Publications by authors named "Kei Higashikawa"

17 Publications

  • Page 1 of 1

[Long-term Quality Control Test of a Ge/Ga Generator].

Kaku Igaku 2021 ;58(1):47-58

Central Institute of Isotope Science, Hokkaido University.

Quality of the Ga solution eluted from a Ge/Ga generator (Galli Eo) was evaluated. Elution was performed 488 times from 21 to 484 days (ca. 15 months) after the calibration date. The eluted Ga activity was 329 MBq to 1,148 MBq, which decreased with the decay of Ge, but no significant change was observed in the elution yields (62.8±2.2%). The half-life of the eluted radioactivity was 67.8±0.1 min, the radionuclide purity of Ga was ≥99.9%, the Ge breakthrough was 0.000024 ±0.000004%, and the radiochemical purity of Ga was 99.7±0.2%. Fe and Zn were detected as metal impurities in the eluent, but both were ≤10 μg/GBq. The endotoxin concentration of the eluate was ≤5 EU/mL, and the eluent passed the sterility test. These results show that the generator can stably provide Ga solution over a 15-month period.
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http://dx.doi.org/10.18893/kakuigaku.tr.2102DOI Listing
January 2021

Transferrin-based radiolabeled probe predicts the sensitivity of human renal cancer cell lines to ferroptosis inducer erastin.

Biochem Biophys Rep 2021 Jul 24;26:100957. Epub 2021 Feb 24.

Department of Biomedical Imaging, Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan.

Ferroptosis induction has been recognized as a novel cancer therapeutic strategy. To effectively apply ferroptosis-targeting cancer therapy to individual patients, a diagnostic indicator for selecting this therapeutic strategy from a number of molecular targeting drugs is needed. However, to date, methods that can predict the efficacy of ferroptosis-targeting treatment have not been established yet. In this study, we focused on the iron metabolic pathway to develop a nuclear imaging technique for diagnosing the susceptibility of cancer cells to ferroptosis. As a nuclear probe, human transferrin (Tf) was labeled with Gallium-68 (Ga) using 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) as a chelator (Ga-NOTA-Tf). Western blot assay and clonogenic survival assay with human renal cancer cell lines A498 and 786-O revealed that the protein expression level of transferrin receptor1 (TfR1) and sensitivity to a ferroptosis inducer, erastin, were correlated. A cellular uptake assay with Ga-NOTA-Tf revealed that the cancer cells sensitive to erastin highly internalized the Ga-NOTA-Tf. Furthermore, treatment with the TfR1 inhibitor ferristatin II reduced the cellular uptake of Ga-NOTA-Tf, indicating that the intracellular uptake of the probe was mediated by TfR1. These results suggest that Ga-NOTA-Tf can be useful in predicting the sensitivity of cancer cells to ferroptosis inducers.
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http://dx.doi.org/10.1016/j.bbrep.2021.100957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910409PMC
July 2021

Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment.

Am J Pathol 2021 01;191(1):144-156

Department of Pathology, Hokkaido University, Sapporo, Japan.

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. In this study, we demonstrate that mice with proteasomal dysfunction exhibited memory impairment with associated neuronal loss, accumulation of phosphorylated tau, and activation of endoplasmic reticulum (ER) stress-related apoptosis pathways. Impaired proteasomal activity also activated ER stress-related apoptosis pathways in HT-22, a murine hippocampal neuronal cell line. HT-22 cell death, caused by proteasomal inhibition, was prevented by an inhibitor of c-Jun N-terminal kinase, an ER stress-related molecule. Collective evidence suggests that impaired proteasomal activity alters proteostasis, and subsequent ER stress-mediated pathways play pivotal roles in neuronal loss. Because aging decreases proteasomal function, age-related impairment of proteasomes may be involved in the development and progression of AD in elderly patients.
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http://dx.doi.org/10.1016/j.ajpath.2020.10.004DOI Listing
January 2021

Characterization of brown adipose tissue thermogenesis in the naked mole-rat (Heterocephalus glaber), a heterothermic mammal.

Sci Rep 2020 11 10;10(1):19488. Epub 2020 Nov 10.

Department of Aging and Longevity Research, Kumamoto University, Kumamoto, 860-0811, Japan.

The naked mole-rat (NMR) is a heterothermic mammal that forms eusocial colonies consisting of one reproductive female (queen), several reproductive males, and subordinates. Despite their heterothermy, NMRs possess brown adipose tissue (BAT), which generally induces thermogenesis in cold and some non-cold environments. Previous studies suggest that NMR-BAT induces thermogenesis by cold exposure. However, detailed NMR-BAT characteristics and whether NMR-BAT thermogenesis occurs in non-cold environments are unknown. Here, we show beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential of NMR-BAT, which contributes to thermogenesis in the isolated queen in non-cold environments (30 °C). NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activity in vitro and in vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment (20 °C), it was insufficient to prevent the decrease in the body temperatures. Even at 30 °C, NMRs are known to prevent the decrease of and maintain their body temperature by heat-sharing behaviors within the colony. However, isolated NMRs maintained their body temperature at the same level as when they are in the colony. Interestingly, we found that queens, but not subordinates, induce BAT thermogenesis in this condition. Our research provides novel insights into NMR thermoregulation.
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http://dx.doi.org/10.1038/s41598-020-74929-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656259PMC
November 2020

Association of Hydrophobic Carboxyl-Terminal Dendrimers with Lymph Node-Resident Lymphocytes.

Polymers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

Delivery systems to lymph node-resident T cells around tumor tissues are essential for cancer immunotherapy, in order to boost the immune responses. We previously reported that anionic dendrimers, such as carboxyl-, sulfonyl-, and phosphate-terminal dendrimers, were efficiently accumulated in lymph nodes via the intradermal injection. Depending on the terminal structure, their cell association properties were different, and the carboxyl-terminal dendrimers did not associate with any immune cells majorly. In this study, we investigated the delivery of carboxyl-terminal dendrimers with different hydrophobicity to lymph node-resident lymphocytes. Four types of carboxyl-terminal dendrimers-succinylated (C) and 2-carboxy-cyclohexanoylated (Chex) dendrimers with and without phenylalanine (Phe)-were synthesized and named C-den, C-Phe-den, Chex-den, and Chex-Phe-den, respectively. Chex-Phe-den was well associated with lymphocytes, but others were not. Chex-Phe-den, intradermally injected at the footpads of mice, was accumulated in the lymph node, and was highly associated with the lymphocytes, including T cells. Our results suggest that Chex-Phe-den has the potential for delivery to the lymph node-resident T cells, without any specific T cell-targeted ligands.
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http://dx.doi.org/10.3390/polym12071474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408625PMC
June 2020

Inhibition of xanthine oxidase in the acute phase of myocardial infarction prevents skeletal muscle abnormalities and exercise intolerance.

Cardiovasc Res 2021 Feb;117(3):805-819

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Aims: Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischaemic tissue. Here, we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production.

Methods And Results: Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analysed. XO-derived ROS production was significantly increased in MI mice from Days 1 to 3 post-surgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham + vehicle (Sham + Veh), MI + vehicle (MI + Veh), and MI + febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI + Feb). Febuxostat or vehicle was administered at 1 and 24 h before surgery, and once-daily on Days 1-7 post-surgery. On Day 28 post-surgery, exercise capacity and mitochondrial respiration in skeletal muscle fibres were significantly decreased in MI + Veh compared with Sham + Veh mice. An increase in damaged mitochondria in MI + Veh compared with Sham + Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibres (higher XO-derived ROS) was reduced via the down-regulation of protein synthesis-associated mTOR-p70S6K signalling in MI + Veh compared with Sham + Veh mice. These impairments were ameliorated in MI + Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function.

Conclusion: XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF.
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http://dx.doi.org/10.1093/cvr/cvaa127DOI Listing
February 2021

FTY720 Protects Against Ischemia-Reperfusion Injury by Preventing the Redistribution of Tight Junction Proteins and Decreases Inflammation in the Subacute Phase in an Experimental Stroke Model.

Transl Stroke Res 2020 10 27;11(5):1103-1116. Epub 2020 Feb 27.

Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

Injury due to brain ischemia followed by reperfusion (I/R) may be an important therapeutic target in the era of thrombectomy. FTY720, a widely known sphingosine-1-phosphate receptor agonist, exerts various neuroprotective effects. The aim of this study was to examine the protective effect of FTY720 with respect to I/R injury, especially focusing on blood-brain barrier (BBB) protection and anti-inflammatory effects. Male rats were subjected to transient ischemia and administered vehicle or 0.5 or 1.5 mg/kg of FTY720 immediately before reperfusion. Positron emission tomography (PET) with [F]DPA-714 was performed 2 and 9 days after the insult to serially monitor neuroinflammation. Bovine and rat brain microvascular endothelial cells (MVECs) were also subjected to oxygen-glucose deprivation (OGD) and reperfusion, and administered FTY720, phosphorylated-FTY720 (FTY720-P), or their inhibitor. FTY720 dose-dependently reduced cell death, the infarct size, cell death including apoptosis, and inflammation. It also ameliorated BBB disruption and neurological deficits compared to in the vehicle group. PET indicated that FTY720 significantly inhibited the worsening of inflammation in later stages. FTY720-P significantly prevented the intracellular redistribution of tight junction proteins but did not increase their mRNA expression. These results suggest that FTY720 can ameliorate I/R injury by protecting the BBB and regulating neuroinflammation.
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http://dx.doi.org/10.1007/s12975-020-00789-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496052PMC
October 2020

Carboxyl-, sulfonyl-, and phosphate-terminal dendrimers as a nanoplatform with lymph node targeting.

Int J Pharm 2020 Feb 7;576:119021. Epub 2020 Jan 7.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-2, Gakuen-cho, Naka-ku, Sakai, Osaka 599-8570, Japan. Electronic address:

The development of drug delivery vehicles to cancer and/or immune cells in lymph nodes is important for cancer diagnosis, therapy, and immunotherapy. We previously reported that anionic carboxyl-terminal dendrimers were accumulated in lymph nodes. In this study, three anionic dendrimers with carboxyl-, sulfonyl-, and phosphate-terminal groups were prepared to examine the lymph node targeting and the association with immune cells in the lymph nodes. These anionic dendrimers were accumulated in the lymph node by intradermal injection. Although the carboxyl- and sulfonyl-terminal dendrimers were diffused from the injection site, the phosphate-terminal dendrimers were mostly retained. The phosphate-terminal dendrimer was recognized by the macrophages, dendritic cells, and B cells in the lymph node, whereas the carboxyl- and sulfonyl-terminal dendrimers were not. Our results show that these anionic dendrimers were accumulated in the lymph node where the association with immune cells could be controlled by the terminal structure of the dendrimer. The phosphate-terminal dendrimer can be used as a nanoplatform for the delivery of some bioactive molecules to some immune cells, including B cells, in the lymph node.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119021DOI Listing
February 2020

Preclinical investigation of potential use of thymidine phosphorylase-targeting tracer for diagnosis of nonalcoholic steatohepatitis.

Nucl Med Biol 2020 Mar - Apr;82-83:25-32. Epub 2019 Dec 16.

Central Institute of Isotope Science, Hokkaido University, Hokkaido 060-0815, Japan; Graduate School of Biomedical Science and Engineering, Hokkaido University, Hokkaido 060-0815, Japan.

Introduction: Although liver biopsy is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH), it has several problems including high invasiveness and sampling errors. Therefore, the development of alternative methods to overcome these disadvantages is strongly required. In this study, we evaluated the potential use of our tracer targeting thymidine phosphorylase (TYMP), 5-[I]iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ([I]IIMU) for the diagnosis of NASH.

Methods: The mice used as the NASH model (hereafter, NASH mice) were prepared by feeding a methionine- and choline-deficient diet for 4 weeks. A control group was similarly given a control diet. The expression levels of the TYMP gene and protein in the liver were examined by real-time reverse-transcription polymerase chain reaction and western blot analyses. The localizations of [I]IIMU and the TYMP protein in the liver were examined by autoradiography and immunohistochemical staining, respectively. Finally, the mice were injected with [I]IIMU and single-photon emission tomography (SPECT) imaging was conducted.

Results: The hepatic expression levels of TYMP were significantly lower in the NASH mice than in the control mice at both mRNA and protein levels, suggesting that a decrease in TYMP level could be an indicator of NASH. [I]IIMU was uniformly distributed in the liver of the control mice, whereas it showed a patchy distribution in that of the NASH mice. The localization of [I]IIMU was visually consistent with that of the TYMP protein in the liver of the control and NASH mice. SPECT analysis indicated that the hepatic accumulation of [I]IIMU in the NASH mice was significantly lower than that in the control mice [SUV (g/ml): 4.14 ± 0.87 (Control) vs 2.31 ± 0.29 (NASH)].

Conclusions: [I]IIMU may provide a noninvasive means for imaging TYMP expression in the liver and may be applicable to the diagnosis of NASH.
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http://dx.doi.org/10.1016/j.nucmedbio.2019.12.006DOI Listing
May 2021

Erastin, a ferroptosis-inducing agent, sensitized cancer cells to X-ray irradiation via glutathione starvation in vitro and in vivo.

PLoS One 2019 4;14(12):e0225931. Epub 2019 Dec 4.

Department of Biomedical Imaging, Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan.

High concentrations of antioxidants in cancer cells are huge obstacle in cancer radiotherapy. Erastin was first discovered as an inducer of iron-dependent cell death called ferroptosis accompanied by antioxidant depletion caused by cystine glutamate antiporter inhibition. Therefore, treatment with erastin is expected to potentially enhance cellular radiosensitivity. In this study, we investigated the influence of treatment with erastin on the radiation efficiency against cancers. The clonogenic ability, glutathione peroxidase 4 (GPX4) expression, and glutathione concentration were evaluated using HeLa and NCI-H1975 adenocarcinoma cell lines treated with erastin and/or X-ray irradiation. For in vivo studies, NCI-H1975 cells were transplanted in the left shoulder of nude mice, and then radiosensitizing effect of erastin and glutathione concentration in the cancer were evaluated. Treatment with erastin induced ferroptosis and decreased the concentration of glutathione and GPX4 protein expression levels in the two tumor cell lines. Moreover, erastin enhanced X-ray irradiation-induced cell death in both human tumor cell lines. Furthermore, erastin treatment of a tumor-transplanted mouse model similarly demonstrated the radiosensitizing effect and decrease in intratumoral glutathione concentration in the in vitro study. In conclusion, our study demonstrated the radiosensitizing effect of erastin on two adenocarcinoma cell lines and the tumor xenograft model accompanied by glutathione depletion, indicating that ferroptosis inducers that reduce glutathione concentration could be applied as a novel cancer therapy in combination with radiotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892486PMC
March 2020

Biodistribution and radiation dosimetry of the novel hypoxia PET probe [F]DiFA and comparison with [F]FMISO.

EJNMMI Res 2019 Jul 5;9(1):60. Epub 2019 Jul 5.

Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.

Background: To facilitate hypoxia imaging in a clinical setting, we developed 1-(2,2-dihydroxymethyl-3-[F]-fluoropropyl)-2-nitroimidazole ([F]DiFA) as a new tracer that targets tumor hypoxia with its lower lipophilicity and efficient radiosynthesis. Here, we evaluated the radiation dosage, biodistribution, human safety, tolerability, and early elimination after the injection of [F]DiFA in healthy subjects, and we performed a preliminary clinical study of patients with malignant tumors in a comparison with [F]fluoromisonidazole ([F]FMISO).

Results: The single administration of [F]DiFA in 8 healthy male adults caused neither adverse events nor abnormal clinical findings. Dynamic and sequential whole-body scans showed that [F]DiFA was rapidly cleared from all of the organs via the hepatobiliary and urinary systems. The whole-body mean effective dose of [F]DiFA estimated by using the medical internal radiation dose (MIRD) schema with organ level internal dose assessment/exponential modeling (OLINDA/EXM) computer software 1.1 was 14.4 ± 0.7 μSv/MBq. Among the organs, the urinary bladder received the largest absorbed dose (94.7 ± 13.6 μSv/MBq). The mean absorbed doses of the other organs were equal to or less than those from other hypoxia tracers. The excretion of radioactivity via the urinary system was very rapid, reaching 86.4 ± 7.1% of the administered dose. For the preliminary clinical study, seven patients were subjected to [F]FMISO and [F]DiFA positron emission tomography (PET) at 48-h intervals to compare the two tracers' diagnostic ability for tumor hypoxia. The results of the tumor hypoxia evaluation by [F]DiFA PET at 1 h and 2 h were not significantly different from those obtained with [F]FMISO PET at 4 h ([F]DiFA at 1 h, p = 0.32; [F]DiFA at 2 h, p = 0.08). Moreover, [F]DiFA PET at both 1 h (k = 0.68) and 2 h (k = 1.00) showed better inter-observer reproducibility than [F]FMISO PET at 4 h (k = 0.59).

Conclusion: [F]DiFA is well tolerated, and its radiation dose is comparable to those of other hypoxia tracers. [F]DiFA is very rapidly cleared via the urinary system. [F]DiFA PET generated comparable images to [F]FMISO PET in hypoxia imaging with shorter waiting time, demonstrating the promising potential of [F]DiFA PET for hypoxia imaging and for a multicenter trial.
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http://dx.doi.org/10.1186/s13550-019-0525-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611855PMC
July 2019

Elimination of tumor hypoxia by eribulin demonstrated by F-FMISO hypoxia imaging in human tumor xenograft models.

EJNMMI Res 2019 Jun 3;9(1):51. Epub 2019 Jun 3.

Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.

Background: Eribulin, an inhibitor of microtubule dynamics, shows antitumor potency against a variety of solid cancers through its antivascular activity and remodeling of tumor vasculature. F-Fluoromisonidazole (F-FMISO) is the most widely used PET probe for imaging tumor hypoxia. In this study, we utilized F-FMISO to clarify the effects of eribulin on the tumor hypoxic condition in comparison with histological findings.

Material And Methods: Mice bearing a human cancer cell xenograft were intraperitoneally administered a single dose of eribulin (0.3 or 1.0 mg/kg) or saline. Three days after the treatment, mice were injected with F-FMISO and pimonidazole (hypoxia marker for immunohistochemistry), and intertumoral F-FMISO accumulation levels and histological characteristics were determined. PET/CT was performed pre- and post-treatment with eribulin (0.3 mg/kg, i.p.).

Results: The F-FMISO accumulation levels and percent pimonidazole-positive hypoxic area were significantly lower, whereas the number of microvessels was higher in the tumors treated with eribulin. The PET/CT confirmed that F-FMISO distribution in the tumor was decreased after the eribulin treatment.

Conclusions: Using F-FMISO, we demonstrated the elimination of the tumor hypoxic condition by eribulin treatment, concomitantly with the increase in microvessel density. These findings indicate that PET imaging using F-FMISO may provide the possibility to detect the early treatment response in clinical patients undergoing eribulin treatment.
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http://dx.doi.org/10.1186/s13550-019-0521-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546772PMC
June 2019

Anti PD-1 treatment increases [F]FDG uptake by cancer cells in a mouse B16F10 melanoma model.

EJNMMI Res 2018 Aug 16;8(1):82. Epub 2018 Aug 16.

Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan.

Background: Programmed cell death 1 (PD-1) inhibitors act as immune checkpoint inhibitors and are more effective for improving survival time with less toxicity as compared with conventional chemotherapies. In anti PD-1 therapy, it is important to evaluate metabolism in the cancer microenvironment, as this helps to clarify the pathological conditions. Herein, we investigate the early effects of PD-1 therapy on 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) uptake in vivo, focusing on cell distribution and glycolysis in both cancer and immune cells.

Results: In a B16F10 melanoma model, [F]FDG-positron emission tomography (PET) was performed before treatment and 7 days after the start of treatment. Values were calculated as the percentage-injected activity per gram of tissue (%IA/g). Flow-cytometry was then performed to assess immune cell populations and glucose metabolism. There was a negligible difference in [F]FDG uptake between tumors in the treatment group and non-treatment group before the treatment. In contrast, mean [F]FDG uptake in the treatment group tumors was significantly higher (8.06 ± 0.48 %IA/g; P = 0.0074) than that in the non-treatment group (4.02 ± 1.03 %IA/g) after anti PD-1 treatment. Assessment of tumor immune cell populations showed that treatment slightly enriched CD8 T cells and CD4 T cells; however, infiltration of immune cells was negligible, and thus, immune cells were not responsible for the increase in [F]FDG uptake. On the other hand, anti PD-1 treatment significantly increased glucose transporter 1 (GLUT1) and hexokinase II expression in CD45 cancer cells, indicating that anti PD-1 treatment increased glucose metabolism in cancer cells.

Conclusion: The present study shows that anti PD-1 therapy increases glucose metabolism in cancer cells.
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http://dx.doi.org/10.1186/s13550-018-0433-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095935PMC
August 2018

[F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia.

EJNMMI Res 2018 May 2;8(1):35. Epub 2018 May 2.

Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo, 060-8638, Japan.

Background: The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [F]DPA-714 PET. The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [F]DPA-714 PET was performed 3 and 10 days after MCAO.

Results: Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group.

Conclusions: The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.
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http://dx.doi.org/10.1186/s13550-018-0392-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930298PMC
May 2018

Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.

EJNMMI Res 2016 Dec 12;6(1):90. Epub 2016 Dec 12.

Central Institute of Isotope Science, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.

Background: Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl-H(N)]-3'-fluoro-3'-deoxythythymidine ([H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[F]fluoro-3'-deoxythymidine ([F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [F]FLT.

Results: The dynamic pattern of [F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [F]FLT phosphorylation (k) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [F]FLT forward transport (K) to reverse transport (k), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group).

Conclusions: Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic modeling could provide improved understanding of the biochemical processes involved in tumor responses to therapy.
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http://dx.doi.org/10.1186/s13550-016-0246-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153393PMC
December 2016

64Cu-DOTA-anti-CTLA-4 mAb enabled PET visualization of CTLA-4 on the T-cell infiltrating tumor tissues.

PLoS One 2014 3;9(11):e109866. Epub 2014 Nov 3.

Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Next-generation Imaging Team, RIKEN Center for Life Science Technologies, Kobe, Japan.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) targeted therapy by anti-CTLA-4 monoclonal antibody (mAb) is highly effective in cancer patients. However, it is extremely expensive and potentially produces autoimmune-related adverse effects. Therefore, the development of a method to evaluate CTLA-4 expression prior to CTLA-4-targeted therapy is expected to open doors to evidence-based and cost-efficient medical care and to avoid adverse effects brought about by ineffective therapy. In this study, we aimed to develop a molecular imaging probe for CTLA-4 visualization in tumor. First, we examined CTLA-4 expression in normal colon tissues, cultured CT26 cells, and CT26 tumor tissues from tumor-bearing BALB/c mice and BALB/c nude mice by reverse transcription polymerase chain reaction (RT-PCR) analysis and confirmed whether CTLA-4 is strongly expressed in CT26 tumor tissues. Second, we newly synthesized 64Cu-1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid-anti-mouse CTLA-4 mAb (64Cu-DOTA-anti-CTLA-4 mAb) and evaluated its usefulness in positron emission tomography (PET) and ex-vivo biodistribution analysis in CT26-bearing BALB/c mice. High CTLA-4 expression was confirmed in the CT26 tumor tissues of tumor-bearing BALB/c mice. However, CTLA-4 expression was extremely low in the cultured CT26 cells and the CT26 tumor tissues of tumor-bearing BALB/c nude mice. The results suggested that T cells were responsible for the high CTLA-4 expression. Furthermore, 64Cu-DOTA-anti-CTLA-4 mAb displayed significantly high accumulation in the CT26 tumor, thereby realizing non-invasive CTLA-4 visualization in the tumor. Together, the results indicate that 64Cu-DOTA-anti-CTLA-4 mAb would be useful for the evaluation of CTLA-4 expression in tumor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109866PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217715PMC
August 2015

Exploration of target molecules for molecular imaging of inflammatory bowel disease.

Biochem Biophys Res Commun 2011 Jul 6;410(3):416-21. Epub 2011 Jun 6.

Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.

Molecular imaging technology is a powerful tool for the diagnosis of inflammatory bowel disease (IBD) and the efficacy evaluation of various drug therapies for it. However, it is difficult to elucidate directly the relationships between the responsible molecules and IBD using existing probes. Therefore, the development of an alternative probe that is able to elucidate the pathogenic mechanism and provide information on the appropriate guidelines for treatment is earnestly awaited. In this study, we investigated pathognomonic molecules in the intestines of model mice. The accumulation of fluorine-18 fluorodeoxyglucose ((18)F-FDG) in the inflamed area of the intestines of dextran sulfate sodium (DSS)- or indomethacin (IND)-induced IBD model mice was measured by positron emission tomography (PET) and autoradiography to confirm the inflamed area. The results suggested that the inflammation was selectively induced in the colons of mice by the administration of DSS, whereas it was induced mainly in the ilea and the proximal colons of mice by the administration of IND. To explore attractive target molecules for the molecular imaging of IBD, we evaluated the gene expression levels of cytokines and cytokine receptors in the inflamed area of the intestines of both model mice. We found that the expression levels of cytokines and cytokine receptors were significantly increased during the progression of IBD, whereas the expression levels were decreased as the mucosa began to heal. In particular, the expression levels of these molecules had already changed before the symptoms of IBD appeared. In addition, the alterations of cytokine and cytokine receptor expression levels indicated differences in the expression pattern depending on the pathogenic mechanism or the region of inflammation (e.g., TNF-α). Our results suggest that these cytokines or cytokine receptors participate in the pathogenesis of IBD and are valuable biomarkers for the detection of the different circumstances underlying inflammation by the molecular imaging method. Finally, the development of an imaging probe for our target molecules is expected to improve our understanding of the inflammatory conditions of IBD.
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http://dx.doi.org/10.1016/j.bbrc.2011.05.146DOI Listing
July 2011
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