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1.  F-18 Sodium Fluoride Positron Emission Tomography/Computed Tomography for Detection of Thyroid Cancer Bone Metastasis Compared with Bone Scintigraphy 
Korean Journal of Radiology  2016;17(2):281-288.
The aim of the study was to compare the diagnostic performances of F-18 sodium fluoride positron emission tomography/computed tomography (bone PET/CT) and bone scintigraphy (BS) for the detection of thyroid cancer bone metastasis.
Materials and Methods
We retrospectively enrolled 6 thyroid cancer patients (age = 44.7 ± 9.8 years, M:F = 1:5, papillary:follicular = 2:4) with suspected bone metastatic lesions in the whole body iodine scintigraphy or BS, who subsequently underwent bone PET/CT. Pathologic diagnosis was conducted for 4 lesions of 4 patients.
Of the 17 suspected bone lesions, 10 were metastatic and 7 benign. Compared to BS, bone PET/CT exhibited superior sensitivity (10/10 = 100% vs. 2/10 = 20%, p = 0.008), and accuracy (14/17 = 82.4% vs. 7/17 = 41.2%, p < 0.025). The specificity (4/7 = 57.1%) of bone PET/CT was not significantly different from that of BS (5/7 = 71.4%, p > 0.05).
Bone PET/CT may be more sensitive and accurate than BS for the detection of thyroid cancer bone metastasis.
PMCID: PMC4781769  PMID: 26957915
Thyroid cancer; Bone metastasis; Bone scintigraphy; F-18 sodium fluoride; Positron emission tomography
2.  Bone Positron Emission Tomography with or without CT Is More Accurate than Bone Scan for Detection of Bone Metastasis 
Korean Journal of Radiology  2013;14(3):510-519.
Na18F bone positron emission tomography (bone PET) is a new imaging modality which is useful for the evaluation of bone diseases. Here, we compared the diagnostic accuracies between bone PET and bone scan for the detection of bone metastasis (BM).
Materials and Methods
Sixteen cancer patients (M:F = 10:6, mean age = 60 ± 12 years) who underwent both bone PET and bone scan were analyzed. Bone PET was conducted 30 minutes after the injection of 370 MBq Na18F, and a bone scan was performed 3 hours after the injection of 1295 MBq 99mTc-hydroxymethylene diphosphonate.
In the patient-based analysis (8 patients with BM and 8 without BM), the sensitivities of bone PET (100% = 8/8) and bone scan (87.5% = 7/8) were not significantly different (p > 0.05), whereas the specificity of bone PET (87.5% = 7/8) was significantly greater than that of the bone scan (25% = 2/8) (p < 0.05). In the lesion-based analysis (43 lesions in 14 patients; 31 malignant and 12 benign), the sensitivity of bone PET (100% = 31/31) was significantly greater than that of bone scan (38.7% = 12/31) (p < 0.01), and the specificity of bone PET (75.0% = 9/12) was also significantly higher than that of bone scan (8.3% = 1/12) (p < 0.05). The receiver operating characteristic curve analysis showed that bone PET was significantly more accurate than the bone scan in the patient (p = 0.0306) and lesion (p = 0.0001) based analyses.
Na18F bone PET is more accurate than bone scan for BM evaluation.
PMCID: PMC3655309  PMID: 23690722
Na18F; Positron emission tomography; Positron emission tomography/computed tomography; 99mTc-HDP; Bone scan; Bone metastasis
3.  Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus 
Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4+ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4+ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.
Twenty-five adult patients with SLE and 26 healthy subjects matched for gender and age (± 2 years) were recruited. Peripheral blood mononuclear cells (PBMCs) from patients and healthy subjects were stimulated for 4 h ex vivo with phorbol myristate acetate (PMA) and ionomycin. The frequency of CD4+ T cells producing IL-17 and/or IFN-γ was measured by using flow cytometry. Expression of Th17-associated chemokine receptors CCR4 and CCR6 on CD4+ T cells as well as plasma levels of Th17-polarizing cytokines were assessed. Disease activity was evaluated by the SLE disease activity index score (SLEDAI). Unpaired t test and Pearson correlation were used for statistical analyses.
Patients with SLE had an increased frequency of CD4+IL-17+ T cells compared with healthy subjects. However, the frequency of CD4+IFN-γ+ T cells was similar between the two groups, indicating an altered balance of Th17 and Th1 cell responses in SLE. Patients with SLE also had an increased frequency of CD4+CCR4+CCR6+ T cells that are known to produce IL-17. The frequency of CD4+IL-17+ T cells and CD4+CCR4+CCR6+ T cells correlated with disease activity. In measuring plasma levels of the Th17-polarizing cytokines, levels of IL-6 were higher in patients with SLE than in healthy subjects, although levels of IL-1β, IL-21, IL-23, and transforming growth factor (TGF)-β were not different between the two groups.
We demonstrate an enhanced Th17 cell response that correlates with disease activity in patients with SLE, suggesting a role for IL-17 in the pathogenesis of lupus. Our data indicate that the mechanisms involved in balancing Th1 and Th17 regulation, as well as in producing IL-6, are aberrant in SLE, leading to an increased Th17 response. We suggest that CCR4 and CCR6 expression on CD4+ T cells should be considered as markers of disease activity, and that IL-17 blocking may offer a therapeutic target in SLE.
PMCID: PMC2888202  PMID: 20334681
4.  IL-6 Receptor α Defines Effector Memory CD8+ T Cells Producing Th2 Cytokines and Expanding in Asthma 
Rationale: Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor α (IL-6Rα) with asthma was reported, suggesting their involvement in asthma.
Objectives: To determine whether and how IL-6Rα defines a distinct effector memory (EM) CD8+ T-cell population in health and disease.
Methods: EM CD8+ T cells expressing IL-6Rα (IL-6Rαhigh) were identified in human peripheral blood and analyzed for function, gene, and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum.
Measurements and Main Results: A unique population of IL-6Rαhigh EM CD8+ T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison with other EM CD8+ T cells. In fact, GATA3 was required for IL-6Rα expression. Patients with asthma had an increased frequency of IL-6Rαhigh EM CD8+ T cells in peripheral blood compared with healthy control subjects. Also, IL-6Rαhigh EM CD8+ T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens.
Conclusions: Human IL-6Rαhigh EM CD8+ T cells is a unique cell subset that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.
PMCID: PMC4299645  PMID: 25390970
IL-6 receptor; CD8+ T cells; Th2 cytokines; asthma; human
5.  Tc-99m Hydroxymethylene Diphosphonate (HMDP) Renal Uptake as a Surrogate Marker of Postoperative Impairment of the Glomerular Filtration Rate in Renal Tumor Patients Following Nephron-Sparing Surgery 
Purpose: We investigated Tc-99m hydroxymethylene diphosphonate (HMDP) scintigraphy findings in renal tumor patients from the perspective of postoperative renal dysfunction following nephron-sparing surgery (NSS). Methods: Forty-three renal tumor patients (M:F = 28:15, age 53.9 ± 12.5 years) who had undergone Tc-99m HMDP scintigraphy after NSS were enrolled. The patients were divided into HMDP+ or HMDP− groups by visual assessment, and the asymmetric index (ASI) was calculated using a region-of-interest analysis. In 16 patients, the total and split glomerular filtration rate (GFR) was assessed using Tc-99m diethylenetriaminepentaacetic acid (DTPA) scintigraphy at baseline and at 3 and 6 months post-NSS. Results: High Tc-99m HMDP uptake was observed in the operated kidneys, but this did not persist later than 7 days post-NSS. Split GFR of the operated kidneys at baseline (58.5 ± 9.3 ml/min) was significantly reduced at 6 months post-NSS (40.1 ± 5.9 ml/min, p < 0.001) in only those who showed intense uptake of Tc-99m HMDP. Declines in both total GFR (p = 0.010 and p = 0.002 for 3 and 6 months, respectively) and split GFR of the operated kidneys (p < 0.001 and p < 0.001 for 3 and 6 months, respectively) were clearly evidenced at 3 and 6 months post-NSS only in patients with high Tc-99m HMDP in the operated kidneys. The ASI was negatively correlated with %change in the split GFR of these operated kidneys at 6 months post-NSS (rho =−0.578, p = 0.0304). Conclusions: Tc-99m HMDP uptake within 1 week following NSS is a surrogate marker of GFR impairment over 6 months post-NSS.
PMCID: PMC4571664  PMID: 26396630
Tc-99m phosphonate; Scintigraphy; Glomerular filtration rate; Nephrectomy
6.  CD4+VEGFR1HIGH T cell as a novel Treg subset regulates inflammatory bowel disease in lymphopenic mice 
Cellular and Molecular Immunology  2015;12(5):592-603.
Regulatory T cells (Tregs) are a specialized subpopulation of T cells that control the immune response and thereby maintain immune system homeostasis and tolerance to self-antigens. Many subsets of CD4+ Tregs have been identified, including Foxp3+, Tr1, Th3, and Foxp3neg iT(R)35 cells. In this study, we identified a new subset of CD4+VEGFR1high Tregs that have immunosuppressive capacity. CD4+VEGFR1high T cells, which constitute approximately 1.0% of CD4+ T cells, are hyporesponsive to T-cell antigen receptor stimulation. Surface marker and FoxP3 expression analysis revealed that CD4+VEGFR1high T cells are distinct from known Tregs. CD4+VEGFR1high T cells suppressed the proliferation of CD4+CD25− T cell as efficiently as CD4+CD25high natural Tregs in a contact-independent manner. Furthermore, adoptive transfer of CD4+VEGFR1+ T cells from wild type to RAG-2-deficient C57BL/6 mice inhibited effector T-cell-mediated inflammatory bowel disease. Thus, we report CD4+ VEGFR1high T cells as a novel subset of Tregs that regulate the inflammatory response in the intestinal tract.
PMCID: PMC4579660  PMID: 26211666
inflammatory bowel disease; regulatory T cells; suppression; vascular endothelial growth factor receptor 1
7.  Functional Phenotype of Synovial Monocytes Modulating Inflammatory T-Cell Responses in Rheumatoid Arthritis (RA) 
PLoS ONE  2014;9(10):e109775.
Monocytes function as crucial innate effectors in the pathogenesis of chronic inflammatory diseases, including autoimmunity, as well as in the inflammatory response against infectious pathogens. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. Although accumulating evidence suggests distinct functions of monocyte subsets in inflammatory conditions, their pathogenic roles in autoimmune diseases remain unclear. Thus, we investigated the phenotypic and functional characteristics of monocytes derived from synovial fluid and peripheral blood in RA patients in order to explore the pathogenic roles of these cells. In RA patients, CD14+CD16+, but not CD14dimCD16+, monocytes are predominantly expanded in synovial fluid and, to a lesser degree, in peripheral blood. Expression of co-signaling molecules of the B7 family, specifically CD80 and CD276, was markedly elevated on synovial monocytes, while peripheral monocytes of RA and healthy controls did not express these molecules without stimulation. To explore how synovial monocytes might gain these unique properties in the inflammatory milieu of the synovial fluid, peripheral monocytes were exposed to various stimuli. CD16 expression on CD14+ monocytes was clearly induced by TGF-β, although co-treatment with IL-1β, TNF-α, or IL-6 did not result in any additive effects. In contrast, TLR stimulation with LPS or zymosan significantly downregulated CD16 expression such that the CD14+CD16+ monocyte subset could not be identified. Furthermore, treatment of monocytes with IFN-γ resulted in the induction of CD80 and HLA-DR expression even in the presence of TGF-β. An in vitro assay clearly showed that synovial monocytes possess the unique capability to promote Th1 as well as Th17 responses of autologous peripheral CD4 memory T cells. Our findings suggest that the cytokine milieu of the synovial fluid shapes the unique features of synovial monocytes as well as their cardinal role in shaping inflammatory T-cell responses in RA.
PMCID: PMC4201467  PMID: 25329467
8.  Multiparametric Monitoring of Early Response to Antiangiogenic Therapy: A Sequential Perfusion CT and PET/CT Study in a Rabbit VX2 Tumor Model 
The Scientific World Journal  2014;2014:701954.
Objectives. To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Methods. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group) or saline infusion (control group). Perfusion CT was analyzed to calculate blood flow (BF), blood volume (BV), and permeability surface area product (PS); FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG), entropy, and homogeneity. The flow-metabolic ratio (FMR) was also calculated and immunohistochemical analysis of microvessel density (MVD) was performed. Results. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. Conclusions. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism.
PMCID: PMC4213998  PMID: 25383376
9.  CD39-mediated effect of human bone marrow-derived mesenchymal stem cells on the human Th17 cell function 
Purinergic Signalling  2013;10(2):357-365.
This study investigated the immune-modulatory effects of human bone marrow-derived mesenchymal stem cells (hBMSCs) on human Th17 cell function through the CD39-mediated adenosine-producing pathway. The suppressive effects of hBMSCs were evaluated by assessing their effects on the proliferation of Th17 cells and the secretion of interferon (IFN)-γ and interleukin (IL)-17A by Th17 cells with or without anti-CD39 treatment. Changes in CD39 and CD73 expression on the T cells with or without co-culture of hBMSCs were evaluated by flow cytometry. hBMSCs effectively suppressed the proliferation of Th17 cells and the secretion of both IL-17A and IFN-γ from Th17 cells using by both flow cytometry and ELISA, while anti-CD39 treatment significantly reduced the inhibitory effects of hBMSCs on the proliferation and secretion of the Th17 cells. The hBMSCs induced increased expression of the CD39 and CD73 on T cells correlated with the suppressive function of hBMSCs, which was accompanied by increased adenosine production. Our data suggests that hBMSCs can effectively suppress immune responses of the Th17 cells via the CD39-CD73-mediated adenosine-producing pathway.
Electronic supplementary material
The online version of this article (doi:10.1007/s11302-013-9385-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4040175  PMID: 24043462
Bone marrow-derived mesenchymal stem cells; Th17 cells; CD39; CD73; Interleukin-17; Interferon-γ; Adenosine
10.  Impaired Coronary Flow Reserve Is the Most Important Marker of Viable Myocardium in the Myocardial Segment-Based Analysis of Dual-Isotope Gated Myocardial Perfusion Single-Photon Emission Computed Tomography 
Korean Journal of Radiology  2014;15(2):277-285.
The aim of this study was to investigate the most robust predictor of myocardial viability among stress/rest reversibility (coronary flow reserve [CFR] impairment), 201Tl perfusion status at rest, 201Tl 24 hours redistribution and systolic wall thickening of 99mTc-methoxyisobutylisonitrile using a dual isotope gated myocardial perfusion single-photon emission computed tomography (SPECT) in patients with coronary artery disease (CAD) who were re-vascularized with a coronary artery bypass graft (CABG) surgery.
Materials and Methods
A total of 39 patients with CAD was enrolled (34 men and 5 women), aged between 36 and 72 years (mean 58 ± 8 standard in years) who underwent both pre- and 3 months post-CABG myocardial SPECT. We analyzed 17 myocardial segments per patient. Perfusion status and wall motion were semi-quantitatively evaluated using a 4-point grading system. Viable myocardium was defined as dysfunctional myocardium which showed wall motion improvement after CABG.
The left ventricular ejection fraction (LVEF) significantly increased from 37.8 ± 9.0% to 45.5 ± 12.3% (p < 0.001) in 22 patients who had a pre-CABG LVEF lower than 50%. Among 590 myocardial segments in the re-vascularized area, 115 showed abnormal wall motion before CABG and 73.9% (85 of 115) had wall motion improvement after CABG. In the univariate analysis (n = 115 segments), stress/rest reversibility (p < 0.001) and 201Tl rest perfusion status (p = 0.024) were significant predictors of wall motion improvement. However, in multiple logistic regression analysis, stress/rest reversibility alone was a significant predictor for post-CABG wall motion improvement (p < 0.001).
Stress/rest reversibility (impaired CFR) during dual-isotope gated myocardial perfusion SPECT was the single most important predictor of wall motion improvement after CABG.
PMCID: PMC3955796  PMID: 24642696
Myocardium; Tissue viability; Ischemia; Coronary artery bypass grafting; Single-photon emission-computed tomography
11.  Maintenance of CMV-specific CD8+ T cell responses and the relationship of IL-27 to IFN-γ levels with aging 
Cytokine  2012;61(2):485-490.
We investigated whether healthy young (age ≤ 40) and elderly (age ≥ 65) people infected with cytomegalovirus (CMV) had similar levels of CD8+ T cell cytokine production and proliferation in response to an immunodominant CMV pp65 peptide pool given the role of CD8+ T cells in controlling viral infection and the association of CMV with immunosenescence. Plus, we determined the effects of aging and CMV-infectious status on plasma levels of IL-27, an innate immune cytokine with pro- and anti-inflammatory properties, as well as on its relationship to IFN-γ in that IL-27 can promote the production of IFN-γ. The results of our study show that young and elderly people had similar levels of CD8+ T cell proliferation, and IFN-γ and TNF-α production in response to CMV pp65 peptides. Plasma levels of IL-27 were similar between the two groups although CMV-infected young and elderly people had a trend toward increased levels of IL-27. Regardless of aging and CMV-infectious status, plasma levels of IL-27 correlated highly with plasma levels of IFN-γ. These findings suggest the maintenance of CMV pp65-specific CD8+ T cell proliferation and cytokine production with aging as well as the sustaining of circulatory IL-27 levels and its biological link to IFN-γ in young and elderly people irrespective of CMV infection.
PMCID: PMC3563774  PMID: 23280240
CD8+ T cells; IL-27; Human; aging; cytomegalovirus (CMV)
12.  Improved measurement of the glomerular filtration rate from Tc-99m DTPA scintigraphy in patients following nephrectomy 
European Radiology  2013;24(2):413-422.
We aimed to improve Tc-99m DTPA glomerular filtration rate (GFR) scintigraphy (Gates’ method) in a prospective study using Cr-51 EDTA GFR test as a gold standard.
Fifty-seven Tc-99m DTPA GFR scintigrams in 45 subjects (male/female = 33:12, age = 45.9 ± 17.6 years, 14 healthy volunteers and 31 nephrectomised patients) were compared using Cr-51 EDTA GFR tests. Using the %renal uptake of Tc-99m DTPA and Cr-51 EDTA GFR, a revised equation for GFR was established through linear regression analysis.
The revised equation for improved GFR was GFR(mL/min) = (%renal uptake × 11.7773) − 0.7354. Gates’ original GFRs (70.1 ± 20.5 mL/min/1.73 m2) were significantly lower than Cr-51 EDTA GFRs (97.0 ± 31.9 mL/min/1.73 m2; P < 0.0001), but the improved GFRs (98.0 ± 26.3 mL/min/1.73 m2) were not different from (P = 0.7360) and had a significant correlation with (r = 0.73, P < 0.0001) the Cr-51 EDTA GFRs. The revised GFR equation effectively demonstrated perioperative GFR changes in kidneys that were operated on and the contralateral kidneys at 3 and 6 months post-partial nephrectomy (n = 25).
GFR measurement using Tc-99m DTPA scintigraphy could be significantly improved by a revised equation derived from the comparison with Cr-51 EDTA GFR.
Key Points
• Measurement of glomerular filtration rate is difficult following nephrectomy.
• Measurements can be significantly improved by new renal sctintigraphic methods.
• This helps physicians to measure kidney function of patients following nephrectomy.
• Management of renal tumour patients should become more effective.
PMCID: PMC3890538  PMID: 24141715
Gamma camera imaging; Glomerular filtration rate; Tc-99m DTPA; Nephrectomy; Cr-51 EDTA
13.  Stem cell membrane engineering for cell rolling using peptide conjugation and tuning of cell-selectin interaction kinetics 
Biomaterials  2012;33(20):5004-5012.
Dynamic cell-microenvironment interactions regulate many biological events and play a critical role in tissue regeneration. Cell homing to targeted tissues requires well balanced interactions between cells and adhesion molecules on blood vessel walls. However, many stem cells lack affinity with adhesion molecules. It is challenging and clinically important to engineer these stem cells to modulate their dynamic interactions with blood vessels. In this study, a new chemical strategy was developed to engineer cell-microenvironment interactions. This method allowed the conjugation of peptides onto stem cell membranes without affecting cell viability, proliferation or multipotency. Mesenchymal stem cells (MSCs) engineered in this manner showed controlled firm adhesion and rolling on E-selectin under physiological shear stresses. For the first time, these biomechanical responses were achieved by tuning the binding kinetics of the peptide-selectin interaction. Rolling of engineered MSCs on E-selectin is mediated by a Ca2+ independent interaction, a mechanism that differs from the Ca2+ dependent physiological process. This further illustrates the ability of this approach to manipulate cell-microenvironment interactions, in particular for the application of delivering cells to targeted tissues. It also provides a new platform to engineer cells with multiple functionalities.
PMCID: PMC3366278  PMID: 22494889
14.  The Relationship of Cytomegalovirus (CMV) Infection with circulatory IFN-α levels and IL-7 receptor α expression on CD8+ T cells in Human Aging 
Cytokine  2012;58(3):332-335.
The IL-7 receptor alpha (IL-7Rα) is the high affinity receptor for IL-7 which is essential for T cell homeostasis. We recently reported an age-associated expansion of human effector memory (EM) CD8+ T cells expressing IL-7Rα low (IL-7Rαlow), which could be detrimental to hosts by occupying “immunological space”. We investigated the potential mechanisms for this phenomenon, focusing on cytomegalovirus (CMV) infection and INF-α. In the elderly (age≥65), CMV infection was associated with a decreased frequency of naïve CD8+ T cells as well as with an increased frequency of total EM and IL-7Rαlow EM CD8+ T cells. However, in the young (age≤40), this viral infection was associated only with an increased frequency of IL-7Rαlow EM CD8+ T cells. There was no association found between CMV immune status and plasma levels of IFN-α. In CMV-infected young and elderly people, INF-α levels had no correlation with the frequency of IL-7Rαlow EM CD8+ T cells although this cytokine levels correlated with the frequency of IL-7Rαlow CD45RA+ EM CD8+ T cells in CMV-uninfected elderly people. Our findings suggest that the effect of CMV infection on the frequency of CD8+ T cell subsets may begin with IL-7Rαlow EM CD8+ T cells and spread to other subsets with aging. Also, IFN-α could be associated with the expansion of IL-7Rαlow CD45RA+ EM CD8+ T cells in the CMV-uninfected elderly.
PMCID: PMC3340433  PMID: 22484243
Human; aging; cytomegalovirus (CMV); IL-7; CD8+ T cells
15.  1,25(OH)2 vitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved non-coding sequence region 
Forkhead box P3 (FOXP3)-positive regulatory T cells (Treg) are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4+ T cells (induced Treg, iTreg) by T cell receptor (TCR) triggering, IL-2 and TGF-β or retinoic acid. 1,25(OH)2 vitamin D3 (VD3) affects the functions of immune cells including T cells. 1,25(OH)2VD3 binds the nuclear vitamin D receptor (VDR) that binds target DNA sequences known as the vitamin D response element (VDRE). Although 1,25(OH)2VD3 can promote FOXP3 expression in CD4+ T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)2VD3 is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)2VD3-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. Here we demonstrated the presence of VDREs in the intronic conserved non-coding sequence (CNS) region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)2VD3. In addition, VD-iTreg cells suppressed the proliferation of target CD4+ T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)2VD3 can affect human immune responses by regulating FOXP3 expression in CD4+ T cells through direct VDR binding to the FOXP3 gene which is essential for inhibitory function of VD-iTreg cells.
PMCID: PMC3358577  PMID: 22529297
16.  Active Hexose Correlated Compound promotes T helper (Th) 17 and 1 cell responses via inducing IL-1β production from monocytes in humans. 
Cellular Immunology  2012;275(1-2):19-23.
The differentiation of T helper (Th) cells is critically dependent on cytokine milieu. The innate immune monocytes produce IL-1β which can affect the development of Th17 and Th1 cells that predominantly produce IL-17 and IFN-γ, respectively. Oligosaccharides from microorganisms, crops and mushrooms can stimulate innate immune cells. Active Hexose Correlated Compound (AHCC) that contains a large amount of oligosaccharides is a natural extract prepared from the mycelium of the edible Basidiomycete fungus. This compound is reported to modulate immune responses against pathogens although the mechanisms for this effect are largely unknown. Here we show that AHCC could induce high levels of IL-1β production from human monocytes. Furthermore, AHCC-treated monocytes increased the production of IL-17 and IFN-γ from autologous CD4+ T cells, which was blocked by adding IL-1 receptor antagonist. These finding provide new insight into how food supplements like AHCC could enhance human immunity by modulating monocytes and Th cells.
PMCID: PMC3348379  PMID: 22531483
Cytokines; T helper cells; monocytes
17.  Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity 
Nature medicine  2012;18(10):1518-1524.
The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced ERK phosphorylation in naïve CD4+ T cells (P<0.0001) while other signals, such as ZAP70 and PLC-γ1 phosphorylation were not impaired. The defective ERK signaling was caused by the dual specific phosphatase (DUSP) 6 whose protein levels increased with age (r = 0.68, P < 0.0001) due to a decline in repression by miR-181a (r = −0.59, P < 0.0001). Reconstitution of miR-181a lowered DUSP6 levels in naïve CD4+ T cells in elderly individuals. DUSP6 repression with miR-181a or specific siRNA, and DUSP6 inhibition with the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4+ T cell responses as seen by increased expression of activation markers, improved proliferation and supported preferential TH1 differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.
PMCID: PMC3466346  PMID: 23023500
18.  Usefulness of Combined Metabolic–Volumetric Indices of 18F-FDG PET/CT for the Early Prediction of Neoadjuvant Chemotherapy Outcomes in Breast Cancer 
The purpose of this study was to investigate the usefulness of metabolic-volumetric indices of 18F- fluorodeoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for the evaluation of neoadjuvant chemotherapy outcomes in breast cancer.
Twenty-four patients with locally advanced breast cancer were enrolled in the study. They underwent baseline 18F-FDG PET/CT scan and received four or six cycles of neoadjuvant chemotherapy, interim 18F-FDG PET/CT was done after second cycle of chemotherapy. Maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary lesions were calculated. Reduction rates of these parameters were obtained between baseline and interim 18F-FDG PET/CT. Chemotherapy outcomes were assessed using tumor size reduction rate and histological grading system (Miller and Payne system). Reduction rates of SUVmax, MTV, and TLG correlated with chemotherapy outcomes.
MTV and TLG reduction rates showed significant correlation with tumor size reduction rate (R = 0.68, P = 0.0004; R = 0.62, P = 0.002, respectively). However, SUVmax reduction rate showed no significant correlation. MTV and TLG reduction rates were significantly higher in responders than nonresponders, as determined by Miller and Payne system (P < 0.0007, P < 0.002). However, SUVmax reduction rate showed no significant difference. On ROC analysis, the area under the MTV and TLG curves was 0.886, and that of SUVmax was 0.743. Sensitivity, specificity, positive predictive value, and negative predictive value to predict histopathologic response were the same for MTV and TLG, and the values were 100 %, 85.7 %, 83.3 %, and 100 %, respectively (at the reduction rate of 93.2 % for MTV, and 95.8 % for TLG).
Changes of metabolic–volumetric indices successfully reflected the neoadjuvant chemotherapy outcomes. MTV and TLG could be robust indices in discriminating pathologic responder as SUVmax, after neoadjuvant chemotherapy.
PMCID: PMC4035214  PMID: 24895506
Breast cancer; Neoadjuvant chemotherapy; Metabolic tumor volume; Total lesion glycolysis; 18F-FDG PET/CT
19.  Evaluation of Salivary Gland Dysfunction Using Salivary Gland Scintigraphy in Sjögren’s Syndrome Patients and in Thyroid Cancer Patients after Radioactive Iodine Therapy 
Salivary gland scintigraphy (SGS) provides an objective means of diagnosing salivary gland dysfunction in Sjögren’s syndrome (SS) patients and in thyroid cancer patients after radioactive iodine (RAI) therapy. In the present study, SGS was performed in SS patients and in thyroid cancer patients post-RAI, and scintigraphic parameters were compared.
Twenty-eight SS patients (males:females = 1:27, age 53.3 ± 11.9 years), 28 controls (males:females = 3:25, age 54.1 ± 10.1 years), and 92 thyroid cancer patients (males:females = 28:64, age 46.2 ± 12.9) who had undergone a session of high-dose RAI therapy (mean dose, 5.2 ± 1.5 GBq) were included. SGS was performed using Tc-99m pertechnetate (925 MBq). Scintigraphic parameters (parotid uptake ratio PU, submandibular uptake ratio SU, percentage parotid excretion %PE, and percentage submandibular excretion %SE) were measured and compared for SS, thyroid cancer post-RAI, and control patients.
PU, SU, %SE, and %PE were all significantly lower in SS than in post-RAI thyroid cancer or control patients (p < 0.05), whereas only %PE was significantly lower in post-RAI thyroid cancer patients than in controls (p < 0.05). SU and %SE were found to be correlated with the unstimulated whole salivary flow rate.
Scintigraphic parameters derived from SGS can play a crucial role in the detection of salivary gland dysfunction in SS patients and in post-RAI thyroid cancer patients.
PMCID: PMC4043001  PMID: 24899999
Salivary gland scintigraphy; Sjögren’s syndrome; Radioactive iodine therapy; Thyroid cancer; Tc-99m pertechnetate
20.  Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis 
IL-1b signaling augments continued splenic monocyte supply during acute inflammation.
Monocytes (Mo) and macrophages (MΦ) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MΦ and their effector functions without compromising innate immunity’s critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MΦ in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1β; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MΦ exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MΦ flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure.
PMCID: PMC3260875  PMID: 22213805
21.  Age-associated alteration in naive and memory Th17 cell response in humans 
Th17 cells produce IL-17 that plays an important role in host defense. However, little is known about whether aging affects human Th17 cells. Here we demonstrated that healthy elderly people (age≥65) had a decreased frequency of IL-17-producing cells in memory CD4+ T cells compared to healthy young people (age≤40) while both groups had similar frequencies of IFN-γ-producing cells in the same memory cell subset as measured by flow cytometry. In contrast, the healthy elderly had increased differentiation of IL-17-producing effector cells but not IFN-γ-producing cells from naïve CD4+ T cells compared to the healthy young. The results of ELISA also showed similar findings with increased IL-17 production from naïve CD4+ T cells and decreased IL-17 production from memory CD4+ T cells in the elderly compared to the young. These findings indicate that aging differentially affects naïve and memory Th17 cell responses in humans.
PMCID: PMC3115516  PMID: 21489886
Human; aging; IL-17; T helper 17 (Th17) cells; CD4+ T cells
22.  Antibacterial effect of citrus press-cakes dried by high speed and far-infrared radiation drying methods 
Nutrition Research and Practice  2012;6(3):187-194.
In this study, the antibacterial effect was evaluated to determine the benefits of high speed drying (HSD) and far-infrared radiation drying (FIR) compared to the freeze drying (FD) method. Citrus press-cakes (CPCs) are released as a by-product in the citrus processing industry. Previous studies have shown that the HSD and FIR drying methods are much more economical for drying time and mass drying than those of FD, even though FD is the most qualified drying method. The disk diffusion assay was conducted, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined with methanol extracts of the dried CPCs against 11 fish and five food-related pathogenic bacteria. The disk diffusion results indicated that the CPCs dried by HSD, FIR, and FD prevented growth of all tested bacteria almost identically. The MIC and MBC results showed a range from 0.5-8.0 mg/mL and 1.0-16.0 mg/mL respectively. Scanning electron microscopy indicated that the extracts changed the morphology of the bacteria cell wall, leading to destruction. These results suggest that CPCs dried by HSD and FIR showed strong antibacterial activity against pathogenic bacteria and are more useful drying methods than that of the classic FD method in CPCs utilization.
PMCID: PMC3395782  PMID: 22808341
Citrus press-cakes; fish and food-related pathogenic bacteria; high speed drying; far-infrared radiation drying; antibacterial agent
23.  Therapeutic siRNA silencing in inflammatory monocytes 
Nature biotechnology  2011;29(11):1005-1010.
Inflammatory monocytes -- but not the non-inflammatory subset -- depend on the chemokine receptor CCR2 for distribution to injured tissue and stimulate disease progression. Precise therapeutic targeting of this inflammatory monocyte subset could spare innate immunity's essential functions for maintenance of homeostasis and thus limit unwanted effects. Here we developed siRNA nanoparticles targeting CCR2 expression in inflammatory monocytes. We identified an optimized lipid nanoparticle and silencing siRNA sequence that when administered systemically, had rapid blood clearance, accumulated in spleen and bone marrow and showed high cellular localization of fluorescently tagged siRNA inside monocytes. Efficient degradation of CCR2 mRNA in monocytes prevented their accumulation in sites of inflammation. Specifically, the treatment attenuated their number in atherosclerotic plaques, reduced infarct size following coronary artery occlusion, prolonged normoglycemia in diabetic mice after pancreatic islet transplantation and resulted in reduced tumor volumes and lower numbers of tumor-associated macrophages. Taken together, siRNA nanoparticle-mediated CCR2 gene silencing in leukocytes selectively modulates functions of innate immune cell subtypes and may allow for the development of specific anti-inflammatory therapy.
PMCID: PMC3212614  PMID: 21983520
24.  PET/MRI of inflammation in myocardial infarction 
The aim of this study was to explore post-MI myocardial inflammation.
Innate immune cells are centrally involved in infarct healing and are emerging therapeutic targets in cardiovascular disease, however; clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the non-ischemic remote zone recruits monocytes.
Acute inflammation was followed in mice with coronary ligation by 18FDG PET/MRI, FACS, PCR and histology.
Gd-DTPA enhanced infarcts showed high 18FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b+ cells had 4-fold higher 18FDG uptake than the infarct tissue from which they were isolated (P<0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (~104/mg myocardium, 5.6-fold increase, P<0.01), a finding mirrored by macrophage infiltration in remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative PCR showed robust increase of recruiting adhesion molecules and chemokines in remote myocardium (e.g. 12-fold increase of MCP-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in non-infarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post MI dilation.
These studies shed light on the innate inflammatory response in remote myocardium after myocardial infarction.
PMCID: PMC3257823  PMID: 22222080
PET/MRI; myocardial infarction; inflammation; remote myocardium
25.  Regulation of T cell receptor signaling by activation-induced zinc influx 
Zinc enhances TCR signaling in part by inhibiting Shp-1 recruitment to the TCR synapse.
Zinc is a trace element that is essential for innate and adaptive immune responses. In addition to being a structural element of many proteins, zinc also functions as a neurotransmitter and an intracellular messenger. Temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. We provide evidence that zinc functions as an ionic signaling molecule after T cell activation. Cytoplasmic zinc concentrations increased within 1 min after T cell receptor (TCR) triggering, in particular in the subsynaptic compartment. The increase depended on the extracellular zinc concentrations and was inhibited by silencing zinc transporter Zip6. Increased zinc influx reduced the recruitment of SHP-1 to the TCR activation complex, augmented ZAP70 phosphorylation and sustained calcium influx. By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli.
PMCID: PMC3135340  PMID: 21422171

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