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Evaluating the Role of Methylated Circulating Tumor DNA in Combination With Pathological Prognostic Factors for Predicting Recurrence of Colorectal Cancer. 评估甲基化循环肿瘤 DNA 与病理预后因素相结合在预测结直肠癌复发方面的作用
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-02-28 eCollection Date: 2024-01-01 DOI: 10.1177/11772719241232870
Hiba Al Naji, Jean M Winter, Susanne K Pedersen, Amitesh Roy, Susan E Byrne, Graeme P Young, Erin L Symonds

Background: Colorectal cancer (CRC) has a high rate of recurrence, in particular for advanced disease, but prognosis based on staging and pathology at surgery can have limited efficacy. The presence of circulating tumor DNA (ctDNA) at diagnosis could be used to improve the prediction for disease recurrence.

Objectives: To assess the impact of detecting methylated BCAT1/IKZF1 ctDNA at diagnosis in combination with demographic, lifestyle, clinical factors and tumor pathology, to assess predictive value for recurrence.

Design: A retrospective cohort study.

Methods: The cohort included 180 patients (36 with recurrent CRC), who had undergone complete treatment and surveillance for a minimum of 3 years. Participant clinical details and ctDNA methylated BCAT1/IKZF1 results were compared between those with and without recurrence, and cox regression analysis assessed each factor on disease-free survival.

Results: Clinical factors independently associated with reduced disease-free survival included nodal involvement (HR = 3.83, 95% CI 1.56-9.43, P = .003), M1 stage (HR = 4.41, 95% CI 1.18-16.45, P = .027), a resection margin less than 2 mm (HR = 4.60, 95% CI 1.19-17.76, P = .027), perineural involvement (HR = 2.50, 95% CI 1.01-6.17, P = .047) and distal tumors (HR = 3.13, 95% CI 1.07-9.18, P = .037). Methylated BCAT1/IKZF1 was detected in 51.7% (93/180) of pre-treatment plasma samples. When a positive ctDNA finding was considered in combination with these clinical prognostic factors, there was improved predictive power of recurrence for patients with perineural involvement (HR = 4.44, 95% CI 1.92-10.26, P < .001), and it marginally improved the predictive factor for M1 stage (HR = 7.59, 95% CI 2.30-25.07, P = .001) and distal tumors (HR = 5.04, 95% CI 1.88-13.49, P = .001).

Conclusions: Nodal invasion, metastatic disease, distal tumor site, low resection margins and perineural invasion were associated with disease recurrence. Pre-treatment methylated ctDNA measurement can improve the predictive value for recurrence in a subset of patients, particularly those with perineural involvement.

Registration: Australian and New Zealand Clinical Trials Registry #12611000318987.

背景:结直肠癌(CRC)的复发率很高,尤其是晚期患者,但根据手术分期和病理结果进行预后的效果有限。诊断时出现的循环肿瘤 DNA(ctDNA)可用于改善疾病复发的预测:评估诊断时检测甲基化 BCAT1/IKZF1 ctDNA 与人口统计学、生活方式、临床因素和肿瘤病理学相结合对复发预测价值的影响:设计:一项回顾性队列研究:该队列包括 180 名患者(36 名复发性 CRC 患者),他们接受了至少 3 年的完整治疗和监测。对复发和未复发患者的临床详情和ctDNA甲基化BCAT1/IKZF1结果进行比较,并通过cox回归分析评估各因素对无病生存率的影响:与无病生存率降低独立相关的临床因素包括结节受累(HR = 3.83,95% CI 1.56-9.43,P = .003)、M1 分期(HR = 4.41,95% CI 1.18-16.45,P = .027)、切除边缘小于 2 mm(HR = 4.60,95% CI 1.19-17.76,P = .027)、神经周围受累(HR = 2.50,95% CI 1.01-6.17,P = .047)和远端肿瘤(HR = 3.13,95% CI 1.07-9.18,P = .037)。在51.7%(93/180)的治疗前血浆样本中检测到甲基化的BCAT1/IKZF1。如果将ctDNA阳性结果与这些临床预后因素结合起来考虑,则神经周围受累(HR = 4.44,95% CI 1.92-10.26,P = .001)和远端肿瘤(HR = 5.04,95% CI 1.88-13.49,P = .001)患者的复发预测能力有所提高:结节侵犯、转移性疾病、远端肿瘤部位、切除边缘低和神经周围侵犯与疾病复发有关。治疗前甲基化ctDNA测量可提高对部分患者复发的预测价值,尤其是那些有神经周围受累的患者:澳大利亚和新西兰临床试验注册号:12611000318987。
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引用次数: 0
mRNA Expression and Methylation of the RAD51, ATM, ATR, BRCA1, and BRCA2 Genes in Gastric Adenocarcinoma. 胃腺癌中 RAD51、ATM、ATR、BRCA1 和 BRCA2 基因的 mRNA 表达和甲基化。
IF 3.4 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-29 eCollection Date: 2024-01-01 DOI: 10.1177/11772719231225206
Joel Del Bel Pádua, Carolline Fontes Alves Mariano, Alexandre Todorovic Fabro, Fermino Sanches Lizarte Neto, Rogério Lenotti Zuliani, Cláudia Tarcila Gomes Sares, José Sebastião Dos Santos, Ajith Kumar Sankarankutty, Daniela Pretti da Cunha Tirapelli, Vanessa da Silva Silveira, Greice Andreotti de Molfetta, Wilson Araújo da Silva Júnior, Mariângela Ottoboni Brunaldi

Background: Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers.

Objective and design: This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm.

Methods: We evaluated mRNA expression and methylation of RAD51, ATM, ATR, BRCA1, and BRCA2 in tumor and non-tumor frozen samples from gastrectomy specimens by RT-qPCR and MS-HRM, correlating our results with previous immunohistochemistry data and prognostic features.

Results: RAD51, ATR, BRCA1, BRCA2, and ATM mRNA expression was detected in 93.75% (45/48), 93.75% (45/48), 91.67% (44/48), 83.33% (40/48), and 89.58% (43/48) of the tumors; partial or complete methylation, in 94.87% (37/39), 0 (0/42), 97.56% (40/41), 100% (41/41), and 0 (0/40), respectively. Most gene pairs showed significant weak to moderate positive correlations of tumoral mRNA expression with each other: RAD51 with ATR (P = .027), BRCA1 (P < .001), and BRCA2 (P < .001); ATR with BRCA1 (P = .007), and ATM (P = .001); BRCA1 with BRCA2 (P = 0.001). BRCA1 mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, P = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, P = .035). Greater tumoral RAD51 mRNA levels correlated with perineural invasion (1.822 vs 0.725, P = .010) and death (1.664 vs 0.929, P = .036), but not with survival time. There was an inverse association between nuclear immunohistochemical positivity for ATR and its mRNA levels (0.487 vs 0.907, P = .032), and no significant correlation for the other markers.

Conclusions: Our results suggest RAD51, BRCA1, and BRCA2 methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced BRCA1 expression participates in disease progression, and show an association between RAD51 mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for ATR, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.

背景:已知同源重组相关蛋白 RAD51、ATM、BRCA1 和 BRCA2 在胃腺癌(最致命的癌症之一)中的免疫组化预后意义:这项回顾性队列研究旨在评估该肿瘤中一些同源重组相关基因的 mRNA 表达和启动子甲基化情况:我们通过RT-qPCR和MS-HRM评估了胃切除术标本中肿瘤和非肿瘤冷冻样本中RAD51、ATM、ATR、BRCA1和BRCA2的mRNA表达和甲基化情况,并将我们的结果与之前的免疫组化数据和预后特征相关联:93.75%(45/48)、93.75%(45/48)、91.67%(44/48)、83.33%(40/48)和89.58%(43/48)的肿瘤检测到RAD51、ATR、BRCA1、BRCA2和ATM mRNA表达;94.87%(37/39)、0(0/42)、97.56%(40/41)、100%(41/41)和0(0/40)的肿瘤检测到部分或完全甲基化。大多数基因对之间的肿瘤 mRNA 表达呈明显的弱至中度正相关:RAD51 与 ATR(P = 0.027)、BRCA1(P BRCA2(P ATR 与 BRCA1(P = 0.007)和 ATM(P = 0.001);BRCA1 与 BRCA2(P = 0.001)。与非肿瘤性粘膜相比,肿瘤中的 BRCA1 mRNA 减少(0.345 vs 1.272,P = .015);除新辅助治疗病例外,T3 至 T4 肿瘤中的 BRCA1 mRNA 减少(0.414 vs 0.954,P = .035)。肿瘤RAD51 mRNA水平升高与神经周围侵犯(1.822 vs 0.725,P = .010)和死亡(1.664 vs 0.929,P = .036)相关,但与生存时间无关。ATR的核免疫组化阳性与mRNA水平呈反向关系(0.487 vs 0.907,P = .032),与其他标记物无显著相关性:我们的研究结果表明,RAD51、BRCA1 和 BRCA2 甲基化是胃癌中一种常见的表观遗传机制,支持 BRCA1 表达减少参与疾病进展的假设,并显示 RAD51 mRNA 与会厌浸润和死亡率之间存在关联,考虑到之前的免疫组化研究,这种关联可能被认为是出乎意料的。免疫组化与 mRNA 之间缺乏相关性,甚至与 ATR 呈反向关系,这表明转录后或翻译后调控机制发挥作用,有待进一步研究。
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引用次数: 0
Prognostic Value of Neutrophils-to-Lymphocytes Ratio and Platelets-to-Lymphocytes Ratio in Sepsis Patients With Lymphopenia. 淋巴细胞减少症败血症患者的中性粒细胞-淋巴细胞比率和血小板-淋巴细胞比率的预后价值
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-04 eCollection Date: 2024-01-01 DOI: 10.1177/11772719231223156
Xianming Qiu, Quanzhen Wang, Yuke Zhang, Qiannan Zhao, Zhiming Jiang, Lei Zhou

Background: Inflammation plays a critical role in sepsis. The integration of neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocytes ratio (PLR) from multiple cell types offers a novel approach to rapidly assess inflammation status. However, the predictive role of NLR and PLR in sepsis with lymphopenia remains uncertain.

Objectives: The purpose of this study was to explore the prognostic value of NLR and PLR in sepsis patients with lymphopenia.

Design and methods: In this observational retrospective study, we included 172 sepsis patients with lymphopenia and collected clinical characteristics for analysis. Through binary logistic regression analysis, we identified independent factors. Receiver-operating characteristic curves (ROC) and areas under the curves (AUC) were employed to assess the ability to predict hospital mortality risk.

Results: Our results showed a total hospital mortality rate of 53.49%. Multivariate analysis demonstrated that NLR (OR = 1.11, P < .001) and PLR (OR = 1.01, P = .003) were independent predictors associated with hospital mortality in sepsis patients with lymphopenia. The AUCs of NLR and PLR were 0.750 (95% CI: 0.634-0.788, P < .001) and 0.662 (95% CI: 0.580-0.743, P < .001), respectively. Notably, an optimal cut-off value of 18.93 for NLR displayed a sensitivity of 75.0% and specificity of 63.0% in discriminating hospital mortality in sepsis patients with lymphopenia, while the optimal cut-off value for PLR was 377.50, with a sensitivity of 67.5% and specificity of 64.1%.

Conclusion: NLR and PLR serve as independent predictors of hospital mortality in sepsis patients with lymphopenia.

背景:炎症在败血症中起着至关重要的作用。整合多种细胞类型的中性粒细胞与淋巴细胞比率(NLR)和血小板与淋巴细胞比率(PLR)为快速评估炎症状态提供了一种新方法。然而,NLR 和 PLR 在伴有淋巴细胞减少的败血症中的预测作用仍不确定:本研究旨在探讨 NLR 和 PLR 在淋巴细胞减少症脓毒症患者中的预后价值:在这项观察性回顾研究中,我们纳入了172名淋巴细胞减少症脓毒症患者,并收集了他们的临床特征进行分析。通过二元逻辑回归分析,我们确定了独立因素。采用接收者工作特征曲线(ROC)和曲线下面积(AUC)来评估预测住院死亡率风险的能力:结果显示,住院总死亡率为 53.49%。多变量分析表明,NLR(OR = 1.11,P P = .003)是与淋巴细胞减少症脓毒症患者住院死亡率相关的独立预测因子。NLR 和 PLR 的 AUC 值为 0.750(95% CI:0.634-0.788,P P 结论:NLR和PLR是淋巴细胞减少症脓毒症患者住院死亡率的独立预测指标。
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引用次数: 0
Detection of Inflammatory Biomarker suPAR in COVID-19 Disease With CHORUS TRIO Instrument. 合唱三重奏仪检测COVID-19疾病炎症标志物suPAR
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-11-29 eCollection Date: 2023-01-01 DOI: 10.1177/11772719231210407
Cerutti Helena, Tesi Giulia, Cartocci Alessandra, Guerranti Roberto, Silvestrini Caterina, Gori Sabrina, Bianciardi Simone, Bandini Tommaso, Brogi Alessandra, Leoncini Roberto

Background: Deregulation in the urokinase-type plasminogen activator receptor (uPA/uPAR) system is reported in many diseases where the immune system is activated. During SARS-CoV-2 infection, a rise in soluble uPAR (suPAR) levels has been detected and its concentration above 6 µg/L predicts worsening to severe respiratory failure 14 days earlier, with a positive predictive value of 85.9%, and was the prerequisite for a treatment with anakinra, a recombinant IL-1 receptor antagonist that blocks the activity of both IL-1α and IL-1β.

Objectives: To compare suPAR concentrations measured by CHORUS suPAR on CHORUS TRIO instrument of DIESSE with the commercially available suPARnostic (ViroGates) ELISA assay.

Design: A single-centre, non-pharmacological, diagnostic study was performed.

Results: A total of 522 serum samples from patients with COVID-19 were tested for suPAR. CHORUS suPAR resulted accurate and reliable, with a high grade of specificity (97.9%), accuracy (97.3%) and sensitivity (96.9%). The median concentration of suPAR, as determined with CHORUS suPAR, was 6.8 µg/L (interquartile range 4.5-9.7) in patients with moderate disease (n = 465) and 8.5 µg/L (interquartile range 5.4-10.6) in patients with severe disease. Among patients with moderate and severe disease, 60.6% and 71.9%, respectively, reached the cut-off concentration of suPAR ⩾6 µg/L, defining their illness severity and suggesting eligibility to anakinra treatment.

Conclusion: CHORUS suPAR kit resulted as sensitive, specific, accurate and able to quantify suPAR concentrations in patients with moderate and severe COVID-19.

背景:尿激酶型纤溶酶原激活物受体(uPA/uPAR)系统的失调在许多免疫系统被激活的疾病中被报道。在SARS-CoV-2感染期间,已检测到可溶性uPAR (suPAR)水平升高,其浓度高于6µg/L可提前14天恶化至严重呼吸衰竭,阳性预测值为85.9%,这是使用anakinra治疗的先决条件,anakinra是一种重组IL-1受体拮抗剂,可阻断IL-1α和IL-1β的活性。目的:比较DIESSE的CHORUS TRIO仪器上CHORUS suPAR测定的suPAR浓度与市售的suPARnostic (ViroGates) ELISA法测定的suPAR浓度。设计:进行单中心、非药物、诊断性研究。结果:对522例COVID-19患者血清样本进行了suPAR检测。CHORUS suPAR结果准确可靠,特异度(97.9%)、准确度(97.3%)和灵敏度(96.9%)高。用CHORUS suPAR测定的suPAR中位浓度在中度疾病(n = 465)患者中为6.8µg/L(四分位数范围4.5-9.7),在重度疾病患者中为8.5µg/L(四分位数范围5.4-10.6)。在患有中度和重度疾病的患者中,分别有60.6%和71.9%达到suPAR小于6µg/L的截止浓度,定义了他们的疾病严重程度,并建议有资格接受阿那白拉治疗。结论:CHORUS suPAR试剂盒具有敏感性、特异性、准确性,能够定量中重度COVID-19患者的suPAR浓度。
{"title":"Detection of Inflammatory Biomarker suPAR in COVID-19 Disease With CHORUS TRIO Instrument.","authors":"Cerutti Helena, Tesi Giulia, Cartocci Alessandra, Guerranti Roberto, Silvestrini Caterina, Gori Sabrina, Bianciardi Simone, Bandini Tommaso, Brogi Alessandra, Leoncini Roberto","doi":"10.1177/11772719231210407","DOIUrl":"10.1177/11772719231210407","url":null,"abstract":"<p><strong>Background: </strong>Deregulation in the urokinase-type plasminogen activator receptor (uPA/uPAR) system is reported in many diseases where the immune system is activated. During SARS-CoV-2 infection, a rise in soluble uPAR (suPAR) levels has been detected and its concentration above 6 µg/L predicts worsening to severe respiratory failure 14 days earlier, with a positive predictive value of 85.9%, and was the prerequisite for a treatment with anakinra, a recombinant IL-1 receptor antagonist that blocks the activity of both IL-1α and IL-1β.</p><p><strong>Objectives: </strong>To compare suPAR concentrations measured by CHORUS suPAR on CHORUS TRIO instrument of DIESSE with the commercially available suPARnostic (ViroGates) ELISA assay.</p><p><strong>Design: </strong>A single-centre, non-pharmacological, diagnostic study was performed.</p><p><strong>Results: </strong>A total of 522 serum samples from patients with COVID-19 were tested for suPAR. CHORUS suPAR resulted accurate and reliable, with a high grade of specificity (97.9%), accuracy (97.3%) and sensitivity (96.9%). The median concentration of suPAR, as determined with CHORUS suPAR, was 6.8 µg/L (interquartile range 4.5-9.7) in patients with moderate disease (n = 465) and 8.5 µg/L (interquartile range 5.4-10.6) in patients with severe disease. Among patients with moderate and severe disease, 60.6% and 71.9%, respectively, reached the cut-off concentration of suPAR ⩾6 µg/L, defining their illness severity and suggesting eligibility to anakinra treatment.</p><p><strong>Conclusion: </strong>CHORUS suPAR kit resulted as sensitive, specific, accurate and able to quantify suPAR concentrations in patients with moderate and severe COVID-19.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719231210407"},"PeriodicalIF":3.8,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multiomic Approaches for Cancer Biomarker Discovery in Liquid Biopsies: Advances and Challenges. 液体活检中癌症生物标志物发现的多组学方法:进展和挑战。
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-10-14 eCollection Date: 2023-01-01 DOI: 10.1177/11772719231204508
Paola Monterroso Diaz, Ashton Leehans, Prashanth Ravishankar, Anna Daily

Cancer is a complex and heterogeneous disease that poses a significant threat to global health. Early diagnosis and treatment are critical for improving patient outcomes, and the use of liquid biopsies has emerged as a promising approach for cancer detection and monitoring. Traditionally, cancer diagnosis has relied on invasive tissue biopsies, the collection of which can prove challenging for patients and the results of which may not always provide accurate results due to tumor heterogeneity. Liquid biopsies have gained increasing attention as they provide a non-invasive and accessible source of cancer biomarkers, which can be used to diagnose cancer, monitor treatment response, and detect relapse. The integration of -omics technologies, such as proteomics, genomics, and metabolomics, has further enhanced the capabilities of liquid biopsies by introducing precision oncology and enabling the tailoring of treatment for individual patients based on their unique tumor biology. In this review, we will discuss the challenges and advances in the field of cancer liquid biopsies and the integration of -omics technologies for different types of liquid biopsies, including blood, tear, urine, sweat, saliva, and cerebrospinal fluid.

癌症是一种复杂而异质的疾病,对全球健康构成重大威胁。早期诊断和治疗对于改善患者的预后至关重要,液体活检的使用已成为癌症检测和监测的一种有前途的方法。传统上,癌症的诊断依赖于侵入性组织活检,其收集可能对患者具有挑战性,并且由于肿瘤异质性,其结果可能并不总是提供准确的结果。液体活检越来越受到关注,因为它们提供了癌症生物标志物的非侵入性和可获取来源,可用于诊断癌症、监测治疗反应和检测复发。蛋白质组学、基因组学和代谢组学等组学技术的集成,通过引入精确肿瘤学,并能够根据患者独特的肿瘤生物学为其量身定制治疗方法,进一步增强了液体活检的能力。在这篇综述中,我们将讨论癌症液体活检领域的挑战和进展,以及不同类型液体活检的组学技术整合,包括血液、眼泪、尿液、汗液、唾液和脑脊液。
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引用次数: 0
The Latest Developments in Using Proteomic Biomarkers from Urine and Serum for Non-Invasive Disease Diagnosis and Prognosis. 尿和血清蛋白质组学标志物在非侵入性疾病诊断和预后中的最新进展。
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-01 DOI: 10.1177/11772719231190218
Anurag Shama, Thomson Soni, Ishwerpreet Kaur Jawanda, Garima Upadhyay, Anshika Sharma, Vijay Prabha

Due to diagnostic improvements, medical diagnostics is demanding non-invasive or minimally invasive methods. Non-invasively obtained body fluids (eg., Urine, serum) can replace cerebral fluid, amniotic fluid, synovial fluid, bronchoalveolar lavage fluid, and others for diagnostic reasons. Many illnesses are induced by perturbations of cellular signaling pathways and associated pathway networks as a result of genetic abnormalities. These disturbances are represented by a shift in the protein composition of the fluids surrounding the tissues and organs that is, tissue interstitial fluid (TIF). These variant proteins may serve as diagnostic "signatures" for a variety of disorders. This review provides a concise summary of urine and serum biomarkers that may be used for the diagnosis and prognosis of a variety of disorders, including cancer, brain diseases, kidney diseases, and other system diseases. The studies reviewed in this article suggest that serum and urine biomarkers of various illnesses may be therapeutically useful for future diagnostics. Correct illness management is crucial for disease prognosis, hence non-invasive serum and urine biomarkers have been extensively studied for diagnosis, subclassification, monitoring disease activity, and predicting treatment results and consequences.

由于诊断的改进,医疗诊断要求非侵入性或微创方法。非侵入性获取的体液(例如:(如尿、血清)可代替脑液、羊水、滑液、支气管肺泡灌洗液和其他诊断原因。许多疾病是由基因异常引起的细胞信号通路和相关通路网络的扰动引起的。这些紊乱表现为组织和器官周围的液体,即组织间质液(TIF)的蛋白质组成的变化。这些变异蛋白可以作为多种疾病的诊断“标志”。本文简要介绍了可用于多种疾病(包括癌症、脑部疾病、肾脏疾病和其他系统疾病)诊断和预后的尿液和血清生物标志物。本文综述的研究表明,各种疾病的血清和尿液生物标志物可能对未来的诊断有治疗价值。正确的疾病管理对疾病预后至关重要,因此无创血清和尿液生物标志物已被广泛研究用于诊断、亚分类、监测疾病活动以及预测治疗结果和后果。
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引用次数: 0
The Use of Biomarkers in Pharmacovigilance: A Systematic Review of the Literature. 生物标志物在药物警戒中的应用:文献系统综述。
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-01 DOI: 10.1177/11772719231164528
Maribel Salas, Maxine Gossell-Williams, Priyanka Yalamanchili, Sameer Dhingra, Marina A Malikova, Omar Aimer, Toluwalope Junaid
Background The use of biomarkers varies from disease etiognosis and diagnosis to signal detection, risk prediction, and management. Biomarker use has expanded in recent years, however, there are limited reviews on the use of biomarkers in pharmacovigilance and specifically in the monitoring and management of adverse drug reactions (ADRs). Objective The objective of this manuscript is to identify the multiple uses of biomarkers in pharmacovigilance irrespective of the therapeutic area. Design This is a systematic review of the literature. Data Sources and Methods Embase and MEDLINE database searches were conducted for literature published between 2010-March 19, 2021. Scientific articles that described the potential use of biomarkers in pharmacovigilance in sufficient detail were reviewed. Papers that did not fulfill the United States Food and Drug Administration (US FDA) definition of a biomarker were excluded, which is based on the International Conference on Harmonisation (ICH)-E16 guidance. Results Twenty-seven articles were identified for evaluation. Most articles involved predictive biomarkers (41%), followed by safety biomarkers (38%), pharmacodynamic/response biomarkers (14%), and diagnostic biomarkers (7%). Some articles described biomarkers that applied to multiple categories. Conclusion Various categories of biomarkers including safety, predictive, pharmacodynamic/response, and diagnostic biomarkers are being investigated for potential use in pharmacovigilance. The most frequent potential uses of biomarkers in pharmacovigilance in the literature were the prediction of the severity of an ADR, mortality, response, safety, and toxicity. The safety biomarkers identified were used to evaluate patient safety during dose escalation, identify patients who may benefit from further biomarker testing during treatment, and monitor ADRs.
背景:生物标志物的使用从疾病的病因诊断到信号检测、风险预测和管理各不相同。近年来,生物标志物的应用已经扩大,然而,关于生物标志物在药物警戒特别是药物不良反应(adr)监测和管理中的应用的综述有限。目的:本文的目的是确定生物标志物在药物警戒中的多种用途,而不考虑治疗领域。设计:这是一篇系统的文献综述。数据来源和方法:对2010年至2021年3月19日发表的文献进行Embase和MEDLINE数据库检索。对详细描述生物标志物在药物警戒中的潜在应用的科学文章进行了综述。不符合美国食品和药物管理局(FDA)生物标志物定义的论文被排除在外,这是基于国际协调会议(ICH)-E16指南。结果:筛选出27篇文献进行评价。大多数文章涉及预测性生物标志物(41%),其次是安全性生物标志物(38%),药效学/反应性生物标志物(14%)和诊断性生物标志物(7%)。一些文章描述了应用于多个类别的生物标志物。结论:各种生物标志物,包括安全性、预测性、药效学/反应性和诊断性生物标志物,正在研究其在药物警戒中的潜在用途。在文献中,生物标志物在药物警戒中最常见的潜在用途是预测不良反应的严重程度、死亡率、反应、安全性和毒性。确定的安全性生物标志物用于评估剂量递增期间患者的安全性,确定可能从治疗期间进一步生物标志物检测中受益的患者,并监测不良反应。
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引用次数: 0
Caveat Medicus: It's Time to Re-Think Stratification, You May Not Be Helping. 警告:是时候重新考虑分层了,你可能帮不上忙。
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-01 DOI: 10.1177/11772719231174746
Ognjen Arandjelović

Background: The focus of the present Letter is on the large and seemingly fertile body of work captured under the umbrella of 'patient stratification'.

Objectives: I identify and explain a fundamental methodological flaw underlying the manner in which the development of an increasingly large number of new stratification strategies is approached.

Design: I show an inherent conflict between the assumptions made, and the very purpose of stratification and its application in practice.

Methods: I analyse the methodological underpinnings of stratification as presently done and draw parallels with conceptually similarly flawed precedents which are now widely recognized.

Results: The highlighted flaw is shown to undermine the overarching ultimate goal of improved patient outcomes by undue fixation on an ill-founded proxy.

Conclusion: I issue a call for a re-think of the problem and the processes leading to the adoption of new stratification strategies in the clinic.

背景:本信函的重点是在“患者分层”的保护伞下捕获的大量看似丰富的工作。目标:我发现并解释了一个基本的方法论缺陷,这种缺陷潜藏在越来越多的新分层策略的发展方式之下。设计:我展示了所做的假设与分层的目的及其在实践中的应用之间的内在冲突。方法:我分析了分层的方法学基础,如目前所做的,并与概念上类似的有缺陷的先例,现在被广泛认可的相似之处。结果:突出的缺陷被证明破坏了改善患者预后的总体最终目标,因为过度固定在一个没有根据的代理上。结论:我呼吁重新思考这个问题和导致在临床中采用新的分层策略的过程。
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引用次数: 0
Validation of Prognostic Club Cell Secretory Protein (CC16) Cut-point in an Independent ALTA Cohort. 独立ALTA队列中预后俱乐部细胞分泌蛋白(CC16)切点的验证。
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-01 DOI: 10.1177/11772719231156308
Sultan Almuntashiri, Aaron Chase, Andrea Sikora, Duo Zhang

Background: Club cell secretory protein (CC16) has demonstrated utility as a lung-specific biomarker in predicting mortality in acute respiratory distress syndrome (ARDS). These findings have been observed in pre-clinical trials and a re-analysis of a large, randomized controlled trial of ARDS (Fluid and Catheter Treatment Trial (FACTT)).

Objectives: The purpose of this study was to validate previous findings by evaluating CC16 level as a mortality predictor in patients from the albuterol to treat acute lung injury (ALTA) trial.

Design and method: In this secondary biomarker analysis, plasma CC16 level was measured from 100 ALTA subjects using enzyme-linked immunosorbent assay (ELISA). The rate of mortality was assessed in patients with high (⩾45 ng/mL) versus low CC16 (<45 ng/mL) levels. This cut-off level was applied based on our previous analysis from FACTT trial. Significance was assessed using Kaplan-Meier curves and a log-rank test.

Results: Subjects were an average of 50 years old and 46% of them were females. Patients with high CC16 levels had higher 90-day mortality compared to those with low CC16 levels, (37.73% vs 8.95%, P < .001). Other clinical outcomes including ICU-free days, ventilator-free days, and organ failure free days were significantly different between the groups (All P < .05).

Conclusion: In this validation study, we demonstrated that ARDS patients with high plasma CC16 concentration had a higher mortality rate than those with low CC16 levels, confirming previous findings that CC16 levels are associated with ARDS mortality.

背景:俱乐部细胞分泌蛋白(CC16)已被证明是预测急性呼吸窘迫综合征(ARDS)死亡率的肺特异性生物标志物。这些发现已在临床前试验和对一项大型ARDS随机对照试验(液体和导管治疗试验(FACTT))的再分析中观察到。目的:本研究的目的是通过评估CC16水平作为沙丁胺醇治疗急性肺损伤(ALTA)试验患者死亡率预测因子来验证先前的研究结果。设计和方法:在这项二级生物标志物分析中,使用酶联免疫吸附法(ELISA)测量了100名ALTA受试者的血浆CC16水平。在高(小于45 ng/mL)与低CC16的患者中评估死亡率(结果:受试者平均年龄为50岁,其中46%是女性)。结论:在本验证性研究中,我们证实血浆CC16浓度高的ARDS患者的死亡率高于血浆CC16浓度低的患者,证实了CC16水平与ARDS死亡率相关的先前研究结果。
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引用次数: 1
What is the Diagnostic Accuracy of Novel Urine Biomarkers for Urinary Tract Infection? 新型尿液生物标志物诊断尿路感染的准确性如何?
IF 3.8 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-01 DOI: 10.1177/11772719221144459
George Edwards, Anna Seeley, Adam Carter, Maia Patrick Smith, Elizabeth LA Cross, Kathryn Hughes, Ann Van den Bruel, Martin J Llewelyn, Jan Y Verbakel, Gail Hayward

Background: Urinary tract infection (UTI) affects half of women at least once in their lifetime. Current diagnosis involves urinary dipstick and urine culture, yet both methods have modest diagnostic accuracy, and cannot support decision-making in patient populations with high prevalence of asymptomatic bacteriuria, such as older adults. Detecting biomarkers of host response in the urine of hosts has the potential to improve diagnosis.

Objectives: To synthesise the evidence of the diagnostic accuracy of novel biomarkers for UTI, and of their ability to differentiate UTI from asymptomatic bacteriuria.

Design: A systematic review.

Data sources and methods: We searched MEDLINE, EMBASE, CINAHL and Web of Science for studies of novel biomarkers for the diagnosis of UTI. We excluded studies assessing biomarkers included in urine dipsticks as these have been well described previously. We included studies of adult patients (≥16 years) with a suspected or confirmed urinary tract infection using microscopy and culture as the reference standard. We excluded studies using clinical signs and symptoms, or urine dipstick only as a reference standard. Quality appraisal was performed using QUADAS-2. We summarised our data using point estimates and data accuracy statistics.

Results: We included 37 studies on 4009 adults measuring 66 biomarkers. Study quality was limited by case-control design and study size; only 4 included studies had a prospective cohort design. IL-6 and IL-8 were the most studied biomarkers. We found plausible evidence to suggest that IL-8, IL-6, GRO-a, sTNF-1, sTNF-2 and MCR may benefit from more rigorous evaluation of their potential diagnostic value for UTI.

Conclusions: There is insufficient evidence to recommend the use of any novel biomarker for UTI diagnosis at present. Further evaluation of the more promising candidates, is needed before they can be recommended for clinical use.

背景:尿路感染(UTI)影响一半的妇女在其一生中至少一次。目前的诊断包括尿试纸和尿培养,但这两种方法的诊断准确性都不高,不能支持无症状细菌尿高发的患者群体(如老年人)的决策。在宿主尿液中检测宿主反应的生物标志物有可能改善诊断。目的:综合新的UTI生物标志物诊断准确性的证据,以及它们区分UTI和无症状细菌尿的能力。设计:系统回顾。数据来源和方法:检索MEDLINE、EMBASE、CINAHL和Web of Science,寻找诊断UTI的新型生物标志物。我们排除了评估尿试纸中包含的生物标志物的研究,因为这些研究之前已经被很好地描述过。我们纳入了用显微镜和培养作为参考标准的疑似或确诊尿路感染的成人患者(≥16岁)的研究。我们排除了将临床体征和症状或尿液试纸仅作为参考标准的研究。采用QUADAS-2进行质量评价。我们使用点估计和数据准确性统计来总结我们的数据。结果:我们纳入了37项研究,涉及4009名成年人,测量了66种生物标志物。研究质量受到病例对照设计和研究规模的限制;只有4项纳入的研究采用前瞻性队列设计。IL-6和IL-8是研究最多的生物标志物。我们发现可信的证据表明,对IL-8、IL-6、GRO-a、sTNF-1、sTNF-2和MCR的潜在诊断价值进行更严格的评估可能会受益。结论:目前没有足够的证据推荐使用任何新的生物标志物来诊断尿路感染。在推荐临床使用之前,需要对更有希望的候选药物进行进一步评估。
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引用次数: 4
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Biomarker Insights
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