James B Mitchell | PubFacts

Publications by authors named "James B Mitchell"

222 Publications

Real-Time insight into in vivo redox status utilizing hyperpolarized [1-C] N-acetyl cysteine.

Authors:
Kazutoshi Yamamoto Ana Opina Deepak Sail Burchelle Blackman Keita Saito Jeffrey R Brender Ronja M Malinowski Tomohiro Seki Nobu Oshima Daniel R Crooks Shun Kishimoto Yu Saida Yasunori Otowa Peter L Choyke Jan H Ardenkjær-Larsen James B Mitchell W Marston Linehan Rolf E Swenson Murali C Krishna

Sci Rep 2021 06 9;11(1):12155. Epub 2021 Jun 9.

Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.
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http://dx.doi.org/10.1038/s41598-021-90921-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190077PMC
June 2021

Radiation-Induced Senescence Reprograms Secretory and Metabolic Pathways in Colon Cancer HCT-116 Cells.

Authors:
Chandrasekharam N Nagineni Sarwat Naz Rajani Choudhuri Gadisetti V R Chandramouli Murali C Krishna Jeffrey R Brender John A Cook James B Mitchell

Int J Mol Sci 2021 May 3;22(9). Epub 2021 May 3.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Understanding the global metabolic changes during the senescence of tumor cells can have implications for developing effective anti-cancer treatment strategies. Ionizing radiation (IR) was used to induce senescence in a human colon cancer cell line HCT-116 to examine secretome and metabolome profiles. Control proliferating and senescent cancer cells (SCC) exhibited distinct morphological differences and expression of senescent markers. Enhanced secretion of pro-inflammatory chemokines and IL-1, anti-inflammatory IL-27, and TGF-β1 was observed in SCC. Significantly reduced levels of VEGF-A indicated anti-angiogenic activities of SCC. Elevated levels of tissue inhibitors of matrix metalloproteinases from SCC support the maintenance of the extracellular matrix. Adenylate and guanylate energy charge levels and redox components NAD and NADP and glutathione were maintained at near optimal levels indicating the viability of SCC. Significant accumulation of pyruvate, lactate, and suppression of the TCA cycle in SCC indicated aerobic glycolysis as the predominant energy source for SCC. Levels of several key amino acids decreased significantly, suggesting augmented utilization for protein synthesis and for use as intermediates for energy metabolism in SCC. These observations may provide a better understanding of cellular senescence basic mechanisms in tumor tissues and provide opportunities to improve cancer treatment.
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http://dx.doi.org/10.3390/ijms22094835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124941PMC
May 2021

Pharmacological Inhibition of HSP90 Radiosensitizes Head and Neck Squamous Cell Carcinoma Xenograft by Inhibition of DNA Damage Repair, Nucleotide Metabolism, and Radiation-Induced Tumor Vasculogenesis.

Authors:
Sarwat Naz Andrew J Leiker Rajani Choudhuri Olivia Preston Anastasia L Sowers Sangeeta Gohain Janet Gamson Askale Mathias Carter Van Waes John A Cook James B Mitchell

Int J Radiat Oncol Biol Phys 2021 08 7;110(5):1295-1305. Epub 2021 Apr 7.

Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Purpose: Recent preclinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and head and neck squamous cell carcinoma (HNSCC). These studies emphasized that AT13387 downregulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity. Metabolomic analysis of HSP90 inhibition by AT13387 was conducted to identify metabolic biomarkers of radiosensitization and whether modulations of key proteins were involved in IR-induced tumor vasculogenesis, a process involved in tumor recurrence.

Methods And Materials: HNSCC and non-small cell lung cancer cell lines were used to evaluate the AT13387 radiosensitization effect in vitro and in vivo. Flow cytometry, immunofluorescence, and immunoblot analysis were used to evaluate cell cycle changes and HSP90 client protein's role in DNA damage repair. Metabolic analysis was performed using liquid chromatography-Mass spectrometry. Immunohistochemical examination of resected tumors post-AT13387 and IR treatment were conducted to identify biomarkers of IR-induced tumor vasculogenesis.

Results: In agreement with recent studies, AT13387 treatment combined with IR resulted in a G2/M cell cycle arrest and inhibited DNA repair. Metabolomic profiling indicated a decrease in key metabolites in glycolysis and tricarboxylic acid cycle by AT13387, a reduction in Adenosine 5'-triphosphate levels, and rate-limiting metabolites in nucleotide metabolism, namely phosphoribosyl diphosphate and aspartate. HNSCC xenografts treated with the combination exhibited increased tumor regrowth delay, decreased tumor infiltration of CD45 and CD11b+ bone marrow-derived cells, and inhibition of HIF-1 and SDF-1 expression, thereby inhibiting IR-induced vasculogenesis.

Conclusions: AT13387 treatment resulted in pharmacologic inhibition of cancer cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence postradiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment.
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http://dx.doi.org/10.1016/j.ijrobp.2021.03.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286306PMC
August 2021

Multimodal Molecular Imaging Detects Early Responses to Immune Checkpoint Blockade.

Authors:
Yu Saida Jeffrey R Brender Kazutoshi Yamamoto James B Mitchell Murali C Krishna Shun Kishimoto

Cancer Res 2021 Jul 9;81(13):3693-3705. Epub 2021 Apr 9.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

Immune checkpoint blockade (ICB) has become a standard therapy for several cancers, however, the response to ICB is inconsistent and a method for noninvasive assessment has not been established to date. To investigate the capability of multimodal imaging to evaluate treatment response to ICB therapy, hyperpolarized C MRI using [1-C] pyruvate and [1,4-C2] fumarate and dynamic contrast enhanced (DCE) MRI was evaluated to detect early changes in tumor glycolysis, necrosis, and intratumor perfusion/permeability, respectively. Mouse tumor models served as platforms for high (MC38 colon adenocarcinoma) and low (B16-F10 melanoma) sensitivity to dual ICB of PD-L1 and CTLA4. Glycolytic flux significantly decreased following treatment only in the less sensitive B16-F10 tumors. Imaging [1,4-C2] fumarate conversion to [1,4-C2] malate showed a significant increase in necrotic cell death following treatment in the ICB-sensitive MC38 tumors, with essentially no change in B16-F10 tumors. DCE-MRI showed significantly increased perfusion/permeability in MC38-treated tumors, whereas a similar, but statistically nonsignificant, trend was observed in B16-F10 tumors. When tumor volume was also taken into consideration, each imaging biomarker was linearly correlated with future survival in both models. These results suggest that hyperpolarized C MRI and DCE MRI may serve as useful noninvasive imaging markers to detect early response to ICB therapy. SIGNIFICANCE: Hyperpolarized C MRI and dynamic contrast enhanced MRI in murine tumor models provide useful insight into evaluating early response to immune checkpoint blockade therapy..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277685PMC
July 2021

Multimodal Functional Imaging for Cancer/Tumor Microenvironments Based on MRI, EPRI, and PET.

Authors:
Ken-Ichiro Matsumoto James B Mitchell Murali C Krishna

Molecules 2021 Mar 14;26(6). Epub 2021 Mar 14.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1002, USA.

Radiation therapy is one of the main modalities to treat cancer/tumor. The response to radiation therapy, however, can be influenced by physiological and/or pathological conditions in the target tissues, especially by the low partial oxygen pressure and altered redox status in cancer/tumor tissues. Visualizing such cancer/tumor patho-physiological microenvironment would be a useful not only for planning radiotherapy but also to detect cancer/tumor in an earlier stage. Tumor hypoxia could be sensed by positron emission tomography (PET), electron paramagnetic resonance (EPR) oxygen mapping, and in vivo dynamic nuclear polarization (DNP) MRI. Tissue oxygenation could be visualized on a real-time basis by blood oxygen level dependent (BOLD) and/or tissue oxygen level dependent (TOLD) MRI signal. EPR imaging (EPRI) and/or T-weighted MRI techniques can visualize tissue redox status non-invasively based on paramagnetic and diamagnetic conversions of nitroxyl radical contrast agent. C-DNP MRI can visualize glycometabolism of tumor/cancer tissues. Accurate co-registration of those multimodal images could make mechanisms of drug and/or relation of resulted biological effects clear. A multimodal instrument, such as PET-MRI, may have another possibility to link multiple functions. Functional imaging techniques individually developed to date have been converged on the concept of theranostics.
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http://dx.doi.org/10.3390/molecules26061614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002164PMC
March 2021

Hypoxia-Activated Prodrug Evofosfamide Treatment in Pancreatic Ductal Adenocarcinoma Xenografts Alters the Tumor Redox Status to Potentiate Radiotherapy.

Authors:
Shun Kishimoto Jeffrey R Brender Gadisetti V R Chandramouli Yu Saida Kazutoshi Yamamoto James B Mitchell Murali C Krishna

Antioxid Redox Signal 2021 Oct 15;35(11):904-915. Epub 2020 Sep 15.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

In hypoxic tumor microenvironments, the strongly reducing redox environment reduces evofosfamide (TH-302) to release a cytotoxic bromo-isophosphoramide (Br-IPM) moiety. This drug therefore preferentially attacks hypoxic regions in tumors where other standard anticancer treatments such as chemotherapy and radiation therapy are often ineffective. Various combination therapies with evofosfamide have been proposed and tested in preclinical and clinical settings. However, the treatment effect of evofosfamide monotherapy on tumor hypoxia has not been fully understood, partly due to the lack of quantitative methods to assess tumor pO . Here, we use quantitative pO imaging by electron paramagnetic resonance (EPR) to evaluate the change in tumor hypoxia in response to evofosfamide treatment using two pancreatic ductal adenocarcinoma xenograft models: MIA Paca-2 tumors responding to evofosfamide and Su.86.86 tumors that do not respond. EPR imaging showed that oxygenation improved globally after evofosfamide treatment in hypoxic MIA Paca-2 tumors, in agreement with the results obtained from hypoxia staining by pimonidazole and in apparent contrast to the decrease in K observed in dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). The observation that evofosfamide not only kills the hypoxic region of the tumor but also improves oxygenation in the residual tumor regions provides a rationale for combination therapies using radiation and antiproliferatives post evofosfamide for improved outcomes. This study suggests that reoxygenation after evofosfamide treatment is due to decreased oxygen demand rather than improved perfusion. Following the change in pO after treatment may therefore yield a way of monitoring treatment response. . 35, 904-915.
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http://dx.doi.org/10.1089/ars.2020.8131DOI Listing
October 2021

Pseudocapacitance: From Fundamental Understanding to High Power Energy Storage Materials.

Authors:
Simon Fleischmann James B Mitchell Ruocun Wang Cheng Zhan De-En Jiang Volker Presser Veronica Augustyn

Chem Rev 2020 Jul 28;120(14):6738-6782. Epub 2020 Jun 28.

Department of Materials Science & Engineering, North Carolina State University, Raleigh, North Carolina 27606, United States.

There is an urgent global need for electrochemical energy storage that includes materials that can provide simultaneous high power and high energy density. One strategy to achieve this goal is with pseudocapacitive materials that take advantage of reversible surface or near-surface Faradaic reactions to store charge. This allows them to surpass the capacity limitations of electrical double-layer capacitors and the mass transfer limitations of batteries. The past decade has seen tremendous growth in the understanding of pseudocapacitance as well as materials that exhibit this phenomenon. The purpose of this Review is to examine the fundamental development of the concept of pseudocapacitance and how it came to prominence in electrochemical energy storage as well as to describe new classes of materials whose electrochemical energy storage behavior can be described as pseudocapacitive.
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http://dx.doi.org/10.1021/acs.chemrev.0c00170DOI Listing
July 2020

Radiation-induced Adaptive Response: New Potential for Cancer Treatment.

Authors:
C Norman Coleman Iris Eke Adeola Y Makinde Sunita Chopra Sandra Demaria Silvia C Formenti Shannon Martello Michelle Bylicky James B Mitchell Molykutty J Aryankalayil

Clin Cancer Res 2020 11 17;26(22):5781-5790. Epub 2020 Jun 17.

Radiation Oncology Branch and Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Radiotherapy is highly effective due to its ability to physically focus the treatment to target the tumor while sparing normal tissue and its ability to be combined with systemic therapy. This systemic therapy can be utilized before radiotherapy as an adjuvant or induction treatment, during radiotherapy as a radiation "sensitizer," or following radiotherapy as a part of combined modality therapy. As part of a unique concept of using radiation as "focused biology," we investigated how tumors and normal tissues adapt to clinically relevant multifraction (MF) and single-dose (SD) radiation to observe whether the adaptations can induce susceptibility to cell killing by available drugs or by immune enhancement. We identified an adaptation occurring after MF (3 × 2 Gy) that induced cell killing when AKT-mTOR inhibitors were delivered following cessation of radiotherapy. In addition, we identified inducible changes in integrin expression 2 months following cessation of radiotherapy that differ between MF (1 Gy × 10) and SD (10 Gy) that remain targetable compared with preradiotherapy. Adaptation is reflected across different "omics" studies, and thus the range of possible molecular targets is not only broad but also time, dose, and schedule dependent. While much remains to be studied about the radiation adaptive response, radiation should be characterized by its molecular perturbations in addition to physical dose. Consideration of the adaptive effects should result in the design of a tailored radiotherapy treatment plan that accounts for specific molecular changes to be targeted as part of precision multimodality cancer treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669567PMC
November 2020

Molecular Imaging of the Tumor Microenvironment Reveals the Relationship between Tumor Oxygenation, Glucose Uptake, and Glycolysis in Pancreatic Ductal Adenocarcinoma.

Authors:
Kazutoshi Yamamoto Jeffrey R Brender Tomohiro Seki Shun Kishimoto Nobu Oshima Rajani Choudhuri Stephen S Adler Elaine M Jagoda Keita Saito Nallathamby Devasahayam Peter L Choyke James B Mitchell Murali C Krishna

Cancer Res 2020 06 3;80(11):2087-2093. Epub 2020 Apr 3.

Radiation Biology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Molecular imaging approaches for metabolic and physiologic imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiologic and metabolic aspects of tumors is not fully understood. Here, we developed new hyperpolarized MRI and electron paramagnetic resonance imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiologic and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between F-FDG-PET and lactate production, while pO was inversely related to lactate production and F-2-fluoro-2-deoxy-D-glucose (F-FDG) uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging. F-FDG uptake negatively correlated with pO in the center of the tumor and positively correlated with pO on the periphery. In contrast to pO and F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. SIGNIFICANCE: Novel multimodal molecular imaging techniques reveal the potential of three interrelated imaging biomarkers to profile the tumor microenvironment and interrelationships of hypoxia, glucose uptake, and glycolysis.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272278PMC
June 2020

Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.

Authors:
Nobu Oshima Ryo Ishida Shun Kishimoto Kristin Beebe Jeffrey R Brender Kazutoshi Yamamoto Daniel Urban Ganesha Rai Michelle S Johnson Gloria Benavides Giuseppe L Squadrito Dan Crooks Joseph Jackson Abhinav Joshi Bryan T Mott Jonathan H Shrimp Michael A Moses Min-Jung Lee Akira Yuno Tobie D Lee Xin Hu Tamara Anderson Donna Kusewitt Helen H Hathaway Ajit Jadhav Didier Picard Jane B Trepel James B Mitchell Gordon M Stott William Moore

Cell Rep 2020 02;30(6):1798-1810.e4

Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, MD 24060, USA.

The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo.
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http://dx.doi.org/10.1016/j.celrep.2020.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039685PMC
February 2020

Eli J. Glatstein: Inspiring and Provoking Critical Thinking.

Authors:
C Norman Coleman James B Mitchell Stephen M Hahn W Gillies McKenna

Radiat Res 2020 04 30;193(4):318-321. Epub 2020 Jan 30.

Department of Oxford Institute for Radiation Oncology, Oxford, United Kingdom.

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http://dx.doi.org/10.1667/RR00EG.1DOI Listing
April 2020

Proteasome inhibition disrupts the metabolism of fumarate hydratase- deficient tumors by downregulating p62 and c-Myc.

Authors:
Carole Sourbier Christopher J Ricketts Pei-Jyun Liao Shingo Matsumoto Darmood Wei Martin Lang Reema Railkar Youfeng Yang Ming-Hui Wei Piyush Agarwal Murali Krishna James B Mitchell Jane B Trepel Len Neckers W Marston Linehan

Sci Rep 2019 12 5;9(1):18409. Epub 2019 Dec 5.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is characterized by germline mutations of the FH gene that encodes for the TCA cycle enzyme, fumarate hydratase. HLRCC patients are at risk for the development of an aggressive form of type 2 papillary renal cell carcinoma. By studying the mechanism of action of marizomib, a proteasome inhibitor able to cross the blood-brain barrier, we found that it modulates the metabolism of HLRCC cells. Marizomib decreased glycolysis in vitro and in vivo by downregulating p62 and c-Myc. C-Myc downregulation decreased the expression of lactate dehydrogenase A, the enzyme catalyzing the conversion of pyruvate to lactate. In addition, proteasomal inhibition lowered the expression of the glutaminases GLS and GLS2, which support glutamine metabolism and the maintenance of the redox balance. Thus, in HLRCC cells, proteasome inhibition disrupts glucose and glutamine metabolism, restricting nutrients and lowering the cells' anti-oxidant response capacity. Although the cytotoxicity induced by proteasome inhibitors is complex, the understanding of their metabolic effects in HLRCC may lead to the development of effective therapeutic strategies or to the development of markers of efficacy.
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http://dx.doi.org/10.1038/s41598-019-55003-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895110PMC
December 2019

Abemaciclib: A multi-functional radiation modifier.

Authors:
Sarwat Naz John A Cook James B Mitchell

Oncotarget 2019 Feb 8;10(12):1230-1232. Epub 2019 Feb 8.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

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http://dx.doi.org/10.18632/oncotarget.26652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383816PMC
February 2019

Rationale for hypoxia assessment and amelioration for precision therapy and immunotherapy studies.

Authors:
Mark W Dewhirst Yvonne M Mowery James B Mitchell Murali K Cherukuri Timothy W Secomb

J Clin Invest 2019 02 7;129(2):489-491. Epub 2019 Jan 7.

Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, USA.

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http://dx.doi.org/10.1172/JCI126044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355230PMC
February 2019

Imaging Metabolic Processes to Predict Radiation Responses.

Authors:
Sarwat Naz Shun Kishimoto James B Mitchell Murali C Krishna

Semin Radiat Oncol 2019 01;29(1):81-89

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.

The aberrant vasculature in the tumor microenvironment creates hypoxic zones, poor perfusion, and high interstitial fluid pressure. Also, the tumor cell metabolic phenotype utilizes the aerobic glycolytic pathways for energy source and generation of cell mass. These physiologic and metabolic phenotypes in solid tumors are amenable for molecular imaging techniques to extract imaging biomarkers such as pO and enzyme kinetics reflecting glycolysis. The imaging biomarkers have value in diagnostic and prognostic purposes. Additionally, they can be used to guide choices for tailored treatment regimens. Electron paramagnetic resonance imaging for pO imaging and C magnetic resonance imaging with hyperpolarized C probes such as C-labeled pyruvate have shown significant potential in characterizing the tumor microenvironment physiologically and metabolically.
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http://dx.doi.org/10.1016/j.semradonc.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333210PMC
January 2019

Synthesis and evaluation of C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized C-MRI.

Authors:
Keita Saito Deepak Sail Kazutoshi Yamamoto Shingo Matsumoto Burchelle Blackman Shun Kishimoto Jeffrey R Brender Rolf E Swenson James B Mitchell Murali C Krishna

Free Radic Biol Med 2019 02 22;131:18-26. Epub 2018 Nov 22.

Radiation Biology Branch, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Effective means to identify the role of reactive oxygen species (ROS) mediating several diseases including cancer, ischemic heart disease, stroke, Alzheimer's and other inflammatory conditions in in vivo models would be useful. The cyclic nitrone 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) is a spin trap frequently used to detect free radicals in vitro using Electron Paramagnetic Resonance (EPR) spectroscopy. In this study, we synthesized C-labeled DMPO for hyperpolarization by dynamic nuclear polarization, in which C NMR signal increases more than 10,000-fold. This allows in vivo C MRI to investigate the feasibility of in vivo ROS detection by the C-MRI. DMPO was C-labeled at C5 position, and deuterated to prolong the T relaxation time. The overall yield achieved for 5-C-DMPO-d was 15%. Hyperpolarized 5-C-DMPO-d provided a single peak at 76 ppm in the C-spectrum, and the T was 60 s in phosphate buffer making it optimal for in vivo C MRI. The buffered solution of hyperpolarized 5-C-DMPO-d was injected into a mouse placed in a 3 T scanner, and C-spectra were acquired every 1 s. In vivo studies showed the signal of 5-C-DMPO-d was detected in the mouse, and the T decay of C signal of hyperpolarized 5-C-DMPO-d was 29 s. C-chemical shift imaging revealed that 5-C-DMPO-d was distributed throughout the body in a minute after the intravenous injection. A strong signal of 5-C-DMPO-d was detected in heart/lung and kidney, whereas the signal in liver was small compared to other organs. The results indicate hyperpolarized 5-C-DMPO-d provided sufficient C signal to be detected in the mouse in several organs, and can be used to detect ROS in vivo.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983923PMC
February 2019

Effects of oxygen challenging to tissue redox and pO status.

Authors:
Ken-Ichiro Matsumoto James B Mitchell Murali C Krishna

Free Radic Biol Med 2019 01 2;130:343-347. Epub 2018 Nov 2.

Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1002, USA.

Nitroxide free radicals can serve as redox-sensitive MRI contrast agents useful to image the redox status of tissue of interest. In this study, the effect of oxygen content in the inspired gas on the kinetics of metabolism of three nitroxides has been evaluated in the muscle and tumor in mice. SCC tumors (approximate size of 1.0 cm) on the right hind leg of female C3H/Hen MTV mice were prepared. Three nitroxides, 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP), 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP), and 4-hydroxy-tetramethylpiperidine-N-oxyl (TEMPOL), having different lipophilicities were compared using MR redox imaging. T-mapping of the tissues was obtained using a multi-slice multi-echo (MSME) sequence with several TRs. The three nitroxides showed differences in accumulation and metabolism/clearance in muscle and tumor. The cell impermeable nitroxide CxP displayed kinetic patterns of slow enhancement followed by a slow decline typical of clearance rather than metabolism. The cell permeable CmP on the other hand showed a relatively faster uptake and metabolism with a modestly higher rate of metabolism in the tumor than muscle. The TEMPOL on the other hand displayed a rapid uptake and reduction with a trend of significantly rapid decay rate in tumor tissue, while slightly higher maximum signal intensity and slower decay rate was observed in normal muscle. The reduction rate of TEMPOL in the tumor was significantly enhanced when the breathing gas had 100%-oxygen while it was not significantly different in the muscle. EPR oximetry studies monitoring the oxygen dependent linewidth of TEMPOL showed that the pO in the healthy tissue during carbogen breathing significantly increased normal tissue pO compared to air breathing whereas breathing 100%-oxygen made normal tissue slight hypoxic. Since TEMPOL is a radioprotector, our studies show that a combination of 100%-oxygen breathing and TEMPOL has a potential to enhance radioprotective effects to normal tissue.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.10.454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202967PMC
January 2019

A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response.

Authors:
Yoichi Takakusagi Sarwat Naz Kaori Takakusagi Masahiro Ishima Hiroshi Murata Keisuke Ohta Masahiko Miura Fumio Sugawara Kengo Sakaguchi Shun Kishimoto Jeeva P Munasinghe James B Mitchell Murali C Krishna

Cancer Res 2018 12 9;78(24):6828-6837. Epub 2018 Oct 9.

Radiation Biology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

: Hypoxic zones in solid tumors contribute to radioresistance, and pharmacologic agents that increase tumor oxygenation prior to radiation, including antiangiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of α-sulfoquinovosylacyl-1,3-propanediol (SQAP or CG-0321; a synthetic derivative of an antiangiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO), oxyhemoglobin saturation (sO), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. Five days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 minutes prior to irradiation significantly delayed growth of tumor xenografts. Three days of daily treatment improved tumor oxygenation and decreased tumor microvascular density on T2*-weighted images with USPIO, suggesting vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO, sO, and Gd-DTPA contrast-enhanced imaging. SQAP treatment improved perfusion and tumor pO (ΔpO: 3.1 ± 1.0 mmHg) and was accompanied by decreased sO (20%-30% decrease) in SCCVII implants 20-30 minutes after SQAP administration. These results provide evidence that SQAP transiently enhanced tumor oxygenation by facilitating oxygen dissociation from oxyhemoglobin and improving tumor perfusion. Therefore, SQAP-mediated sensitization to radiation can be attributed to increased tumor oxygenation. SIGNIFICANCE: A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127870PMC
December 2018

Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation.

Authors:
Masayuki Matsuo Tatsuya Kawai Shun Kishimoto Keita Saito Jeeva Munasinghe Nallathamby Devasahayam James B Mitchell Murali C Krishna

Oncotarget 2018 May 18;9(38):25089-25100. Epub 2018 May 18.

Radiation Biology Branch, Center for Cancer research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

To examine the relationship between local oxygen partial pressure and energy metabolism in the tumor, electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) with hyperpolarized [1-C] pyruvate were performed. SCCVII and HT29 solid tumors implanted in the mouse leg were imaged by EPRI using OX063, a paramagnetic probe and C-MRI using hyperpolarized [1-C] pyruvate. Local partial oxygen pressure and pyruvate metabolism in the two tumor implants were examined. The effect of a single dose of 5-Gy irradiation on the pO and metabolism was also investigated by sequential imaging of EPRI and C-MRI in HT29 tumors. A phantom study using tubes filled with different concentration of [1-C] pyruvate, [1-C] lactate, and OX063 at different levels of oxygen confirmed the validity of this sequential imaging of EPRI and hyperpolarized C-MRI. studies revealed SCCVII tumor had a significantly larger hypoxic fraction (pO < 8 mmHg) compared to HT29 tumor. The flux of pyruvate-to-lactate conversion was also higher in SCCVII than HT29. The lactate-to-pyruvate ratio in hypoxic regions (pO < 8 mmHg) 24 hours after 5-Gy irradiation was significantly higher than those without irradiation (0.76 vs. 0.36) in HT29 tumor. The study showed an increase in extracellular acidification rate after irradiation. In conclusion, co-imaging of pO and pyruvate-to-lactate conversion kinetics successfully showed the local metabolic changes especially in hypoxic area induced by radiation therapy.
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http://dx.doi.org/10.18632/oncotarget.25317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982751PMC
May 2018

Metabolic and Physiologic Imaging Biomarkers of the Tumor Microenvironment Predict Treatment Outcome with Radiation or a Hypoxia-Activated Prodrug in Mice.

Authors:
Shingo Matsumoto Shun Kishimoto Keita Saito Yoichi Takakusagi Jeeva P Munasinghe Nallathamby Devasahayam Charles P Hart Robert J Gillies James B Mitchell Murali C Krishna

Cancer Res 2018 07 23;78(14):3783-3792. Epub 2018 May 23.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here, we define two imaging biomarkers that predict differences in tumor response to therapy: (i) partial oxygen pressure (pO), measured by EPR imaging; and (ii) [1-C] pyruvate metabolism rate, measured by hyperpolarized C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa2, and Su.86.86) were grown in mice. The median pO of the mature Hs766t, MiaPaCa2, and Su.86.86 tumors was 9.1 ± 1.7, 11.1 ± 2.2, and 17.6 ± 2.6 mm Hg, and the rate of pyruvate-to-lactate conversion was 2.72 ± 0.48, 2.28 ± 0.26, and 1.98 ± 0.51 per minute, respectively ( = 6, each). These results are in agreement with steady-state data of matabolites quantified by mass spectroscopy and histologic analysis, indicating glycolytic and hypoxia profile in Hs766t, MiaPaca2, and Su.86.86 tumors. Fractionated radiotherapy (5 Gy × 5) resulted in a tumor growth delay of 16.7 ± 1.6 and 18.0 ± 2.7 days in MiaPaca2 and Su.86.86 tumors, respectively, compared with 6.3 ± 2.7 days in hypoxic Hs766t tumors. Treatment with gemcitabine, a first-line chemotherapeutic agent, or the hypoxia-activated prodrug TH-302 was more effective against Hs766t tumors (20.0 ± 3.5 and 25.0 ± 7.7 days increase in survival time, respectively) than MiaPaCa2 (2.7 ± 0.4 and 6.7 ± 0.7 days) and Su.86.86 (4.7 ± 0.6 and 0.7 ± 0.6 days) tumors. Collectively, these results demonstrate the ability of molecular imaging biomarkers to predict the response of PDAC to treatment with radiotherapy and TH-302. pO2 imaging data and clinically available metabolic imaging data provide useful insight into predicting the treatment efficacy of chemotherapy, radiation, and a hypoxia-activated prodrug as monotherapies and combination therapies in PDAC tumor xenograft models. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092078PMC
July 2018

Operando Atomic Force Microscopy Reveals Mechanics of Structural Water Driven Battery-to-Pseudocapacitor Transition.

Authors:
Ruocun Wang James B Mitchell Qiang Gao Wan-Yu Tsai Shelby Boyd Matt Pharr Nina Balke Veronica Augustyn

ACS Nano 2018 Jun 21;12(6):6032-6039. Epub 2018 May 21.

Department of Materials Science & Engineering , North Carolina State University , Raleigh , North Carolina 27695 , United States.

The presence of structural water in tungsten oxides leads to a transition in the energy storage mechanism from battery-type intercalation (limited by solid state diffusion) to pseudocapacitance (limited by surface kinetics). Here, we demonstrate that these electrochemical mechanisms are linked to the mechanical response of the materials during intercalation of protons and present a pathway to utilize the mechanical coupling for local studies of electrochemistry. Operando atomic force microscopy dilatometry is used to measure the deformation of redox-active energy storage materials and to link the local nanoscale deformation to the electrochemical redox process. This technique reveals that the local mechanical deformation of the hydrated tungsten oxide is smaller and more gradual than the anhydrous oxide and occurs without hysteresis during the intercalation and deintercalation processes. The ability of layered materials with confined structural water to minimize mechanical deformation likely contributes to their fast energy storage kinetics.
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http://dx.doi.org/10.1021/acsnano.8b02273DOI Listing
June 2018

Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non-Small Cell Lung Cancer and .

Authors:
Sarwat Naz Anastasia Sowers Rajani Choudhuri Maria Wissler Janet Gamson Askale Mathias John A Cook James B Mitchell

Clin Cancer Res 2018 08 1;24(16):3994-4005. Epub 2018 May 1.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of the CDK4/6 inhibitor abemaciclib in non-small cell lung cancer (NSCLC) cells and IR enhancement by abemaciclib in a variety of NSCLC cell lines was assessed by clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by γH2AX analysis. Global metabolic alterations by abemaciclib and IR combination were evaluated by LC/MS mass spectrometry and YSI bioanalyzer. Effects of abemaciclib and IR combination were studied by xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry. Abemaciclib enhanced the radiosensitivity of NSCLC cells independent of RAS or EGFR status. Enhancement of radiosensitivity was lost in cell lines deficient for functional p53 and RB protein. After IR, abemaciclib treatment inhibited DNA damage repair as measured by γH2AX. Mechanistically, abemaciclib inhibited RB phosphorylation, leading to cell-cycle arrest. It also inhibited mTOR signaling and reduced intracellular amino acid pools, causing nutrient stress. , abemaciclib, when administered in an adjuvant setting for the second week after fractionated IR, further inhibited vasculogenesis and tumor regrowth, with sustained inhibition of RB/E2F activity, mTOR pathway, and HIF-1 expression. In summary, our study signifies inhibiting the CDK4/6 pathway by abemaciclib in combination with IR as a promising therapeutic strategy to treat NSCLC. Abemaciclib in combination with IR enhances NSCLC radiosensitivity in preclinical models, potentially providing a novel biomarker-driven combination therapeutic strategy for patients with NSCLC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137329PMC
August 2018

Wireless implantable coil with parametric amplification for in vivo electron paramagnetic resonance oximetric applications.

Authors:
Ayano Enomoto Chunqi Qian Nallathamby Devasahayam Shun Kishimoto Nobu Oshima Burchelle Blackman Rolf E Swenson James B Mitchell Alan P Koretsky Murali C Krishna

Magn Reson Med 2018 11 30;80(5):2288-2298. Epub 2018 Mar 30.

Radiation Biology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Purpose: To develop an implantable wireless coil with parametric amplification capabilities for time-domain electron paramagnetic resonance (EPR) spectroscopy operating at 300 MHz.

Methods: The wireless coil and lithium phthalocyanine (LiPc), a solid paramagnetic probe, were each embedded individually in a biocompatible polymer polydimethoxysiloxane (PDMS). EPR signals from the LiPc embedded in PDMS (LiPc/PDMS) were generated by a transmit-receive surface coil tuned to 300 MHz. Parametric amplification was configured with an external pumping coil tuned to 600 MHz and placed between the surface coil resonator and the wireless coil.

Results: Phantom studies showed significant enhancement in signal to noise using the pumping coil. However, no influence of the pumping coil on the oxygen-dependent EPR spectral linewidth of LiPc/PDMS was observed, suggesting the validity of parametric amplification of EPR signals for oximetry by implantation of the encapsulated wireless coil and LiPc/PDMS in deep regions of live objects. In vivo studies demonstrate the feasibility of this approach to longitudinally monitor tissue pO in vivo and also monitor acute changes in response to pharmacologic challenges. The encapsulated wireless coil and LiPc/PDMS engendered no host immune response when implanted for ∼3 weeks and were found to be well tolerated.

Conclusions: This approach may find applications for monitoring tissue oxygenation to better understand the pathophysiology associated with wound healing, organ transplantation, and ischemic diseases.
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http://dx.doi.org/10.1002/mrm.27185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534116PMC
November 2018

Hyperpolarized [1-C]-Pyruvate Magnetic Resonance Spectroscopic Imaging of Prostate Cancer Predicts Efficacy of Targeting the Warburg Effect.

Authors:
Bradley T Scroggins Masayuki Matsuo Ayla O White Keita Saito Jeeva P Munasinghe Carole Sourbier Kazutoshi Yamamoto Vivian Diaz Yoichi Takakusagi Kazuhiro Ichikawa James B Mitchell Murali C Krishna Deborah E Citrin

Clin Cancer Res 2018 07 29;24(13):3137-3148. Epub 2018 Mar 29.

Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

To evaluate the potential of hyperpolarized [1-C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) of prostate cancer as a predictive biomarker for targeting the Warburg effect. Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-C]-pyruvate MRSI after systemic delivery of [1-C] pyruvic acid. Steady-state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady-state lactate concentrations were measured with proton (H) MRS. Perfusion and oxygenation of xenografts were measured with electron paramagnetic resonance (EPR) imaging with OX063. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 μg/mouse/day for 5 days × 2 weekly cycles). Lactate production, pyruvate uptake, extracellular acidification rates, and oxygen consumption of the prostate cancer cell lines were analyzed LDH activity was assessed in tumor homogenates. DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-C]-pyruvate MRSI compared with PC3 and a corresponding greater sensitivity to LDH inhibition. No difference was observed between PC3 and DU145 xenografts in steady-state measures of pyruvate fermentation, oxygenation, or perfusion. The two cell lines exhibited similar sensitivity to FX-11 LDH activity correlated to FX-11 sensitivity. Hyperpolarized [1-C]-pyruvate MRSI of prostate cancer predicts efficacy of targeting the Warburg effect. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984723PMC
July 2018

Cancer Incidence in C3H Mice Protected from Lethal Total-Body Radiation after Amifostine.

Authors:
John A Cook Sarwat Naz Miriam R Anver Anastasia L Sowers Kristin Fabre Murali C Krishna James B Mitchell

Radiat Res 2018 05 12;189(5):490-496. Epub 2018 Mar 12.

a   Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Amifostine is a potent antioxidant that protects against ionizing radiation effects. In this study, we evaluated the effect of Amifostine administered before total-body irradiation (TBI), at a drug dose that protects against TBI lethality, for potential protection against radiation-induced late effects such as a shortened lifespan and cancer. Three groups of mice were studied: 0 Gy control; 10.8 Gy TBI with Amifostine pretreatment; and 5.4 Gy TBI alone. Animals were monitored for their entire lifespan. The median survival times for mice receiving 0, 5.4 or 10.8 Gy TBI were 706, 460 and 491 days, respectively. Median survival of both irradiated groups was significantly shorter compared to nonirradiated mice ( P < 0.0001). Cancer incidence (hematopoietic and solid tumors) was similar between the irradiated groups and was significantly greater than for the 0 Gy controls. The ratio of hematopoietic-to-solid tumors differed among the groups, with the 5.4 Gy group having a higher incidence of hematopoietic neoplasms compared to the 10.8 Gy/Amifostine group (1.8-fold). Solid tumor incidence was greater in the 10.8 Gy/Amifostine group (1.6-fold). There are few mouse lifespan studies for agents that protect against radiation-induced lethality. Mice treated with 10.8 Gy/Amifostine yielded a lower incidence of hematopoietic neoplasms and higher incidence of solid neoplasms. In conclusion, mice protected from lethal TBI have a shortened lifespan, due in large part to cancer induction after exposure compared to nonexposed controls. Amifostine treatment did protect against radiation-induced hematopoietic tumors, while protection against solid neoplasms was significant but incomplete.
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http://dx.doi.org/10.1667/RR14987.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943636PMC
May 2018

PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation.

Authors:
Megan Morisada Paul E Clavijo Ellen Moore Lillian Sun Michael Chamberlin Carter Van Waes James W Hodge James B Mitchell Jay Friedman Clint T Allen

Oncoimmunology 2018;7(3):e1395996. Epub 2017 Nov 27.

Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.

Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8 T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8 T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.
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http://dx.doi.org/10.1080/2162402X.2017.1395996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790397PMC
November 2017

Comparative studies with EPR and MRI on the in vivo tissue redox status estimation using redox-sensitive nitroxyl probes: influence of the choice of the region of interest.

Authors:
Ken-Ichiro Matsumoto James B Mitchell Murali C Krishna

Free Radic Res 2018 Feb 31;52(2):248-255. Epub 2018 Jan 31.

b Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.

In vivo decay rates of a nitroxyl contrast agent were estimated by a MR redox imaging (MRRI) technique and compared with the decay rates obtained by the electron paramagnetic resonance spectroscopy (EPRS) and imaging (EPRI). MRRI is a dynamic imaging technique employing T-weighted pulse sequence, which can visualise a nitroxyl-induced enhancement of signal intensity by T-weighted contrast. EPR techniques can directly measure the paramagnetic nitroxyl radical. Both the squamous cell carcinoma (SCC) tumour-bearing and normal legs of a female C3H mouse were scanned by T-weighted SPGR sequence at 4.7 T with the nitroxyl radical, carbamoyl-proxyl (CmP), as the contrast agent. Similarly, the time course of CmP in normal muscle and tumour tissues was obtained using a 700-MHz EPR spectrometer with a surface coil. The time course imaging of CmP was also performed by 300 MHz CW EPR imager. EPRS and EPRI gave slower decay rates of CmP compared to the MRRI. Relatively slow decay rate at peripheral region of the tumour tissues, which was found in the image obtained by MRRI, may contribute to the slower decay rates observed by EPRS and/or the EPRI measurements. To reliably determine the tissue redox status from the reduction rates of nitroxyls such as CmP, heterogenic structure in the tumour tissue must be considered. The high spatial and temporal resolution of T-weighted MRI and the T-enhancing capabilities of nitroxyls support the use of this method to map tissue redox status which can be a useful biomarker to guide appropriate treatments based on the tumour microenvironment.
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http://dx.doi.org/10.1080/10715762.2018.1427235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333207PMC
February 2018

Molecular imaging of tumor photoimmunotherapy: Evidence of photosensitized tumor necrosis and hemodynamic changes.

Authors:
Shun Kishimoto Nobu Oshima Kazutoshi Yamamoto Jeeva Munasinghe Jan Henrik Ardenkjaer-Larsen James B Mitchell Peter L Choyke Murali C Krishna

Free Radic Biol Med 2018 02 29;116:1-10. Epub 2017 Dec 29.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States. Electronic address:

Near-infrared photoimmunotherapy (NIR PIT) employs the photoabsorbing dye IR700 conjugated to antibodies specific for cell surface epidermal growth factor receptor (EGFR). NIR PIT has shown highly selective cytotoxicity in vitro and in vivo. Cell necrosis is thought to be the main mode of cytotoxicity based mainly on in vitro studies. To better understand the acute effects of NIR PIT, molecular imaging studies were performed to assess its cellular and vascular effects. In addition to in vitro studies for cytotoxicity of NIR PIT, the in vivo tumoricidal effects and hemodynamic changes induced by NIR PIT were evaluated by C MRI using hyperpolarized [1,4-C] fumarate, R* mapping from T*-weighted MRI, and photoacoustic imaging. In vitro studies confirmed that NIR PIT resulted in rapid cell death via membrane damage, with evidence for rapid cell expansion followed by membrane rupture. Following NIR PIT, metabolic MRI using hyperpolarized fumarate showed the production of malate in EGFR-expressing A431 tumor xenografts, providing direct evidence for photosensitized tumor necrosis induced by NIR PIT. R* mapping studies showed temporal changes in oxygenation, with an accompanying increase of deoxyhemoglobin at the start of light exposure followed by a sustained decrease after cessation of light exposure. This result suggests a rapid decrease of blood flow in EGFR-expressing A431 tumor xenografts, which is supported by the results of the photoacoustic imaging experiments. Our findings suggest NIR PIT mediates necrosis and hemodynamic changes in tumors by photosensitized oxidation pathways and that these imaging modalities, once translated, may be useful in monitoring clinical treatment response.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.12.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963721PMC
February 2018

Effect of body temperature on the pharmacokinetics of a triarylmethyl-type paramagnetic contrast agent used in EPR oximetry.

Authors:
Ken-Ichiro Matsumoto Fuminori Hyodo James B Mitchell Murali C Krishna

Magn Reson Med 2018 02 16;79(2):1212-1218. Epub 2017 Nov 16.

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: Pharmacokinetics of the tri[8-carboxy-2,2,6,6-tetrakis(2-hydroxymethyl)benzo[1,2-d:4,5-d']bis(1,3)dithio-4-yl]methyl radical (Oxo63) after a single bolus and/or continuous intravenous infusion was investigated in tumor-bearing C3H mice with or without body temperature control while under anesthesia.

Method: The in vivo time course of Oxo63 in blood was measured using X-band electron paramagnetic resonance spectroscopy. Distribution of Oxo63 in normal muscle and tumor tissues was obtained using a surface coil resonator and a 700-MHz electron paramagnetic resonance spectrometer. The whole-body distribution of Oxo63 was obtained by 300-MHz continuous-wave electron paramagnetic resonance imaging. The high-resolution 300-MHz time-domain electron paramagnetic resonance imaging was also carried out to probe the distribution of Oxo63.

Results: Urination of mice was retarded at low body temperature, causing the concentration of Oxo63 in blood to attain high levels. However, the concentration of Oxo63 in tumor tissue was lower with no control of body temperature than active body temperature control. The nonsystemized blood flow in the tumor tissues may pool Oxo63 at lower body temperature.

Conclusions: Pharmacokinetics of the contrast agent were found to be significantly affected by body temperature of the experimental animal, and can influence the probe distribution and the image patterns. Magn Reson Med 79:1212-1218, 2018. © Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
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http://dx.doi.org/10.1002/mrm.27008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941925PMC
February 2018

Pulsed Electron Paramagnetic Resonance Imaging: Applications in the Studies of Tumor Physiology.

Authors:
Shun Kishimoto Ken-Ichiro Matsumoto Keita Saito Ayano Enomoto Shingo Matsumoto James B Mitchell Nallathamby Devasahayam Murali C Krishna

Antioxid Redox Signal 2018 05 9;28(15):1378-1393. Epub 2018 Jan 9.

1 Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.

Significance: Electron paramagnetic resonance imaging (EPRI) is capable of generating images of tissue oxygenation using exogenous paramagnetic probes such as trityl radicals or nitroxyl radicals. The spatial distribution of the paramagnetic probe can be generated using magnetic field gradients as in magnetic resonance imaging and, from its spectral features, spatial maps of oxygen can be obtained from live objects. In this review, two methods of signal acquisition and image formation/reconstruction are described. The probes used and its application to study tumor physiology and monitor treatment response with chemotherapy drugs in mouse models of human cancer are summarized. Recent Advances: By implementing phase encoding/Fourier reconstruction in EPRI in time domain mode, the frequency contribution to the spatial resolution was avoided and images with improved spatial resolution were obtained. The EPRI-generated pO maps in tumor were useful to detect and evaluate the effects of various antitumor therapies on tumor physiology. Coregistration with other imaging modalities provided a better understanding of hypoxia-related alteration in physiology.

Critical Issues: The high radiofrequency (RF) power of EPR irradiation and toxicity profile of radical probes are the main obstacles for clinical application. The improvement of RF low power pulse sequences may allow for clinical translation.

Future Directions: Pulsed EPR oximetry can be a powerful tool to research various diseases involving hypoxia such as cancer, ischemic heart diseases, stroke, and diabetes. With appropriate paramagnetic probes, it can also be applied for various other purposes such as detecting local acid-base balance or oxidative stress. Antioxid. Redox Signal. 28, 1378-1393.
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http://dx.doi.org/10.1089/ars.2017.7391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910045PMC
May 2018
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