Blood-based biomarker amplification using high intensity focused ultrasound (HIFU

使用高强度聚焦超声 (HIFU) 进行基于血液的生物标志物扩增

• 批准号: 9116839
• 负责人: Tatiana Khokhlova
• 金额: $ 14.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116839
• 关键词: Ablation; Acoustics; Acute; Affect; Animal Model; Animals; Area; Articular Range of Motion; Award; Benign; Benign Prostatic Hypertrophy; Biopsy; Biotechnology; Blood; Blood Circulation; Blood flow; Blood specimen; Cancer Patient; Cardiac; Cells; Clinic; Collaborations; Cytolysis; Detection; Development; Devices; Diagnosis; Dimensions; Disease; Doctor of Philosophy; Elderly man; Engineering; Environment; Explosion; Extracellular Space; Failure; Focused Ultrasound Therapy; Fred Hutchinson Cancer Research Center; Frequencies; Furuncles; Gel; Goals; Heat-Shock Response; Heating; Heterogeneity; Histocompatibility Testing; Hour; Human; Infection; Internal Medicine; K-Series Research Career Programs; Laboratories; Lead; Length; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Mechanics; Medical; Medical Technology; Medicine; Mentors; Methods; MicroRNAs; Microbiology; Monitor; Morbidity - disease rate; Motion; Nature; Outcome; Output; Pancreas; Patients; Pediatric Hospitals; Physics; Physiologic pulse; Plasma; Procedures; Prostate; Prostate-Specific Antigen; Protocols documentation; Public Health; Reporting; Research; Research Personnel; Risk; Sampling; Scheme; Scientist; Serum; Shock; Source; Techniques; Technology; Temperature; Testing; Time; Tissue Sample; Tissues; Translating; Tumor Tissue; Ultrasonic Therapy; Ultrasonography; Ultrasound, High-Intensity Focused, Transrectal; Universities; Washington; Water; Work; absorption; base; blood-based biomarker; cancer classification; cancer diagnosis; clinical application; clinically relevant; cost; design; heat injury; improved; in vivo; in vivo Model; individual patient; interest; medical schools; millisecond; novel; novel therapeutics; prostate biopsy; rectal; respiratory; screening; therapy design; tool; tumor

DESCRIPTION (provided by applicant): Benign prostate hyperplasia (BPH) and prostate cancer are very common prostate conditions in elderly men, and current non-invasive screening tools, e.g., Prostate Specific Antigen (PSA) tests, often fail to differentiate between the two. Ths failure leads to extensive use of prostate biopsies to obtain tissue samples for histological examination. Not only is this procedure uncomfortable, unpleasant and prone to complications, the rate of false negatives is high due to the multifocal nature of prostate cancer. Development of reliable blood-based biomarkers for prostate cancer would eliminate the need for invasive biopsies, but still remains an unmet challenge. Recently a class of small regulatory RNAs - micro-RNAs - has shown great promise as a blood-based biomarker for prostate cancer diagnosis and prognostication. However, according to the studies reported to date, the sensitivity of this technique is too low to be clinically relevant. High intensity focused ultrasoud (HIFU) therapy is a non-invasive ablation method, in which ultrasound energy from an extracorporeal or trans-rectal source can be focused within the body to induce thermal denaturation of tissue at the focus without affecting surrounding tissues. A novel type of HIFU exposure designed for inducing purely mechanical erosion of tissue, viz., histotripsy, was recently proposed. This type of exposure utilizes highly nonlinear short HIFU pulses to induce localized boiling at the focus in as fast as a few milliseconds. Erosive damage to tissue is produced by the explosion of the resulting boiling bubble and its interaction with the HIFU field. The ultimate goal of this proposal is to use HIFU for localized targeted lysis of selected areas of the prostate that will lead to the release of cell contents into the extracellular space and increae the concentration of tissue-specific micro-RNAs in the circulation. Thus, the sensitivity of micro-RNA-based tests for diagnosis of prostate conditions will be significantly enhanced. This combined technique may thus be termed "non-invasive biopsy". The Specific Aims of this proposal are: 1) characterize high amplitude, nonlinear acoustic outputs of the HIFU sources relevant to trans-rectal applications, 2) observe the erosive effect produced by HIFU in transparent tissue-mimicking gel phantoms and 3) ex-vivo tissue with different pulsing protocols, 4) optimize and apply HIFU exposures causing localized tissue lysis in a small animal tumor model in-vivo and 5) determine if the concentration of tumor-specific micro-RNAs in the circulation is enhanced following HIFU- induced localized tumor lysis in a small animal model. The long-term research goal of the candidate applying for this Career Development Award (Tatiana Khokhlova, PhD) is to optimize this non-invasive biopsy technique, transform the corresponding HIFU device to work trans-rectally, and translate the concept into a clinically useful approach to perform non-invasive biopsy of the prostate. The research environment at the University of Washington that includes experts in medical ultrasound (Applied Physics Laboratory, Center for Industrial and Medical Ultrasound), microbiology (Fred Hutchinson Cancer Research Center) and medicine (School of Medicine) is perfect for achieving this goal. Dr. Khokhlova is an ultrasound physicist and engineer, and has worked extensively in the field of medical applications of ultrasound technology. This interdisciplinary background enables Dr. Khokhlova to successfully collaborate with both clinicians and scientists. Dr. Khokhlova plans to pursue research in novel therapeutic ultrasound technologies, to continue current collaborations with the Fred Hutchinson Cancer Research Center and Children's Hospital, and thus be connected with both scientists and clinicians and facilitate more rapid transfer of the exciting new developments in medical ultrasound directly into the clinic. The primary reason for applying for this Award is to permit Dr. Khokhlova to gain further expertise in biotechnology and internal medicine and to develop into an independent investigator while being mentored by three highly successful researchers, Drs. Joo Ha Hwang, Lawrence Crum, and Muneesh Tewari.

描述（由申请人提供）：良性前列腺增生（BPH）和前列腺癌是老年男性中非常常见的前列腺条件，当前的非侵入性筛查工具，例如前列腺特异性抗原（PSA）测试，通常无法区分两者。该失败导致广泛使用前列腺活检以获取组织学检查的组织样品。由于前列腺癌的多灶性性质，这种过程不仅不舒服，不愉快且容易发生并发症，而且假阴性率很高。开发可靠的血液生物标志物用于前列腺癌将消除对侵入性活检的需求，但仍然是一个尚未得到挑战。最近，一类小型调节性RNA -Micro -RNA-作为前列腺癌诊断和预后的血液生物标志物表现出了巨大的希望。但是，根据迄今为止报道的研究，该技术的敏感性太低，无法在临床上相关。高强度聚焦Ultrasoud（HIFU）治疗是一种非侵入性消融方法，其中可以将来自体外或直肠源的超声波能量集中在体内，以在不影响周围组织的情况下诱导聚焦的组织热变性。最近提出了一种新型的HIFU暴露，旨在诱导组织纯机械侵蚀，即组织疗法。这种类型的暴露利用高度非线性的短HIFU脉冲来诱导局部沸腾的焦点，并在几毫秒内快速地诱导焦点。产生的沸腾气泡的爆炸及其与HIFU场的相互作用产生了对组织的侵蚀性损害。该提案的最终目的是将HIFU用于局部针对的目标裂解 将细胞含量释放到细胞外空间并增加循环中组织特异性微RNA的浓度的前列腺。因此，基于微RNA的测试对诊断前列腺疾病的敏感性将显着增强。因此，这种组合技术可以称为“非侵入性活检”。 The Specific Aims of this proposal are: 1) characterize high amplitude, nonlinear acoustic outputs of the HIFU sources relevant to trans-rectal applications, 2) observe the erosive effect produced by HIFU in transparent tissue-mimicking gel phantoms and 3) ex-vivo tissue with different pulsing protocols, 4) optimize and apply HIFU exposures causing localized tissue lysis in a small animal tumor模型在体内和5）确定在小动物模型中HIFU诱导的局部肿瘤裂解后，循环中肿瘤特异性微RNA的浓度是否得到增强。申请该职业发展奖（Tatiana Khokhlova，PhD）的候选人的长期研究目标是优化这种非侵入性活检技术，将相应的HIFU设备转换为跨直体工作，并将概念转化为临床上有用的方法来对前列腺进行无效的生物疗法。华盛顿大学的研究环境包括医学超声专家（应用物理实验室，工业和医疗超声中心），微生物学（Fred Hutchinson Cancer Research Center）和医学（医学院）非常适​​合实现这一目标。 Khokhlova博士是一位超声物理学家和工程师，并在超声技术的医疗应用领域进行了广泛的工作。这种跨学科背景使Khokhlova博士能够与临床医生和科学家成功合作。 Khokhlova博士计划在新型治疗超声技术方面进行研究，以继续与Fred Hutchinson Cancer Research Center和Children Hospital进行当前的合作，从而与科学家和临床医生保持联系，并促进更快地转移到医疗超量量直接进入诊所中令人兴奋的新事态发展。申请该奖项的主要原因是允许Khokhlova博士获得生物技术和内科医学方面的进一步专业知识，并在由三位非常成功的研究人员DRS的指导下发展成为独立的研究人员。 Joo Ha Hwang，Lawrence Crum和Muneesh Tewari。

项目成果

Endoscopic high-intensity focused US: technical aspects and studies in an in vivo porcine model (with video).

• DOI: 10.1016/j.gie.2014.12.019
• 发表时间: 2015-05
• 期刊: GASTROINTESTINAL ENDOSCOPY
• 影响因子: 7.7
• 作者: Li, Tong;Khokhlova, Tatiana;Maloney, Ezekiel;Wang, Yak-Nam;D'Andrea, Samantha;Starr, Frank;Farr, Navid;Morrison, Kyle;Keilman, George;Hwang, Joo Ha
• 通讯作者: Hwang, Joo Ha

Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer.

• DOI: 10.1158/0008-5472.can-15-0296
• 发表时间: 2015-09-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Li T;Wang YN;Khokhlova TD;D'Andrea S;Starr F;Chen H;McCune JS;Risler LJ;Mashadi-Hossein A;Hingorani SR;Chang A;Hwang JH
• 通讯作者: Hwang JH

A new active cavitation mapping technique for pulsed HIFU applications--bubble Doppler.

• DOI: 10.1109/tuffc.2014.006502
• 发表时间: 2014-10
• 期刊: IEEE transactions on ultrasonics, ferroelectrics, and frequency control
• 作者: Li T;Khokhlova TD;Sapozhnikov OA;O'Donnell M;Hwang JH
• 通讯作者: Hwang JH

Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors.

• DOI: 10.1016/j.ultrasmedbio.2014.01.007
• 发表时间: 2014-07
• 期刊: ULTRASOUND IN MEDICINE AND BIOLOGY
• 影响因子: 2.9
• 作者: Li, Tong;Chen, Hong;Khokhlova, Tatiana;Wang, Yak-Nam;Kreider, Wayne;He, Xuemei;Hwang, Joo Ha
• 通讯作者: Hwang, Joo Ha