type 2 diabetes mellitus. 早发性与晚发性2型糖尿病的健康后果比较
IF 5.3 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2022-06-01 DOI: 10.1093/pcmedi/pbac015
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。
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引用次数: 1
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Precision Clinical Medicine
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