低出力パルス超音波は自己免疫疾患での唾液腺炎による唾液分泌低下を改善する

Introduction: Low-intensity pulsed ultrasound (LIPUS) has been known to promote bone healing by nonthermal effects. In recent studies, LIPUS has been shown to reduce inflammation in injured soft tissues. Xerostomia is one of the most common symptoms in Sjögren syndrome (SS). It is caused by a decrease in the quantity or quality of saliva. The successful treatment of xerostomia is still difficult to achieve and often unsatisfactory. The aim of this study is to clarify the therapeutic effects of LIPUS on xerostomia in SS. Methods: Human salivary gland acinar (NS-SV-AC) and ductal (NS-SV-DC) cells were cultured with or without tumor necrosis factor-α (TNF-α; 10 ng/ml) before LIPUS or sham exposure. The pulsed ultrasound signal was transmitted at a frequency of 1.5 MHz or 3 MHz with a spatial average intensity of 30 mW/cm2 and a pulse rate of 20 %. Cell number, net fluid secretion rate, and expression of aquaporin 5 (AQP5) and TNF-α were subsequently analyzed. Inhibitory effects of LIPUS on the nuclear factor κB (NF-κB) pathway were determined by Western blot analysis. The effectiveness of LIPUS in recovering salivary secretion was also examined in a MRL/MpJ/lpr/lpr (MRL/lpr) mouse model of SS with autoimmune sialadenitis. Results: TNF-α stimulation of NS-SV-AC and NS-SV-DC cells resulted in a significant decrease in cell number and net fluid secretion rate (p < 0.01), whereas LIPUS treatment abolished them (p < 0.05). The expression changes of AQP5 and TNF-α were also inhibited in LIPUS treatment by blocking the NF-κB pathway. Furthermore, we found that mRNA expression of A20, a negative feedback regulator, was significantly increased by LIPUS treatment after TNF-α or interleukin 1β stimulation (NS-SV-AC, p < 0.01; NS-SV-DC, p < 0.05). In vivo LIPUS exposure to MRL/lpr mice exhibited a significant increase in both salivary flow and AQP5 expression by reducing inflammation in salivary glands (p < 0.01). Conclusions: These results suggest that LIPUS upregulates expression of AQP5 and inhibits TNF-α production. Thus, LIPUS may restore secretion by inflamed salivary glands. It may synergistically activate negative feedback of NF-κB signaling in response to inflammatory stimulation. Collectively, LIPUS might be a new strategic therapy for xerostomia in autoimmune sialadenitis with SS

In Vivo Simultaneous Imaging of Vascular Pool and Hypoxia with a HT-29 Tumor Model: the Application of Dual-Isotope SPECT/PET/CT

Investigation of vascularity and hypoxia in tumors is important in understanding cancer biology to developthe therapeutic strategies in cancer treatment. ------------------------------------------------------------------------ *Corresponding author . Recently, an imaging technology with the VECTor SPECT/PET/CT small-animal scanner (MILabs) has been developed to obtain simultaneous images usingtwodifferent tracers labeled with SPECT and PET nuclides, respectively. In this study, we developed amethod to simultaneously visualize vascularity and hypoxia witha human colon carcinoma HT-29tumor-bearing mouse model with 99mTc-labeled human serum albumin (99mTc-HSA) to detect blood pool, and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) to detect the over-reduced conditionsunder hypoxia, by applying this SPECT/PET/CT technology.Prior to the in vivo experiments, a phantom study was conducted to confirmquantitativity of the 99mTc/64Cu dual-isotope imaging with the SPECT/PET/CT system,by comparing radioactivities detected by SPECT/PET/CT system and those of standards under the conditions of wide range of radioactivities and various content ratios, in our settings. An in vivoimaging study was conducted with HT-29 tumor-bearing mice. Both 64Cu-ATSM (37 MBq) and 99mTc-HSA (18.5 MBq) were intravenously injected into a mouse (n = 4) at 1 h and 10 min, respectively, before scanning for 20 min; the 99mTc/64Cu dual-isotope SPECT/PET/CT images were then obtained.The phantom study demonstrated that this system has high quantitativity, even when 2 isotopes co-existed and the content ratio was changed over a wide range, indicating the feasibility for in vivo experiments. In vivoSPECT/PET/CT imaging with 64Cu-ATSM and 99mTc-HSA visualized the distribution of each probe and showed that 64Cu-ATSM high-uptake regions barely overlapped with 99mTc-HSA high-uptake regions within HT-29 tumors.We developed a method to simultaneously visualize vascularity and hypoxia within HT-29tumors using in vivodual-isotope SPECT/PET/CT imaging. This methodology would be useful for studies oncancer biology with mouse tumor models anddevelopment of the treatment strategies against cancer. Examination of vascularity and hypoxia within in vivotumors is important in understanding the biology of cancer anddevelopmentof the therapeutic strategies in cancer treatment. For hypervascular tumors, antiangiogenic therapy and antivascular therapy are promising approaches. For antiangiogenic therapy, the anti-vascular endothelial growth factor antibody bevacizumab is now clinically used worldwide [1-4], and for antivascular therapy, a clinical trial withcombrestatin A4 phosphate is conducted[5]. For hypovascular tumor, which is usually associated with hypoxia, intensive treatment is necessary, since tumor hypoxia is reportedly resistant to chemotherapy and radiotherapy [6-8]. In recent years, several therapeutic methods have been proposedto damage to hypoxic regions within tumors, such as intensity modulated radiation therapy with hypoxia positron emission tomography (PET) imaging [9, 10], and carbon-ion radiotherapy, which is able to damage tumor cells even in the absence of oxygen by high linear energy transfer beam [11, 12]. However, considering the difficulty of cancer radical cure at the present moment, more effective drugs and treatment methods for antiangiogenic, antivascular, and antihypoxia therapies need to be developed. In addition, combinations of these therapies would be effective approaches, since they can attacktumor vascularity and hypoxia closely linked each other.However, it is still difficult to observe tumor vascularity and hypoxia both coincidently and concisely in in vivo tumor-bearing mouse model. Recently, a technology of single-photon emission computed tomography/positron emission tomography/computed tomography(SPECT/PET/CT) imaging with the VECTor small-animal scanner, launched from MILabs (Utrecht, Netherlands), has been reportedto obtain truly simultaneous images with twotracers labeled with SPECT and PET nuclides, respectively. Conventionally, dual-isotope imaging studies with SPECT and PET have been performed by obtaining each image independently with 2 separate systems [13, 14]. In contrast, the VECTor system is equipped with a clustered pinhole collimator, which dramatically reduces pinhole-edge penetration of high-energy annihilation ?-photons from PET nuclides and enables it to detect high-energy ?-photons derived from PET nuclides, in a manner similar to SPECT nuclides, and to obtain high-resolution images from positron emitters and single-photon emitters at the same time by separating the images based on the photon energy [15, 16]. Thus, this system has a novel concept to make images of PET nuclides, compared to the typical PET system, which measures the coincidence of annihilation ?-photons. Goorden et al. have reported that this system shows high spatial resolution, with 0.8 mm for PET nuclides and 0.5 mm for SPECT nuclides [15]. Miwa et al. also confirmed its performance in simultaneous detection of 99mTc and 18F using this system [17]. In this study, we developed a methodology to easily observe intratumoralvascularity and hypoxia in a simultaneous manner,by applyingthis SPECT/PET/CT technology. We used 99mTc-labeled human serum albumin (99mTc-HSA) labeled with a SPECT nuclide 99mTc (half-life = 6.0 h; 140 keV ?-ray: 89%) to visualize tumor vascularity by detecting blood pool [18]. The 99mTc-HSAhas been reported to detect tumor blood pool in many types of cancer, including colon cancer, renal cell carcinoma, and liver tumor in both preclinical and clinical studies [19-21]. We also used 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), labeled with a PET nuclide 64Cu (half-life = 12.7 h; ?+-decay: 17.4%; ??-decay: 38.5%; and electron capture: 43%) [22], to detect tumor hypoxia. The Cu-ATSM, labeled with Cu radioisotopes, such as 60Cu, 62Cu, and 64Cu, has been developed as an imaging agent targeting hypoxic regions in tumors for use with PET [23-26].Many studies have demonstrated that Cu-ATSM accumulation is associated with hypoxic conditions of tumor in vitro and in vivo[26-29]. The mechanism of radiolabeled Cu-ATSM accumulation has been studied: Cu-ATSM has small molecular sizeand high membrane permeability, and thus rapidly diffuses into cells and is reduced and trapped within cells under highly reduced intracellular conditions such as hypoxia [24, 29-31]. A clinical study with 62Cu-ATSM demonstrated that high levels of hypoxia-inducible factor-1? (HIF-1?) expression were found in Cu-ATSM uptake regions in the tumors of patients with glioma [32]. In this study, we performed simultaneous in vivo imaging using a SPECT/PET/CT with 99mTc-HSA and 64Cu-ATSM for detecting tumor vascularity and hypoxia with a HT-29 tumor-bearing mouse model

Na/I Symporter (NIS) Reporter Gene Imaging System for Evaluating Angiogenic Gene Therapy Using Hepatocyte Growth Factor

Purpose: Hepatocyte growth factor (HGF) is a unique factor with strong angiogenic and antifibrotic effects, and thus is a promising candidate for an effective therapeutic gene in angiogenic gene therapy for ischemic heart disease. In this study, we aimed at constructing and in vitro validating a coexpression vector of a HGF therapeutic gene and an Na/I symporter (NIS) radionuclide reporter gene, and at in vivo imaging the transferred gene expression in a rat myocardial infarct model. Method: Adenovirus expressing HGF and NIS individually driven by two cytomegalovirus promoters (Ad-CMV-HGF-CMV-NIS) was constructed. In in-vitro experiments, western blotting analysis and Tc-99m pertechnetate uptake rate measurement were performed after infecting Ad-CMV-HGF-CMV-NIS with rat embryonic cardiomyoblast cells (H9c2) in various multiplicity of infection (MOI=0, 1, 5, 10, 20, 50, 100). For in-vivo imaging, Ad-CMV-HGF-CMV-NIS was injected through a thoracotomy directly into the left ventricular myocardium of peri-infarct areas immediately after ligating the left anterior descending (LAD) coronary artery. Three to five days later, expression of the transferred genes was imaged with Tc-99m pertechnetate using a small animal PET/SPECT/CT scanner (Siemens Inveon), also myocardial blood flow with Tc-99m tetrofosmin, and glucose metabolism with F-18 FDG. Results: The western blotting analysis demonstrated the amount of HGF and NIS proteins increased according to MOI and significantly correlated each other (r=0.93). Tc-99m pertechnetate uptake rate increased according to MOI up to 582 times higher than non-infected control, and was blocked by KClO4. In Tc-99m pertechnetate SPECT imaging, the transferred gene expression was clearly visualized as focal tracer accumulation, and its location was prehensible in reference to areas with hypoperfusion or metabolic disorder on fusion images with Tetrofosmin-SPECT or FDG-PET. Conclusion: The NIS reporter gene imaging system offers the potential of evaluating the usefulness of HGF angiogenic gene therapy based on non-invasive monitoring of the therapeutic gene expression.World Molecular Imaging Congres

I-123 BMIPP シンデンズ ドウキ SPECT オ モチイタ シンキン ユウリ シボウサン タイシャ ト サシツ キノウ ノ ドウジ ヒョウカ

京都大学0048新制・課程博士博士(医学)甲第10088号医博第2598号新制||医||827(附属図書館)UT51-2003-H509京都大学大学院医学研究科内科系専攻(主査)教授 北 徹, 教授 野間 昭典, 教授 小西 淳二学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Initial Report on [18F]FAZA-PET/CT Clinical Study in Lung Cancer

Aim: The aim of the clinical study is to investigate whether PET imaging with a hypoxia tracer [18F]fluoroazomycin arabinoside (FAZA) can discriminate between radioresistant and radiosensitive cancers in histologically-proven primary lung cancer patients planned for radiotherapy. Here shown are the initial results on the [18F]FAZA uptake to the primary lesions.Materials & Methods: Eighteen primary lung cancer patients were enrolled (63 +- 9 y/o, male: female = 11: 7, adenocarcinomas: squamous cell carcinomas: large cell carcinomas = 9: 5: 4, clinical stage IIIA: IIIB: IV = 7: 7: 4). [18F]FAZA-PET images were obtained 2 hours after the tracer injection (370 MBq). The standardized uptake values (SUV), the tumor-to-contralateral normal lung (T/N) ratio, the tumor-to-blood measured in the left ventricle (T/Bl) ratio, and the tumor-to-buck muscles (T/M) ratio were calculated as the semiquantitative parameters for [18F]FAZA uptakes to the primary lesions under the guidance of concomitant CT images. The SUV of [18F]Fluorodeoxylucose (FDG) was also compared with these parameters.Results: There was no statistical difference in the maximum tumor diameter or in the SUV of [18F]FDG between genders, among histological types, or among clinical stages. The T/N ratio of [18F]FAZA was significantly higher in patients with large cell carcinomas than those with adenocarcinomas (5.0 +- 1.9 vs 2.5 +- 0.9, p < 0.0001). The T/Bl ratio of [18F]FAZA was significantly correlated with the maximum tumor diameter (R2 = 0.670, p < 0.0001) and with the SUV of [18F]FDG (R2 = 0.507, p < 0.0001), as well as with the SUV of [18F]FAZA (R2 = 0.748, p < 0.0001). The T/M ratio, however, seemed inappropriate as the parameter in lung cancer, since there was a gender difference in the SUV of [18F]FAZA to the buck muscles themselves (male 1.45 +- 0.12 vs female 1.26 +- 0.19, p = 0.02).Conclusion: Histological difference was found in a parameter of [18F]FAZA uptake to the primary lesions in the lung cancer patients. In addition, reasonable relationships with the tumor size and with the tumor [18F]FDG uptake was found in another parameter of the [18F]FAZA uptake. The best parameter of the [18F]FAZA uptake for predicting the resistance to radiotherapy will be determined through following up the therapeutic outcome of these patients. (364 words)EANM\u2711 - Annual Congress of the European Association of Nuclear Medicin

Ideata-base: an intelligent database management system of a body of knowledge

In epistemology, the objects of knowledge as known by the mind are defined as ideata.Aim: For our goal of the inheritance of academic legacies, we developed an intelligent ideata-base system not to collect or to retrieve data (fragmentary knowledge) as conventional data-base management systems have done, but to manage ideata (integrative knowledge). Content Organization: The unique data structure of the ideata-base system allows us to bundle data with any idea into ideatum, and to arrange them with the serial current into ideata, which is suitable for expressing various processes. The prominent case-based reasoning equipped with the ideata-base system is the process of solving new problems based on the solutions of similar past problems, which is powerful for flexible rearrangement and retrieval of ideata. Summary: The ideata-base system can store the relation between knowledge weighted with the significance as well as single pieces of knowledge, reason using the relation automatically, and extend the relation dynamically. Accordingly, this system enabled us to accumulate complex integration of knowledge such as general ideas and thought processes, and to inherit a body of knowledge.RSNA ’09　95th Scientific Assembly and Annual Meetin