Pub Date : 2025-03-01Epub Date: 2024-12-20DOI: 10.1016/j.jmro.2024.100183
Lisa M. Fries , Denis Moll , Ruhuai Mei , Theresa L․ K․ Hune , Josef Elsaßer , Stefan Glöggler
Magnetic Resonance Imaging (MRI) is a valuable non-invasive technique widely used in clinical diagnostics; however, its sensitivity is limited, posing challenges in various medical conditions. Hyperpolarization techniques represent a promising approach to dramatically enhance signals in magnetic resonance imaging (MRI) and allow the use endogenous metabolites as contrast media. In this study, we synthesized N-acetyl-alanine ethyl ester as a novel imaging agent and assessed its in vivo imaging capabilities, potentially offering diagnostic and monitoring capabilities for cardiovascular diseases. It is derived from N-acetyl-alanine, an endogenous metabolic end product of protein degradation. The in vivo experiments resulted in high-resolution images of the circulatory system acquired within sub-seconds. Our findings not only highlight the potential preclinical utility of this new, generally available agent, but also advance the frontier of hyperpolarized contrast agents.
{"title":"Assessing a hyperpolarized [1-13C]-labeled alanine derivative enhanced via parahydrogen for in vivo studies","authors":"Lisa M. Fries , Denis Moll , Ruhuai Mei , Theresa L․ K․ Hune , Josef Elsaßer , Stefan Glöggler","doi":"10.1016/j.jmro.2024.100183","DOIUrl":"10.1016/j.jmro.2024.100183","url":null,"abstract":"<div><div>Magnetic Resonance Imaging (MRI) is a valuable non-invasive technique widely used in clinical diagnostics; however, its sensitivity is limited, posing challenges in various medical conditions. Hyperpolarization techniques represent a promising approach to dramatically enhance signals in magnetic resonance imaging (MRI) and allow the use endogenous metabolites as contrast media. In this study, we synthesized N-acetyl-alanine ethyl ester as a novel imaging agent and assessed its <em>in vivo</em> imaging capabilities, potentially offering diagnostic and monitoring capabilities for cardiovascular diseases. It is derived from N-acetyl-alanine, an endogenous metabolic end product of protein degradation. The <em>in vivo</em> experiments resulted in high-resolution images of the circulatory system acquired within sub-seconds. Our findings not only highlight the potential preclinical utility of this new, generally available agent, but also advance the frontier of hyperpolarized contrast agents.</div></div>","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"22 ","pages":"Article 100183"},"PeriodicalIF":2.624,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143164181","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}
Pub Date : 2025-03-01Epub Date: 2025-01-20DOI: 10.1016/j.jmro.2025.100186
Haoyu Li , Yifan Song , Yu Yin , Juntao Xia , Yun Chen , Maria Grazia Concilio , Xueqian Kong
The phenomenon of intermolecular multiple-quantum coherences (iMQCs) has been known for decades, mainly for spin-1/2 nuclei. However, the iMQC of 23Na, a spin-3/2 quadrupolar nucleus, has not been studied previously. In this communication, we report the observation of 23Na iMQC signals arising from 23Na–23Na long-range dipolar interaction in the aqueous solutions of various sodium salts. We investigated the iMQC signal in response to different experimental parameters. We also formulated a theoretical model to explain the experimental results. Since sodium ions play important roles in biology and industry, 23Na iMQC experiments could bring new insights into ion dynamics and interactions in solutions.
{"title":"23Na intermolecular multiple-quantum coherences in salt solutions","authors":"Haoyu Li , Yifan Song , Yu Yin , Juntao Xia , Yun Chen , Maria Grazia Concilio , Xueqian Kong","doi":"10.1016/j.jmro.2025.100186","DOIUrl":"10.1016/j.jmro.2025.100186","url":null,"abstract":"<div><div>The phenomenon of intermolecular multiple-quantum coherences (iMQCs) has been known for decades, mainly for spin-1/2 nuclei. However, the iMQC of <sup>23</sup>Na, a spin-3/2 quadrupolar nucleus, has not been studied previously. In this communication, we report the observation of <sup>23</sup>Na iMQC signals arising from <sup>23</sup>Na–<sup>23</sup>Na long-range dipolar interaction in the aqueous solutions of various sodium salts. We investigated the iMQC signal in response to different experimental parameters. We also formulated a theoretical model to explain the experimental results. Since sodium ions play important roles in biology and industry, <sup>23</sup>Na iMQC experiments could bring new insights into ion dynamics and interactions in solutions.</div></div>","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"22 ","pages":"Article 100186"},"PeriodicalIF":2.624,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387344","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}
Pub Date : 2025-03-01Epub Date: 2025-02-10DOI: 10.1016/j.jmro.2025.100188
Dihong Fu , Xiaoyun Guo , Bo Duan , Bin Xia
Staphylococcus aureus infections have long been a significant challenge to public health, particularly due to the emergence of multiple drug-resistant strains. SarA is a critical global regulator in S. aureus which binds to AT-rich sequences in the promoter regions of various genes, but the DNA-binding mechanism of SarA remains unclear. Here, we determined the solution structures of a monomeric DNA binding domain of SarA (SarAΔN19) and its complex with an AT-rich double-stranded DNA. The winged helix domain of SarAΔN19 binds to DNA in a classic way, with the α4 helix binding to the major groove of DNA, while the L5 loop binding to the minor groove, covering 10 AT base pairs. Residues L53, P65, and V68 of the α4 helix have hydrophobic interactions with thymine bases and sugar rings. The side chains of Arg90 and Arg84 from the wing are inserted into the minor groove, forming hydrogen bonds with A/T bases. Multiple positively charged or hydrophilic residues, including Lys54, Lys63, Lys69, Lys72, Lys82, and Gln64, interact with the phosphate groups on the DNA backbones. This complex structure provides an in-depth understanding of the molecular mechanism for SarA to bind DNA, and a better structure basis for future anti-bacterial drug design targeting SarA.
{"title":"DNA Binding Mechanism of The Virulence Regulator SarA in Staphylococcus aureus","authors":"Dihong Fu , Xiaoyun Guo , Bo Duan , Bin Xia","doi":"10.1016/j.jmro.2025.100188","DOIUrl":"10.1016/j.jmro.2025.100188","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> infections have long been a significant challenge to public health, particularly due to the emergence of multiple drug-resistant strains. SarA is a critical global regulator in <em>S. aureus</em> which binds to AT-rich sequences in the promoter regions of various genes, but the DNA-binding mechanism of SarA remains unclear. Here, we determined the solution structures of a monomeric DNA binding domain of SarA (SarA<sup>ΔN19</sup>) and its complex with an AT-rich double-stranded DNA. The winged helix domain of SarA<sup>ΔN19</sup> binds to DNA in a classic way, with the α4 helix binding to the major groove of DNA, while the L5 loop binding to the minor groove, covering 10 AT base pairs. Residues L53, P65, and V68 of the α4 helix have hydrophobic interactions with thymine bases and sugar rings. The side chains of Arg90 and Arg84 from the wing are inserted into the minor groove, forming hydrogen bonds with A/T bases. Multiple positively charged or hydrophilic residues, including Lys54, Lys63, Lys69, Lys72, Lys82, and Gln64, interact with the phosphate groups on the DNA backbones. This complex structure provides an in-depth understanding of the molecular mechanism for SarA to bind DNA, and a better structure basis for future anti-bacterial drug design targeting SarA.</div></div>","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"22 ","pages":"Article 100188"},"PeriodicalIF":2.624,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422621","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}
Pub Date : 2025-03-01Epub Date: 2025-01-15DOI: 10.1016/j.jmro.2025.100185
Lucio Frydman , Jeffrey A. Reimer
{"title":"Tribute to Alexander Pines (1945-2024)","authors":"Lucio Frydman , Jeffrey A. Reimer","doi":"10.1016/j.jmro.2025.100185","DOIUrl":"10.1016/j.jmro.2025.100185","url":null,"abstract":"","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"22 ","pages":"Article 100185"},"PeriodicalIF":2.624,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520486","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}
The observation of half-integer quadrupolar nuclei, which represent 66 % of the NMR-active isotopes, is essential to understand the atomic-level structure of inorganic materials near the surfaces with applications in the field of catalysis, biomaterials and optoelectronics. For that purpose, we have recently introduced an efficient technique, which combines the sensitivity gain provided by indirect DNP (dynamic nuclear polarization) under MAS (magic-angle spinning) and the high resolution obtained by refocusing the second-order quadrupolar interaction (H. Nagashima et al., J. Phys. Chem. Lett. 15 (2024) 4858). This technique combines (i) a D-RINEPT (dipolar-mediated refocused INEPT) transfer, (ii) an MQMAS (multiple-quantum MAS) filter, and (iii) a QCPMG (quadrupolar Carr-Purcell Meiboom-Gill) detection. We explain the design of several variants of this pulse sequence and notably the selection of the coherence transfer pathways. In particular, the amplitudes of the coherence transfer pathways through the ±3Q coherence orders of the quadrupolar isotope can be equalized using a train of π-pulses selective of the central transition, instead of a z-filter. This equalization method has the advantage to limit the length of the phase cycles and to enhance slightly the signal intensity. Moreover, for spin-3/2 nuclei subject to moderate or large quadrupolar interactions, more efficient excitation and conversion of 3Q coherences are achieved using cosine-modulated long-pulses (cos-lp), instead of fast-amplitude-modulated (FAM) pulses. The performances of the different D-RINEPT-MQMAS-QCPMG variants are compared through the observation of 35Cl and 27Al isotopes without DNP in l-histidine hydrochloride and isopropylamine-templated microporous aluminophosphate (ipa-AlPO4–14), respectively, as well as the acquisition of DNP-enhanced high-resolution spectra of 11B and 17O nuclei near the surface of partially oxidized boron nitride supported on dendritic and fibrous nanosilica and γ-alumina enriched in 17O isotope using a slurrying approach. The spectra recorded for γ-alumina show that the slurrying method produces less disorder than grinding assisted by 17O-enriched water.
{"title":"MQMAS spectra of half-integer quadrupolar nuclei enhanced by indirect DNP","authors":"Hiroki Nagashima , Julien Trébosc , Olivier Lafon , Jean-Paul Amoureux","doi":"10.1016/j.jmro.2024.100177","DOIUrl":"10.1016/j.jmro.2024.100177","url":null,"abstract":"<div><div>The observation of half-integer quadrupolar nuclei, which represent 66 % of the NMR-active isotopes, is essential to understand the atomic-level structure of inorganic materials near the surfaces with applications in the field of catalysis, biomaterials and optoelectronics. For that purpose, we have recently introduced an efficient technique, which combines the sensitivity gain provided by indirect DNP (dynamic nuclear polarization) under MAS (magic-angle spinning) and the high resolution obtained by refocusing the second-order quadrupolar interaction (H. Nagashima et al.<em>, J. Phys. Chem. Lett.</em> 15 (2024) 4858). This technique combines (i) a <em>D</em>-RINEPT (dipolar-mediated refocused INEPT) transfer, (ii) an MQMAS (multiple-quantum MAS) filter, and (iii) a QCPMG (quadrupolar Carr-Purcell Meiboom-Gill) detection. We explain the design of several variants of this pulse sequence and notably the selection of the coherence transfer pathways. In particular, the amplitudes of the coherence transfer pathways through the ±3Q coherence orders of the quadrupolar isotope can be equalized using a train of π-pulses selective of the central transition, instead of a z-filter. This equalization method has the advantage to limit the length of the phase cycles and to enhance slightly the signal intensity. Moreover, for spin-3/2 nuclei subject to moderate or large quadrupolar interactions, more efficient excitation and conversion of 3Q coherences are achieved using cosine-modulated long-pulses (cos-lp), instead of fast-amplitude-modulated (FAM) pulses. The performances of the different <em>D</em>-RINEPT-MQMAS-QCPMG variants are compared through the observation of <sup>35</sup>Cl and <sup>27</sup>Al isotopes without DNP in <span>l</span>-histidine hydrochloride and isopropylamine-templated microporous aluminophosphate (ipa-AlPO<sub>4</sub>–14), respectively, as well as the acquisition of DNP-enhanced high-resolution spectra of <sup>11</sup>B and <sup>17</sup>O nuclei near the surface of partially oxidized boron nitride supported on dendritic and fibrous nanosilica and γ-alumina enriched in <sup>17</sup>O isotope using a slurrying approach. The spectra recorded for γ-alumina show that the slurrying method produces less disorder than grinding assisted by <sup>17</sup>O-enriched water.</div></div>","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"21 ","pages":"Article 100177"},"PeriodicalIF":2.624,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142722642","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}
Pub Date : 2024-12-01Epub Date: 2024-11-08DOI: 10.1016/j.jmro.2024.100170
Ruud L.E.G. Aspers, Marco Tessari
2D NMR zero-quantum spectroscopy offers a robust and convenient way to resolve hydride resonances in non-hydrogenative ParaHydrogen Induced Polarization experiments. This approach has been recently applied to the detection and quantification of dilute components in biofluids and natural extracts. For certain classes of analytes, however, modulation of the zero-quantum coherence occurs at several kiloHertz frequency, which determines long measurement times for attaining the desired resolution in the indirect dimension. Here, we propose an alternative 2D approach to measure high-resolution NMR spectra that affords enhanced sensitivity and reduced experimental time for optimal sample throughput.
{"title":"Improved 2D hydride detection for NMR-chemosensing via p‐H2 Hyperpolarization","authors":"Ruud L.E.G. Aspers, Marco Tessari","doi":"10.1016/j.jmro.2024.100170","DOIUrl":"10.1016/j.jmro.2024.100170","url":null,"abstract":"<div><div>2D NMR zero-quantum spectroscopy offers a robust and convenient way to resolve hydride resonances in non-hydrogenative ParaHydrogen Induced Polarization experiments. This approach has been recently applied to the detection and quantification of dilute components in biofluids and natural extracts. For certain classes of analytes, however, modulation of the zero-quantum coherence occurs at several kiloHertz frequency, which determines long measurement times for attaining the desired resolution in the indirect dimension. Here, we propose an alternative 2D approach to measure high-resolution NMR spectra that affords enhanced sensitivity and reduced experimental time for optimal sample throughput.</div></div>","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"21 ","pages":"Article 100170"},"PeriodicalIF":2.624,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142653621","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}
Pub Date : 2024-12-01Epub Date: 2024-09-11DOI: 10.1016/j.jmro.2024.100165
Ivan de Kouchkovsky , Hao Nguyen , Hsin-Yu Chen , Xiaoxi Liu , Hecong Qin , Bradley A. Stohr , Romelyn Delos Santos , Michael A. Ohliger , Zhen Jane Wang , Robert A. Bok , Jeremy W. Gordon , Peder E.Z. Larson , Mary Frost , Kimberly Okamoto , Daniel Gebrezgiabhier , Matthew Cooperberg , Daniel B. Vigneron , John Kurhanewicz , Rahul Aggarwal
<div><h3>Background</h3><p>Although multiparametric (mp) <sup>1</sup>H magnetic resonance imaging (MRI) is increasingly used to detect and localize prostate cancer (PC), its correlation with tumor grade is limited. Hyperpolarized (HP) carbon-13 (<sup>13</sup>C) MR is an emerging imaging technique, which can be used to interrogate key biologic processes through in vivo detection of various HP probes. A distinct attribute of HP <sup>13</sup>C MRI is the ability to detect multiple HP probes within a single acquisition. Here we report on the first simultaneous dual HP [1-<sup>13</sup>C]pyruvate and [<sup>13</sup>C]urea MRI with correlations to histopathologic findings in a patient with localized PC scheduled for radical prostatectomy.</p></div><div><h3>Material and methods</h3><p>Paired HP <sup>13</sup>C and standard mp <sup>1</sup>H MRI were performed in a patient with biopsy-proven Gleason score 4 + 3 = 7 adenocarcinoma of the prostate scheduled for radical prostatectomy through a first-in-human pilot study of dual-agent HP MRI (NCT02526368). HP <sup>13</sup>C MRI was performed using a clinical 3T scanner with <sup>13</sup>C transmit-and-receive capabilities. Dynamic series of HP <sup>13</sup>C pyruvate, lactate and urea imaging were acquired following intravenous (IV) injection of co-hyperpolarized [<sup>13</sup>C]urea (25 mM) and [1–<sup>13</sup>C]pyruvate (125 mM). The [1-<sup>13</sup>C]pyruvate-to-[1-<sup>13</sup>C]lactate conversion rate (k<sub>PL</sub>) was calculated using an inputless two-site exchange model; AUC<sub>urea</sub> was the [<sup>13</sup>C]urea signal summed over time. Following radical prostatectomy, whole-mount prostate histopathological slides were prepared and reviewed by an experienced genitourinary pathologist.</p></div><div><h3>Results</h3><p>Following informed consent, the patient underwent paired mp <sup>1</sup>H MRI and dual-agent HP MRI. mp <sup>1</sup>H MRI revealed a 1.2 cm lesion in the left apical posterior zone. Dual-agent HP MRI identified a focus of increased [1-<sup>13</sup>C]pyruvate-to-[1-<sup>13</sup>C]lactate conversion rate (k<sub>PL</sub>) extending from the left apical posterior peripheral zone to the right gland. A corresponding area of abnormal tissue perfusion (AUC<sub>urea</sub>) was seen in the left gland. Metabolism-perfusion mismatch (with several foci of increased <em>k<sub>PL</sub></em>/AUC<sub>urea</sub>) was observed throughout the tumor. Tumor extension to the right midgland was confirmed at the time of radical prostatectomy and staining for lactate dehydrogenase-A was increased throughout the tumor relative to surrounding benign prostatic tissue.</p></div><div><h3>Conclusion</h3><p>This first-in-human radiopathologic study demonstrates the feasibility of dual-agent HP MRI in PC patients. Simultaneous assessment of tumor metabolism and perfusion was able to detect occult disease as well as to show a significant mismatch between intra-tumoral metabolism and tissue perfusion in high-grade PC.
背景虽然多参数（mp）1H 磁共振成像（MRI）越来越多地用于检测和定位前列腺癌（PC），但其与肿瘤分级的相关性有限。超极化（HP）碳-13（13C）磁共振成像是一种新兴的成像技术，可通过在体内检测各种 HP 探针来探查关键的生物过程。HP 13C MRI 的一个显著特点是能在一次采集中检测多个 HP 探针。在此，我们报告了首次同时进行的双 HP [1-13C] 丙酮酸和 [13C] 尿素 MRI 与组织病理学检查结果的相关性，该患者患有局部 PC，计划进行根治性前列腺切除术。材料和方法通过首次在人体中进行的双试剂 HP MRI 试验研究（NCT02526368），对一名经活检证实 Gleason 评分为 4 + 3 = 7 的前列腺腺癌患者进行了成对 HP 13C 和标准 mp 1H MRI。HP 13C MRI 是使用具有 13C 发射和接收功能的临床 3T 扫描仪进行的。在静脉注射共超极化[13C]尿素（25 mM）和[1-13C]丙酮酸（125 mM）后，采集了一系列动态的 HP 13C 丙酮酸、乳酸和尿素成像。[1-13C]丙酮酸到[1-13C]乳酸的转化率（kPL）是通过无输入的双位点交换模型计算得出的；AUCurea是[13C]尿素信号在一段时间内的总和。根治性前列腺切除术后，由经验丰富的泌尿生殖系统病理学家制备并审查整张前列腺组织病理切片。结果在知情同意后，患者接受了成对的 mp 1H MRI 和双试剂 HP MRI 检查。双剂 HP MRI 发现一个[1-13C]丙酮酸-[1-13C]乳酸转化率（kPL）升高的病灶，从左侧心尖后外周区延伸至右侧腺体。左侧腺体出现了相应的组织灌注异常区域（AUCurea）。整个肿瘤都出现了代谢-灌注不匹配现象（有几个 kPL/AUCurea 增高的病灶）。根治性前列腺切除术时证实肿瘤扩展到了右侧腺体中部，与周围良性前列腺组织相比，整个肿瘤的乳酸脱氢酶-A染色增加。同时评估肿瘤的代谢和灌注能够检测出隐匿性疾病，并显示高级别 PC 中肿瘤内代谢和组织灌注之间存在明显的不匹配。有必要对这些发现进行前瞻性验证。
{"title":"Dual hyperpolarized [1-13C]pyruvate and [13C]urea magnetic resonance imaging of prostate cancer","authors":"Ivan de Kouchkovsky , Hao Nguyen , Hsin-Yu Chen , Xiaoxi Liu , Hecong Qin , Bradley A. Stohr , Romelyn Delos Santos , Michael A. Ohliger , Zhen Jane Wang , Robert A. Bok , Jeremy W. Gordon , Peder E.Z. Larson , Mary Frost , Kimberly Okamoto , Daniel Gebrezgiabhier , Matthew Cooperberg , Daniel B. Vigneron , John Kurhanewicz , Rahul Aggarwal","doi":"10.1016/j.jmro.2024.100165","DOIUrl":"10.1016/j.jmro.2024.100165","url":null,"abstract":"<div><h3>Background</h3><p>Although multiparametric (mp) <sup>1</sup>H magnetic resonance imaging (MRI) is increasingly used to detect and localize prostate cancer (PC), its correlation with tumor grade is limited. Hyperpolarized (HP) carbon-13 (<sup>13</sup>C) MR is an emerging imaging technique, which can be used to interrogate key biologic processes through in vivo detection of various HP probes. A distinct attribute of HP <sup>13</sup>C MRI is the ability to detect multiple HP probes within a single acquisition. Here we report on the first simultaneous dual HP [1-<sup>13</sup>C]pyruvate and [<sup>13</sup>C]urea MRI with correlations to histopathologic findings in a patient with localized PC scheduled for radical prostatectomy.</p></div><div><h3>Material and methods</h3><p>Paired HP <sup>13</sup>C and standard mp <sup>1</sup>H MRI were performed in a patient with biopsy-proven Gleason score 4 + 3 = 7 adenocarcinoma of the prostate scheduled for radical prostatectomy through a first-in-human pilot study of dual-agent HP MRI (NCT02526368). HP <sup>13</sup>C MRI was performed using a clinical 3T scanner with <sup>13</sup>C transmit-and-receive capabilities. Dynamic series of HP <sup>13</sup>C pyruvate, lactate and urea imaging were acquired following intravenous (IV) injection of co-hyperpolarized [<sup>13</sup>C]urea (25 mM) and [1–<sup>13</sup>C]pyruvate (125 mM). The [1-<sup>13</sup>C]pyruvate-to-[1-<sup>13</sup>C]lactate conversion rate (k<sub>PL</sub>) was calculated using an inputless two-site exchange model; AUC<sub>urea</sub> was the [<sup>13</sup>C]urea signal summed over time. Following radical prostatectomy, whole-mount prostate histopathological slides were prepared and reviewed by an experienced genitourinary pathologist.</p></div><div><h3>Results</h3><p>Following informed consent, the patient underwent paired mp <sup>1</sup>H MRI and dual-agent HP MRI. mp <sup>1</sup>H MRI revealed a 1.2 cm lesion in the left apical posterior zone. Dual-agent HP MRI identified a focus of increased [1-<sup>13</sup>C]pyruvate-to-[1-<sup>13</sup>C]lactate conversion rate (k<sub>PL</sub>) extending from the left apical posterior peripheral zone to the right gland. A corresponding area of abnormal tissue perfusion (AUC<sub>urea</sub>) was seen in the left gland. Metabolism-perfusion mismatch (with several foci of increased <em>k<sub>PL</sub></em>/AUC<sub>urea</sub>) was observed throughout the tumor. Tumor extension to the right midgland was confirmed at the time of radical prostatectomy and staining for lactate dehydrogenase-A was increased throughout the tumor relative to surrounding benign prostatic tissue.</p></div><div><h3>Conclusion</h3><p>This first-in-human radiopathologic study demonstrates the feasibility of dual-agent HP MRI in PC patients. Simultaneous assessment of tumor metabolism and perfusion was able to detect occult disease as well as to show a significant mismatch between intra-tumoral metabolism and tissue perfusion in high-grade PC. ","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"21 ","pages":"Article 100165"},"PeriodicalIF":2.624,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666441024000207/pdfft?md5=7b66657cb74e70c1242c4491d6fa3a40&pid=1-s2.0-S2666441024000207-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232386","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}
Pub Date : 2024-12-01Epub Date: 2024-09-02DOI: 10.1016/j.jmro.2024.100160
Alex van der Ham
Liquid-state Overhauser Dynamic Nuclear Polarization (ODNP) is an emerging technique, aimed at shortening NMR experiment times. It achieves this by increasing the otherwise poor nuclear polarization at room temperature, by polarization transfer from excited electron spins. The present work explores two ideas, aimed at achieving the optimal signal-to-noise per time unit for a given system, and quantitation of spectra showing a large disparity in ODNP enhancements at high magnetic fields (≥ 9.4 T). Both of these ideas are predicated on, perhaps counterintuitively, not allowing full dynamic nuclear polarization to build up, either by rapid rf pulsing, or gating of the microwave irradiation.
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Pub Date : 2024-12-01Epub Date: 2024-10-28DOI: 10.1016/j.jmro.2024.100171
Nele Reimets, Kerti Ausmees, Indrek Reile
Non-hydrogenative PHIP (nh-PHIP) is an NMR signal enhancement technique that offers several orders of magnitude gains in detection sensitivity. It is one of the few hyperpolarization methods that have been demonstrated to be applicable to chemical analysis of biological samples and potentially metabolomics. It is, however, a chemoselective method and needs to be tuned to particular analyte and metabolite classes at a time.
Herein, we present a systematic study where we apply four nh-PHIP modifications to urine samples from two different species – human and dog. Firstly, this allows to explore the whole analyte class scope and present what information is nh-PHIP capable of providing by varying the composition of the nh-PHIP catalyst system and the sample preparation protocol. Secondly, comparing hyperpolarized spectra from urines from different species demonstrates that this hyperpolarization technique is robust and tolerant of possibly considerable matrix differences: signals of the same metabolites appear at same chemical shifts from urines that differ from one-another much more than is likely in a realistic metabolomics study. Thereby we propose the idea that nh-PHIP is ready for application in metabolomics experiments.
{"title":"Current state of the art of analyte scope in urine metabolome analysis by non-hydrogenative PHIP","authors":"Nele Reimets, Kerti Ausmees, Indrek Reile","doi":"10.1016/j.jmro.2024.100171","DOIUrl":"10.1016/j.jmro.2024.100171","url":null,"abstract":"<div><div>Non-hydrogenative PHIP (nh-PHIP) is an NMR signal enhancement technique that offers several orders of magnitude gains in detection sensitivity. It is one of the few hyperpolarization methods that have been demonstrated to be applicable to chemical analysis of biological samples and potentially metabolomics. It is, however, a chemoselective method and needs to be tuned to particular analyte and metabolite classes at a time.</div><div>Herein, we present a systematic study where we apply four nh-PHIP modifications to urine samples from two different species – human and dog. Firstly, this allows to explore the whole analyte class scope and present what information is nh-PHIP capable of providing by varying the composition of the nh-PHIP catalyst system and the sample preparation protocol. Secondly, comparing hyperpolarized spectra from urines from different species demonstrates that this hyperpolarization technique is robust and tolerant of possibly considerable matrix differences: signals of the same metabolites appear at same chemical shifts from urines that differ from one-another much more than is likely in a realistic metabolomics study. Thereby we propose the idea that nh-PHIP is ready for application in metabolomics experiments.</div></div>","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"21 ","pages":"Article 100171"},"PeriodicalIF":2.624,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587184","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}
Pub Date : 2024-12-01Epub Date: 2024-09-18DOI: 10.1016/j.jmro.2024.100161
Thomas Biedenbänder , Aryana Rodgers , Mirjam Schröder , Liliya Vugmeyster , Björn Corzilius
Molecular dynamics of functional groups contain valuable information about structural properties and functional activities in biomolecules. NMR spectroscopy is a sensitive tool for the investigation of molecular dynamics over a wide range of timescales and thus may deepen the understanding of the biomolecules of interest. Here, we present an approach to use DNP-enhanced 2H NMR to study dynamics of selectively deuterated methyl groups in insoluble proteins such as amyloid beta (Aβ) fibrils. We adopted and optimized the matrix-free DNP approach by varying the amount of added polarizing agent as well as the rehydration level of model proteins. We show that the DNP enhancement obtained in 1H–2H cross-polarization (CP) MAS spectra may increase the sensitivity for selectively deuterated Aβ fibril samples by more than one order of magnitude, accelerating the collection of spin-lattice relaxation data in the DNP-accessible temperature range between 100 and 150 K by up to 400-fold. However, below the coalescence temperature, which describes the transition from the fast to the slow exchange regime, the experimentally obtained relaxation time constants suffer from a paramagnetic relaxation enhancement effect due to the presence of the polarizing agent. This seems to be a general effect for biomolecules as it is also confirmed for two other protein model systems. Our demonstration opens the possibility to extend the scope of 2H NMR for dynamics measurements to effective concentrations and/or temperatures below what is currently accessible; however, the observed interplay between paramagnetic relaxation and molecular dynamics also emphasizes the necessity for a better understanding of relaxation effects in DNP-enhanced NMR.
{"title":"Investigation of biomolecular dynamics by sensitivity-enhanced 1H–2H CPMAS NMR using matrix-free dynamic nuclear polarization","authors":"Thomas Biedenbänder , Aryana Rodgers , Mirjam Schröder , Liliya Vugmeyster , Björn Corzilius","doi":"10.1016/j.jmro.2024.100161","DOIUrl":"10.1016/j.jmro.2024.100161","url":null,"abstract":"<div><div>Molecular dynamics of functional groups contain valuable information about structural properties and functional activities in biomolecules. NMR spectroscopy is a sensitive tool for the investigation of molecular dynamics over a wide range of timescales and thus may deepen the understanding of the biomolecules of interest. Here, we present an approach to use DNP-enhanced <sup>2</sup>H NMR to study dynamics of selectively deuterated methyl groups in insoluble proteins such as amyloid beta (Aβ) fibrils. We adopted and optimized the matrix-free DNP approach by varying the amount of added polarizing agent as well as the rehydration level of model proteins. We show that the DNP enhancement obtained in <sup>1</sup>H–<sup>2</sup>H cross-polarization (CP) MAS spectra may increase the sensitivity for selectively deuterated Aβ fibril samples by more than one order of magnitude, accelerating the collection of spin-lattice relaxation data in the DNP-accessible temperature range between 100 and 150 K by up to 400-fold. However, below the coalescence temperature, which describes the transition from the fast to the slow exchange regime, the experimentally obtained relaxation time constants suffer from a paramagnetic relaxation enhancement effect due to the presence of the polarizing agent. This seems to be a general effect for biomolecules as it is also confirmed for two other protein model systems. Our demonstration opens the possibility to extend the scope of <sup>2</sup>H NMR for dynamics measurements to effective concentrations and/or temperatures below what is currently accessible; however, the observed interplay between paramagnetic relaxation and molecular dynamics also emphasizes the necessity for a better understanding of relaxation effects in DNP-enhanced NMR.</div></div>","PeriodicalId":365,"journal":{"name":"Journal of Magnetic Resonance Open","volume":"21 ","pages":"Article 100161"},"PeriodicalIF":2.624,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320067","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}
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