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Development of Tier 2 LC-MRM-MS protein quantification methods for liquid biopsies 用于液体活检的Tier 2 LC-MRM-MS蛋白质定量方法的开发
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jmsacl.2022.12.007
Nina Diederiks , Cor J. Ravensbergen , Maxim Treep , Madelein van Wezel , Matt Kuruc , L. Renee Ruhaak , Rob A.E.M. Tollenaar , Christa M. Cobbaert , Yuri E.M. van der Burgt , Wilma E. Mesker

In the pursuit of personalized diagnostics and tailored treatments, quantitative protein tests contribute to a more precise definition of health and disease. The development of new quantitative protein tests should be driven by an unmet clinical need and performed in a collaborative effort that involves all stakeholders. With regard to the analytical part, mass spectrometry (MS)-based platforms are an excellent tool for quantification of specific proteins in body fluids, for example focused on cancer. The obtained readouts have great potential in determining tumor aggressiveness to facilitate treatment decisions, and can furthermore be used to monitor patient response. Internationally standardized TNM classifications of malignant tumors are beneficial for diagnosis, however treatment outcome and survival of cancer patients is poorly predicted. To this end, the importance of the tumor microenvironment has endorsed the introduction of the tumor-stroma ratio as a prognostic parameter in solid primary tumor types. Currently, the stromal content of tumor tissues is determined via routine diagnostic pathology slides. With the development of liquid chromatography (LC)-MS methods we aim at quantification of tumor-stroma specific proteins in body fluids. In this mini-review the analytical aspect of this developmental trajectory is further detailed.

在追求个性化诊断和量身定制的治疗过程中,定量蛋白质测试有助于更准确地定义健康和疾病。新的定量蛋白质测试的开发应该由未满足的临床需求驱动,并在所有利益相关者参与的合作中进行。就分析部分而言,基于质谱(MS)的平台是用于量化体液中特定蛋白质的优秀工具,例如专注于癌症。所获得的读数在确定肿瘤侵袭性以促进治疗决策方面具有巨大潜力,并且可以进一步用于监测患者反应。国际标准化的恶性肿瘤TNM分类有利于诊断,但癌症患者的治疗结果和生存率预测较差。为此,肿瘤微环境的重要性支持将肿瘤间质比率作为实体原发性肿瘤类型的预后参数。目前,肿瘤组织的基质含量是通过常规诊断病理切片来确定的。随着液相色谱(LC)-MS方法的发展,我们的目标是定量体液中的肿瘤基质特异性蛋白质。在这篇小型综述中,进一步详细介绍了这一发展轨迹的分析方面。
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引用次数: 1
A distributable LC-MS/MS method for the measurement of serum thyroglobulin 可分配LC-MS/MS法测定血清甲状腺球蛋白
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.005
Junyan Shi , William S. Phipps , Benjamin Y. Owusu , Clark M. Henderson , Thomas J. Laha , Jessica O. Becker , Morteza Razavi , Michelle A. Emrick , Andrew N. Hoofnagle

Background

Despite its clear advantages over immunoassay-based testing, the measurement of serum thyroglobulin by mass spectrometry remains limited to a handful of institutions. Slow adoption by clinical laboratories could reflect limited accessibility to existing methods that have sensitivity comparable to modern immunoassays, as well as a lack of tools for calibration and assay harmonization.

Methods

We developed and validated a liquid chromatography-tandem mass spectrometry-based assay for the quantification of serum thyroglobulin. The protocol combined peptide immunoaffinity purification using a commercially available, well-characterized monoclonal antibody and mobile phase modification with dimethylsulfoxide (DMSO) for enhanced sensitivity. To facilitate harmonization with other laboratories, we developed a novel, serum-based 5-point distributable reference material (Husky Ref).

Results

The assay demonstrated a lower limit of quantification of 0.15 ng/mL (<20 %CV). Mobile phase DMSO increased signal intensity of the target peptide at least 3-fold, improving quantification at low concentrations. Calibration traceable to Husky Ref enabled harmonization between laboratories in an interlaboratory study.

Conclusions

Sensitive mass spectrometry-based thyroglobulin measurement can be achieved using a monoclonal antibody during peptide immunoaffinity purification and the addition of mobile phase DMSO. Laboratories interested in deploying this assay can utilize the provided standard operating procedure and freely-available Husky Ref reference material.

背景:尽管质谱法比基于免疫分析的检测有明显的优势,但它仍然局限于少数机构。临床实验室采用缓慢可能反映了现有方法的可及性有限,这些方法具有与现代免疫测定相当的敏感性,以及缺乏校准和测定统一的工具。方法建立并验证了一种基于液相色谱-串联质谱的血清甲状腺球蛋白定量分析方法。该方案结合了多肽免疫亲和纯化,使用市售的、特性良好的单克隆抗体和二甲基亚砜(DMSO)的流动相修饰,以提高灵敏度。为了促进与其他实验室的协调,我们开发了一种新的、基于血清的5点可分发参考物质(Husky Ref)。结果该方法的定量下限为0.15 ng/mL (20% CV)。流动相DMSO使目标肽的信号强度增加了至少3倍,在低浓度下提高了定量。校准可追溯到赫斯基Ref使实验室之间的协调实验室间的研究。结论在多肽免疫亲和纯化和加入流动相DMSO的过程中,采用单克隆抗体可实现基于质谱法的甲状腺球蛋白检测。有兴趣部署此分析的实验室可以利用提供的标准操作程序和免费提供的赫斯基参考材料。
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引用次数: 5
Corrigendum to “Instability of 7-aminoclonazepam in frozen storage conditions” [Clin. Mass Spectrom. 9 (2018) 23–24] “7-氨基氯硝西泮在冷冻储存条件下的不稳定性”的勘误表[临床]。质谱,9 (2018)23-24 [j]
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.006
Jayme L. Dahlin , Athena K. Petrides
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引用次数: 0
Advances in MS instrumentation: The present and future of the clinical lab 质谱仪器的进展:临床实验室的现在和未来
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.08.003
Christopher D. Chouinard
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引用次数: 0
Validation of atovaquone plasma levels by liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring in pediatric patients 液相色谱-串联质谱法检测阿托伐醌血浆水平用于儿科患者治疗药物监测的验证
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.004
Thomas D. Horvath , Izmarie Poventud-Fuentes , Lily Olayinka , Asha James , Sigmund J. Haidacher , Kathleen M. Hoch , Alexandra M. Stevens , Anthony M. Haag , Sridevi Devaraj

Background

Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability in atovaquone bioavailability highlights the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients using LC-MS/MS.

Methods

Atovaquone was extracted from a 10 µL volume of K2-EDTA human plasma using a solution consisting of ACN: EtOH: DMF (8:1:1 v:v:v), separated using reverse-phase chromatography, and detected using a SCIEX 5500 QTrap MS system. LC-MS/MS assay performance was evaluated for precision, accuracy, carryover, sensitivity, specificity, linearity, and interferences.

Results

Atovaquone and its deuterated internal standard were analyzed using a gradient chromatographic method that had an overall cycle-time of 7.4 min per injection, and retention times of 4.3 min. Atovaquone was measured over a dynamic concentration range of 0.63 – 80 µM with a deviation within ≤ ± 5.1 % of the target value. Intra- and inter-assay precision were ≤ 2.7 % and ≤ 8.4 %, respectively. Dilutional, carryover, and interference studies were also within acceptable limits.

Conclusions

Our studies have shown that our LC-MS/MS-based method is both reliable and robust for the quantification of plasma atovaquone concentrations and can be used to determine the effective dose of atovaquone for pediatric patients treated for AML.

托伐醌传统上被用作抗寄生虫和抗真菌剂,但最近的研究显示其作为抗癌剂的潜力。阿托伐醌生物利用度的高度可变性突出了治疗药物监测的必要性,特别是在儿科患者中。本研究的目的是开发并验证一种利用LC-MS/MS定量儿科癌症患者阿托伐醌血浆浓度的检测方法的性能。方法采用ACN: EtOH: DMF (8:1:1 v:v:v)溶液从10µL体积的K2-EDTA人血浆中提取satovaquone,反相色谱分离,SCIEX 5500 QTrap质谱系统检测。对LC-MS/MS分析的精密度、准确度、携带性、灵敏度、特异性、线性度和干扰度进行评价。结果采用梯度色谱法对阿托伐醌及其氘化内标进行分析,每次注射总循环时间为7.4 min,保留时间为4.3 min。阿托伐醌的动态浓度范围为0.63 ~ 80µM,与靶值的偏差≤±5.1%。测定内精密度≤2.7%,测定间精密度≤8.4%。稀释、结转和干扰研究也在可接受范围内。结论研究表明,基于LC-MS/ ms的方法定量测定阿托伐酮血浆浓度可靠、稳健,可用于确定小儿急性髓性白血病患者阿托伐酮的有效剂量。
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引用次数: 1
Imaging mass spectrometry reveals complex lipid distributions across Staphylococcus aureus biofilm layers 成像质谱显示复杂的脂质分布跨越金黄色葡萄球菌生物膜层
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.003
Emilio S. Rivera , Andy Weiss , Lukasz G. Migas , Jeffrey A. Freiberg , Katerina V. Djambazova , Elizabeth K. Neumann , Raf Van de Plas , Jeffrey M. Spraggins , Eric P. Skaar , Richard M. Caprioli

Introduction

Although Staphylococcus aureus is the leading cause of biofilm-related infections, the lipidomic distributions within these biofilms is poorly understood. Here, lipidomic mapping of S. aureus biofilm cross-sections was performed to investigate heterogeneity between horizontal biofilm layers.

Methods

S. aureus biofilms were grown statically, embedded in a mixture of carboxymethylcellulose/gelatin, and prepared for downstream matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS). Trapped ion mobility spectrometry (TIMS) was also applied prior to mass analysis.

Results

Implementation of TIMS led to a ∼ threefold increase in the number of lipid species detected. Washing biofilm samples with ammonium formate (150 mM) increased signal intensity for some bacterial lipids by as much as tenfold, with minimal disruption of the biofilm structure. MALDI TIMS IMS revealed that most lipids localize primarily to a single biofilm layer, and species from the same lipid class such as cardiolipins CL(57:0) – CL(66:0) display starkly different localizations, exhibiting between 1.5 and 6.3-fold intensity differences between layers (n = 3, p < 0.03). No horizontal layers were observed within biofilms grown anaerobically, and lipids were distributed homogenously.

Conclusions

High spatial resolution analysis of S. aureus biofilm cross-sections by MALDI TIMS IMS revealed stark lipidomic heterogeneity between horizontal S. aureus biofilm layers demonstrating that each layer was molecularly distinct. Finally, this workflow uncovered an absence of layers in biofilms grown under anaerobic conditions, possibly indicating that oxygen contributes to the observed heterogeneity under aerobic conditions. Future applications of this workflow to study spatially localized molecular responses to antimicrobials could provide new therapeutic strategies.

虽然金黄色葡萄球菌是生物膜相关感染的主要原因,但这些生物膜内的脂质组学分布尚不清楚。本研究对金黄色葡萄球菌生物膜横截面进行脂质组学作图,以研究水平生物膜层之间的异质性。金黄色葡萄球菌生物膜静态生长,包埋在羧甲基纤维素/明胶混合物中,制备用于下游基质辅助激光解吸/电离成像质谱(MALDI IMS)。捕获离子迁移谱法(TIMS)也应用于质量分析之前。结果TIMS的实施导致检测到的脂质种类增加了约三倍。用甲酸铵(150毫米)洗涤生物膜样品可使某些细菌脂质的信号强度提高10倍,同时对生物膜结构的破坏最小。MALDI TIMS IMS显示,大多数脂质主要定位于单一的生物膜层,而来自同一脂类的物种,如心磷脂CL(57:0) - CL(66:0)显示出明显不同的定位,在层之间表现出1.5至6.3倍的强度差异(n = 3, p <0.03)。厌氧培养的生物膜内无水平层,脂质分布均匀。结论利用MALDI TIMS IMS对金黄色葡萄球菌生物膜进行高空间分辨率分析,发现水平金黄色葡萄球菌生物膜层之间存在明显的脂质组学异质性,表明各层在分子上是不同的。最后,该工作流程揭示了厌氧条件下生长的生物膜中缺乏层,这可能表明氧气有助于在好氧条件下观察到的异质性。未来应用这一工作流程来研究对抗菌素的空间定位分子反应可以提供新的治疗策略。
{"title":"Imaging mass spectrometry reveals complex lipid distributions across Staphylococcus aureus biofilm layers","authors":"Emilio S. Rivera ,&nbsp;Andy Weiss ,&nbsp;Lukasz G. Migas ,&nbsp;Jeffrey A. Freiberg ,&nbsp;Katerina V. Djambazova ,&nbsp;Elizabeth K. Neumann ,&nbsp;Raf Van de Plas ,&nbsp;Jeffrey M. Spraggins ,&nbsp;Eric P. Skaar ,&nbsp;Richard M. Caprioli","doi":"10.1016/j.jmsacl.2022.09.003","DOIUrl":"https://doi.org/10.1016/j.jmsacl.2022.09.003","url":null,"abstract":"<div><h3>Introduction</h3><p>Although <em>Staphylococcus aureus</em> is the leading cause of biofilm-related infections, the lipidomic distributions within these biofilms is poorly understood. Here, lipidomic mapping of <em>S. aureus</em> biofilm cross-sections was performed to investigate heterogeneity between horizontal biofilm layers.</p></div><div><h3>Methods</h3><p><em>S. aureus</em> biofilms were grown statically, embedded in a mixture of carboxymethylcellulose/gelatin, and prepared for downstream matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS). Trapped ion mobility spectrometry (TIMS) was also applied prior to mass analysis.</p></div><div><h3>Results</h3><p>Implementation of TIMS led to a ∼ threefold increase in the number of lipid species detected. Washing biofilm samples with ammonium formate (150 mM) increased signal intensity for some bacterial lipids by as much as tenfold, with minimal disruption of the biofilm structure. MALDI TIMS IMS revealed that most lipids localize primarily to a single biofilm layer, and species from the same lipid class such as cardiolipins CL(57:0) – CL(66:0) display starkly different localizations, exhibiting between 1.5 and 6.3-fold intensity differences between layers (n = 3, p &lt; 0.03). No horizontal layers were observed within biofilms grown anaerobically, and lipids were distributed homogenously.</p></div><div><h3>Conclusions</h3><p>High spatial resolution analysis of <em>S. aureus</em> biofilm cross-sections by MALDI TIMS IMS revealed stark lipidomic heterogeneity between horizontal <em>S. aureus</em> biofilm layers demonstrating that each layer was molecularly distinct. Finally, this workflow uncovered an absence of layers in biofilms grown under anaerobic conditions, possibly indicating that oxygen contributes to the observed heterogeneity under aerobic conditions. Future applications of this workflow to study spatially localized molecular responses to antimicrobials could provide new therapeutic strategies.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":"26 ","pages":"Pages 36-46"},"PeriodicalIF":2.2,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667145X22000372/pdfft?md5=5cfe45d904dd71d41d3a2372d5f7f9aa&pid=1-s2.0-S2667145X22000372-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92006234","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}
引用次数: 2
LC–MS/MS method for simultaneous quantification of ten antibiotics in human plasma for routine therapeutic drug monitoring LC-MS /MS法同时定量人血浆中10种抗生素,用于常规治疗药物监测
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.11.001
Mirjana Radovanovic , Richard O. Day , Graham D.R. Jones , Peter Galettis , Ross L.G. Norris

Background

Optimizing antimicrobial therapy to attain drug exposure that limits the emergence of resistance, effectively treats the infection, and reduces the risk of side effects is of a particular importance in critically ill patients, in whom normal functions are augmented or/and are infected with pathogens less sensitive to treatment. Achievement of these goals can be enhanced by therapeutic drug monitoring (TDM) for many antibiotics. A liquid chromatography tandem mass spectrometry (LC–MS/MS) method is presented here for simultaneous quantification of ten antimicrobials: cefazolin (CZO), cefepime (CEP), cefotaxime (CTA), ceftazidime (CTZ), ciprofloxacin (CIP), flucloxacillin (FLU), linezolid (LIN), meropenem (MER), piperacillin (PIP) and tazobactam (TAZ) in human plasma.

Methods

Plasma samples were precipitated with acetonitrile and injected into the LC–MS/MS. Chromatographic separation was on a Waters Acquity BEH C18 column. Compounds were eluted with water and acetonitrile containing 0.1 % formic acid, using a gradient (0.5–65 % B), in 3.8 min. The flow rate was 0.4 mL/min, and the run time was 5.8 min.

Results

The calibration curves were linear across the tested concentration ranges (0.5–250, CZO, CEP, CTA, CTZ and FLU; 0.2–100, MER and TAZ; 0.1–50, CIP and LIN and 1–500 mg/L, PIP). The intra and inter-day imprecision was < 11 %. Accuracy ranged from 95 to 114 %. CTZ and MER showed ionization suppression while CIP showed ionization enhancement, which was normalized with the use of the internal standard.

Conclusion

An LC–MS/MS method for simultaneous quantification of ten antimicrobials in human plasma was developed for routine TDM.

优化抗菌药物治疗以达到限制耐药性出现、有效治疗感染并降低副作用风险的药物暴露对危重患者尤其重要,因为这些患者的正常功能得到增强或/并感染了对治疗不太敏感的病原体。这些目标的实现可以通过对许多抗生素进行治疗性药物监测(TDM)来加强。建立了液相色谱串联质谱(LC-MS /MS)同时定量测定人血浆中头孢唑林(CZO)、头孢吡肟(CEP)、头孢噻肟(CTA)、头孢他啶(CTZ)、环丙沙星(CIP)、氟氯西林(FLU)、利奈唑胺(LIN)、美罗培南(MER)、哌拉西林(PIP)和他唑巴坦(TAZ) 10种抗菌剂的方法。方法血浆经乙腈沉淀后,进样于LC-MS /MS中。色谱分离采用Waters Acquity BEH C18色谱柱。用含0.1%甲酸的水和乙腈,梯度洗脱(0.5 ~ 65% B),洗脱时间为3.8 min,流速为0.4 mL/min,运行时间为5.8 min。结果在0.5 ~ 250、CZO、CEP、CTA、CTZ和FLU浓度范围内,标定曲线均呈线性;0.2-100, MER和TAZ;0.1-50, CIP和LIN, 1-500 mg/L, PIP)。日内和日间的不精度为<11%。准确率从95%到114%不等。CTZ和MER表现为电离抑制,而CIP表现为电离增强,并通过使用内标进行归一化。结论建立了同时定量常规TDM患者血浆中10种抗菌药物的LC-MS /MS方法。
{"title":"LC–MS/MS method for simultaneous quantification of ten antibiotics in human plasma for routine therapeutic drug monitoring","authors":"Mirjana Radovanovic ,&nbsp;Richard O. Day ,&nbsp;Graham D.R. Jones ,&nbsp;Peter Galettis ,&nbsp;Ross L.G. Norris","doi":"10.1016/j.jmsacl.2022.11.001","DOIUrl":"10.1016/j.jmsacl.2022.11.001","url":null,"abstract":"<div><h3>Background</h3><p>Optimizing antimicrobial therapy to attain drug exposure that limits the emergence of resistance, effectively treats the infection, and reduces the risk of side effects is of a particular importance in critically ill patients, in whom normal functions are augmented or/and are infected with pathogens less sensitive to treatment. Achievement of these goals can be enhanced by therapeutic drug monitoring (TDM) for many antibiotics. A liquid chromatography tandem mass spectrometry (LC–MS/MS) method is presented here for simultaneous quantification of ten antimicrobials: cefazolin (CZO), cefepime (CEP), cefotaxime (CTA), ceftazidime (CTZ), ciprofloxacin (CIP), flucloxacillin (FLU), linezolid (LIN), meropenem (MER), piperacillin (PIP) and tazobactam (TAZ) in human plasma.</p></div><div><h3>Methods</h3><p>Plasma samples were precipitated with acetonitrile and injected into the LC–MS/MS. Chromatographic separation was on a Waters Acquity BEH C<sub>18</sub> column. Compounds were eluted with water and acetonitrile containing 0.1 % formic acid, using a gradient (0.5–65 % B), in 3.8 min. The flow rate was 0.4 mL/min, and the run time was 5.8 min.</p></div><div><h3>Results</h3><p>The calibration curves were linear across the tested concentration ranges (0.5–250, CZO, CEP, CTA, CTZ and FLU; 0.2–100, MER and TAZ; 0.1–50, CIP and LIN and 1–500 mg/L, PIP). The intra and inter-day imprecision was &lt; 11 %. Accuracy ranged from 95 to 114 %. CTZ and MER showed ionization suppression while CIP showed ionization enhancement, which was normalized with the use of the internal standard.</p></div><div><h3>Conclusion</h3><p>An LC–MS/MS method for simultaneous quantification of ten antimicrobials in human plasma was developed for routine TDM.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":"26 ","pages":"Pages 48-59"},"PeriodicalIF":2.2,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/96/77/main.PMC9756784.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10750302","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}
引用次数: 2
Development and application of a High-Resolution mass spectrometry method for the detection of fentanyl analogs in urine and serum 高分辨率质谱法检测尿液和血清中芬太尼类似物的发展和应用
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.07.005
Yu Zhang , John C. Halifax , Christina Tangsombatvisit , Cassandra Yun , Shaokun Pang , Shirin Hooshfar , Alan H.B. Wu , Kara L. Lynch

Introduction

The use of illicitly manufactured synthetic opioids, specifically fentanyl and its analogs, has escalated exponentially in the United States over the last decade. Due to the targeted nature of drug detection methods in clinical laboratories and the ever-evolving list of synthetic opioids of concern, alternative analytical approaches are needed.

Methods

Using the fentanyl analog screening (FAS) kit produced by the Centers for Disease Control and Prevention (CDC), we developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) synthetic opioid spectral library and data acquisition method using information dependent acquisition of product ion spectra. Chromatographic retention times, limits of detection and matrix effects, in urine and serum, for the synthetic opioids in the FAS kit (n = 150) were established. All urine and serum specimens sent to a clinical toxicology laboratory for comprehensive drug testing in 2019 (n = 856) and 2021 (n = 878) were analyzed with the FAS LC-HRMS library to determine the prevalence of fentanyl analogs and other synthetic opioids, retrospectively (2019) and prospectively (2021).

Results

The limit of detection (LOD) of each opioid ranged from 1 to 10 ng/mL (median, 2.5 ng/mL) in urine and 0.25–2.5 ng/mL (median, 0.5 ng/mL) in serum. Matrix effects ranged from −79 % to 86 % (median, −37 %) for urine, following dilution and direct analysis, and −80 % to 400 % (median, 0 %) for serum, following protein precipitation. The prevalence of fentanyl/fentanyl analogs in serum samples increased slightly from 2019 to 2021 while it remained the same in urine. There were only 2 samples identified that contained a fentanyl analog without the co-occurrence of fentanyl or fentanyl metabolites. Analysis of the established MS/MS spectral library revealed characteristic fragmentation patterns in most fentanyl analogs, which can be used for structure elucidation and drug identification of future analogs.

Conclusions

The LC-HRMS method was capable of detecting fentanyl analogs in routine samples sent for comprehensive drug testing. The method can be adapted to accommodate testing needs for the evolving opioid epidemic.

在过去十年中,非法制造的合成阿片类药物,特别是芬太尼及其类似物的使用在美国呈指数级增长。由于临床实验室药物检测方法的针对性和不断变化的合成阿片类药物清单,需要替代的分析方法。方法利用美国疾病控制与预防中心(CDC)生产的芬太尼类似物筛选(FAS)试剂盒,建立液相色谱-高分辨率质谱(LC-HRMS)合成阿片类药物谱库,并采用信息依赖获取产物离子谱的数据采集方法。建立FAS试剂盒(n = 150)中合成阿片类药物在尿液和血清中的色谱保留时间、检出限和基质效应。采用FAS LC-HRMS文库分析2019年(n = 856)和2021年(n = 878)送往临床毒理学实验室进行综合药物检测的所有尿液和血清样本,回顾性(2019年)和前瞻性(2021年)确定芬太尼类似物和其他合成阿片类药物的流行情况。结果各阿片类药物在尿中的检出限为1 ~ 10 ng/mL(中值为2.5 ng/mL),在血清中的检出限为0.25 ~ 2.5 ng/mL(中值为0.5 ng/mL)。稀释和直接分析后,尿液基质效应为- 79%至86%(中位数,- 37%),蛋白质沉淀后血清基质效应为- 80%至400%(中位数,0%)。从2019年到2021年,血清样本中芬太尼/芬太尼类似物的患病率略有上升,而尿液中芬太尼/芬太尼类似物的患病率保持不变。只有2个样本被确定含有芬太尼类似物,但没有芬太尼或芬太尼代谢物的共存。对建立的MS/MS谱库进行分析,揭示了大多数芬太尼类似物的特征片段模式,可用于未来芬太尼类似物的结构解析和药物鉴定。结论LC-HRMS方法可检出综合药检常规样品中的芬太尼类似物。该方法可以进行调整,以适应不断变化的阿片类药物流行病的检测需求。
{"title":"Development and application of a High-Resolution mass spectrometry method for the detection of fentanyl analogs in urine and serum","authors":"Yu Zhang ,&nbsp;John C. Halifax ,&nbsp;Christina Tangsombatvisit ,&nbsp;Cassandra Yun ,&nbsp;Shaokun Pang ,&nbsp;Shirin Hooshfar ,&nbsp;Alan H.B. Wu ,&nbsp;Kara L. Lynch","doi":"10.1016/j.jmsacl.2022.07.005","DOIUrl":"10.1016/j.jmsacl.2022.07.005","url":null,"abstract":"<div><h3>Introduction</h3><p>The use of illicitly manufactured synthetic opioids, specifically fentanyl and its analogs, has escalated exponentially in the United States over the last decade. Due to the targeted nature of drug detection methods in clinical laboratories and the ever-evolving list of synthetic opioids of concern, alternative analytical approaches are needed.</p></div><div><h3>Methods</h3><p>Using the fentanyl analog screening (FAS) kit produced by the Centers for Disease Control and Prevention (CDC), we developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) synthetic opioid spectral library and data acquisition method using information dependent acquisition of product ion spectra. Chromatographic retention times, limits of detection and matrix effects, in urine and serum, for the synthetic opioids in the FAS kit (n = 150) were established. All urine and serum specimens sent to a clinical toxicology laboratory for comprehensive drug testing in 2019 (n = 856) and 2021 (n = 878) were analyzed with the FAS LC-HRMS library to determine the prevalence of fentanyl analogs and other synthetic opioids, retrospectively (2019) and prospectively (2021).</p></div><div><h3>Results</h3><p>The limit of detection (LOD) of each opioid ranged from 1 to 10 ng/mL (median, 2.5 ng/mL) in urine and 0.25–2.5 ng/mL (median, 0.5 ng/mL) in serum. Matrix effects ranged from −79 % to 86 % (median, −37 %) for urine, following dilution and direct analysis, and −80 % to 400 % (median, 0 %) for serum, following protein precipitation. The prevalence of fentanyl/fentanyl analogs in serum samples increased slightly from 2019 to 2021 while it remained the same in urine. There were only 2 samples identified that contained a fentanyl analog without the co-occurrence of fentanyl or fentanyl metabolites. Analysis of the established MS/MS spectral library revealed characteristic fragmentation patterns in most fentanyl analogs, which can be used for structure elucidation and drug identification of future analogs.</p></div><div><h3>Conclusions</h3><p>The LC-HRMS method was capable of detecting fentanyl analogs in routine samples sent for comprehensive drug testing. The method can be adapted to accommodate testing needs for the evolving opioid epidemic.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":"26 ","pages":"Pages 1-6"},"PeriodicalIF":2.2,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bd/d5/main.PMC9440429.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40352875","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}
引用次数: 7
Corrigendum to “Migration from RIA to LC-MS/MS for aldosterone determination: Implications for clinical practice and determination of plasma and urine reference range intervals in a cohort of healthy Belgian subjects” [Clin. Mass Spectrom. 9 (2018) 7–17] 从RIA到LC-MS/MS测定醛固酮的迁移:对比利时健康受试者队列的临床实践和血浆和尿液参考范围区间测定的影响[临床。质谱,9 (2018)7-17]
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.10.001
Caroline M. Le Goff , Ana Gonzalez-Antuña , Stéphanie D. Peeters , Neus Fabregat-Cabello , Jessica G. Van Der Gugten , Laurent Vroonen , Hans Pottel , Daniel T. Holmes , Etienne Cavalier
{"title":"Corrigendum to “Migration from RIA to LC-MS/MS for aldosterone determination: Implications for clinical practice and determination of plasma and urine reference range intervals in a cohort of healthy Belgian subjects” [Clin. Mass Spectrom. 9 (2018) 7–17]","authors":"Caroline M. Le Goff ,&nbsp;Ana Gonzalez-Antuña ,&nbsp;Stéphanie D. Peeters ,&nbsp;Neus Fabregat-Cabello ,&nbsp;Jessica G. Van Der Gugten ,&nbsp;Laurent Vroonen ,&nbsp;Hans Pottel ,&nbsp;Daniel T. Holmes ,&nbsp;Etienne Cavalier","doi":"10.1016/j.jmsacl.2022.10.001","DOIUrl":"10.1016/j.jmsacl.2022.10.001","url":null,"abstract":"","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":"26 ","pages":"Page 47"},"PeriodicalIF":2.2,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bd/aa/main.PMC9619187.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40464119","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}
引用次数: 0
Corrigendum to “Observation of a positive interference in LC-MS/MS measurement of d6-25-OH-vitamin D3” [Clin. Mass Spectrom. 3 (2017) 22–24] “观察LC-MS/MS测量d6-25- oh -维生素D3的正干扰”的勘误表[临床]。质谱,3 (2017)22-24 [j]
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.002
Danielle Fortuna , Warren R. Korn , Matthew J. Brune , Xiang He , Alexandre Y. Wang , John M. Hevko , Douglas F. Stickle
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引用次数: 0
期刊
Journal of Mass Spectrometry and Advances in the Clinical Lab
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