Prognostic biomarkers for respiratory failure post hematopoietic cell transplantation

造血细胞移植后呼吸衰竭的预后生物标志物

• 批准号: 10688031
• 负责人: Courtney Rowan
• 金额: $ 18.04万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688031
• 关键词: Acute Respiratory Distress Syndrome; Acute respiratory failure; Adult; Allogenic; Appearance; Award; Biological; Biological Assay; Biological Markers; Blood Tests; Bone Marrow Transplantation; Caring; Child; Clinical; Clinical Research; Clinical Trials; Complication; Critical Illness; Data; Development; Development Plans; Diagnostic; Disease; Distress; Early Intervention; Early identification; Etiology; Event; Foundations; Funding; Future; Genetic Diseases; Goals; Hematological Disease; Hospitalization; Idiopathic pneumonia syndrome; Incidence; Indiana; Interleukin-6; Intubation; Kinetics; Knowledge; Life; Lung; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Medical; Mentors; Mentorship; Metabolic Diseases; Methods; Modeling; Monitor; Multicenter Studies; Non-Malignant; Pathway interactions; Patients; Phase; Plasma; Population; Positioning Attribute; Prevention; Prognosis; Prognostic Marker; Prospective Studies; Proteins; Proteomics; Research; Respiratory Failure; Respiratory Signs and Symptoms; Risk; Sampling; Statistical Methods; Supportive care; TNFRSF1A gene; Testing; Time; Training; Translating; Translational Research; Transplant Recipients; United States National Institutes of Health; Universities; Validation; Work; biomarker development; biomarker panel; biomarker validation; candidate marker; career; career development; clinical biomarkers; clinical practice; cohort; design; experience; hematopoietic cell transplantation; high risk; implementation science; improved; innovation; interest; medical schools; mortality; novel; novel strategies; novel therapeutics; pediatric patients; personalized medicine; power analysis; preemptive intervention; prevent; prognostic; prognostic model; prognostic value; prospective; receptor; research study; skills; tandem mass spectrometry; targeted treatment

PROJECT SUMMARY While hematopoietic cell transplantation (HCT) is a life-saving therapy for previously fatal malignant and nonmalignant conditions, pulmonary complications such as respiratory failure (RF) remain a barrier. Currently there is no objective way to determine risk of developing RF, thereby limiting opportunities for early intervention and prevention. We have identified 3 biomarkers, including stimulation 2 (ST2, the IL-33 receptor), interleukin 6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), which hold extreme promise for prognosis of future occurrence of RF when measured as early as day 7 post HCT, well before typical onset of clinical respiratory symptoms. Furthermore, we have conducted the two phases of proteomic discovery using mass spectrometry and have identified 11 additional candidate biomarkers, in addition to ST2, to validate in an independent cohort. Therefore, we hypothesize that prognostic biomarkers can serve as an early warning for the HCT recipient at increased risk for RF. In Aim 1, we propose to investigate the effect of dynamic changes of validated biomarkers at days 0, 7, 14, and 21 post-HCT on prognosis for RF. We will then, in Aim 2, validate additional diagnostic and prognostic candidate biomarkers for RF discovered through our proteomics pipeline. Finally, in Aim 3, we will conduct a prospective real-time multicenter study to determine RF prognostic biomarkers thresholds for enabling a biomarker-based preemptive trial In addition to elucidating biologic etiologies of RF that could lead to improved targeted therapies, this work will lay the foundation for a biomarker-based preemptive clinical trial aimed to reduce RF and RF-related mortality post-HCT. During the award period, I will conduct research at Indiana University School of Medicine under the primary mentorship of Dr. Sophie Paczesny and the remainder of the co-mentors, advisors and collaborators outlined in the career development plan. I will focus on gaining critical skills in translational research needed to successfully compete for NIH-funding and launch an independent research career. Specifically, I will develop a comprehensive knowledge of clinical biomarker development, proteomic discovery using mass spectrometry, advanced statistical methods to approach biomarker research including prognostic modeling, and skills in implementation science to be able to translate these discoveries into clinical practice. With expertise in acute respiratory failure post-HCT, experience leading multicenter collaborative clinical research studies in this population, and a strong team of mentors and advisors, I am uniquely positioned to successfully complete the proposed study and transition to an independent research career.

项目摘要 虽然造血细胞移植（HCT）是一种挽救生命的治疗先前致命的恶性和 在非恶性疾病中，肺部并发症如呼吸衰竭（RF）仍然是一个障碍。目前 没有客观的方法来确定发生RF的风险，从而限制了早期干预的机会 和预防我们已经确定了3个生物标志物，包括刺激2（ST 2，IL-33受体），白细胞介素6 （IL-6）和肿瘤坏死因子受体1（TNFR 1），这对未来的预后有着极大的希望。 当早在HCT后第7天测量时，RF的发生早于临床呼吸系统疾病的典型发作。 症状此外，我们已经进行了两个阶段的蛋白质组发现使用质谱 并且除了ST 2之外，已经确定了11个额外的候选生物标志物，以在独立的队列中进行验证。 因此，我们假设预后生物标志物可以作为HCT接受者的早期警告， 增加RF风险。在目标1中，我们建议研究经验证的生物标志物的动态变化的影响 HCT后第0、7、14和21天对RF预后的影响。然后，我们将在目标2中验证其他诊断和 通过我们的蛋白质组学管道发现了RF的预后候选生物标志物。在目标3中，我们将 进行一项前瞻性实时多中心研究，以确定RF预后生物标志物阈值，以实现 一项基于生物标志物的抢先试验除了阐明RF的生物学病因外， 靶向治疗，这项工作将奠定基础的生物标志物为基础的先发制人的临床试验，旨在 降低HCT后RF和RF相关死亡率。 在获奖期间，我将在印第安纳州大学医学院进行研究， Sophie Paczesny博士和其他共同导师，顾问和合作者的主要指导 在职业发展计划中。我将专注于获得必要的转化研究的关键技能， 成功竞争NIH资金，并开始独立的研究生涯。具体来说，我将开发一个 临床生物标志物开发的全面知识，使用质谱的蛋白质组学发现， 先进的统计方法，以接近生物标志物的研究，包括预后建模，和技能， 实施科学能够将这些发现转化为临床实践。在急性 HCT后呼吸衰竭，经验领先的多中心合作临床研究， 人口，以及强大的导师和顾问团队，我处于独特的地位，能够成功完成 建议学习并过渡到独立的研究生涯。

项目成果

Veno-Venous Extracorporeal Membrane Oxygenation for Children With Cancer or Hematopoietic Cell Transplant: A Ten Center Cohort.

• DOI: 10.1097/mat.0000000000001336
• 发表时间: 2021-08-01
• 期刊: ASAIO journal (American Society for Artificial Internal Organs : 1992)
• 作者: Bridges BC;Kilbaugh TJ;Barbaro RP;Bembea MM;Chima RS;Potera RM;Rosner EA;Sandhu HS;Slaven JE;Tarquinio KM;Cheifetz IM;Rowan CM;Friedman ML;Pediatric ECMO (Pediecmo) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and the Extracorporeal Life Support Organization (ELSO)
• 通讯作者: Pediatric ECMO (Pediecmo) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and the Extracorporeal Life Support Organization (ELSO)

The association of postoperative dexmedetomidine with pain, opiate utilization, and hospital length of stay in children post-Chiari malformation decompression.

• DOI: 10.3171/2021.10.peds21291
• 发表时间: 2022-03-01
• 期刊: JOURNAL OF NEUROSURGERY-PEDIATRICS
• 影响因子: 1.9
• 作者: Cater, Daniel T.;Rogerson, Colin M.;Hobson, Michael J.;Ackerman, Laurie L.;Rowan, Courtney M.
• 通讯作者: Rowan, Courtney M.

Vascular thrombosis after pediatric liver transplantation: Is prevention achievable?

小儿肝移植后血管血栓：可以预防吗？

• DOI: 10.1016/j.liver.2023.100185
• 发表时间: 2023
• 期刊: Journal of liver transplantation
• 作者: Martinez,Mercedes;Kang,Elise;Beltramo,Fernando;Nares,Michael;Jeyapalan,Asumthia;Alcamo,Alicia;Monde,Alexandra;Ridall,Leslie;Kamath,Sameer;Betters,Kristina;Rowan,Courtney;Mangus,RichardShane;Kaushik,Shubhi;Zinter,Matt;Resch,Jo
• 通讯作者: Resch,Jo

Immunocompromised-Associated Pediatric Acute Respiratory Distress Syndrome: Experience From the 2016/2017 Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Prospective Cohort Study.

免疫功能低下相关的小儿急性呼吸窘迫综合征：2016/2017 年小儿急性呼吸窘迫综合征发病率和流行病学前瞻性队列研究的经验。

• DOI: 10.1097/pcc.0000000000003421
• 发表时间: 2024
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
• 作者: Gertz,ShiraJ;Bhalla,Anoopindar;Chima,RanjitS;Emeriaud,Guillaume;Fitzgerald,JulieC;Hsing,DeyinD;Jeyapalan,AsumthiaS;Pike,Francis;Sallee,ColinJ;Thomas,NealJ;Yehya,Nadir;Rowan,CourtneyM;PediatricAcuteRespiratoryDistressSyn
• 通讯作者: PediatricAcuteRespiratoryDistressSyn

Extracorporeal membrane oxygenation in children receiving haematopoietic cell transplantation and immune effector cell therapy: an international and multidisciplinary consensus statement.

• DOI: 10.1016/s2352-4642(21)00336-9
• 发表时间: 2022-03
• 期刊: LANCET CHILD & ADOLESCENT HEALTH
• 影响因子: 36.4
• 作者: Di Nardo, Matteo;Ahmad, Ali H.;Merli, Pietro;Zinter, Matthew S.;Lehman, Leslie E.;Rowan, Courtney M.;Steiner, Marie E.;Hingorani, Sangeeta;Angelo, Joseph R.;Abdel-Azim, Hisham;Khazal, Sajad J.;Shoberu, Basirat;McArthur, Jennifer;Bajwa, Rajinder;Ghafoor, Saad;Shah, Samir H.;Sandhu, Hitesh;Moody, Karen;Brown, Brandon D.;Mireles, Maria E.;Steppan, Diana;Olson, Taylor;Raman, Lakshmi;Bridges, Brian;Duncan, Christine N.;Choi, Sung Won;Swinford, Rita;Paden, Matt;Fortenberry, James D.;Peek, Giles;Tissieres, Pierre;De Luca, Daniele;Locatelli, Franco;Corbacioglu, Selim;Kneyber, Martin;Franceschini, Alessio;Nadel, Simon;Kumpf, Matthias;Loreti, Alessandra;Wosten-Van Asperen, Roelie;Gawronski, Orsola;Brierley, Joe;MacLaren, Graeme;Mahadeo, Kris M.
• 通讯作者: Mahadeo, Kris M.