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1.  Prevalence of Anti-Ganglioside Antibodies and Their Clinical Correlates with Guillain-Barré Syndrome in Korea: A Nationwide Multicenter Study 
Background and Purpose
No previous studies have investigated the relationship between various anti-ganglioside antibodies and the clinical characteristics of Guillain-Barré syndrome (GBS) in Korea. The aim of this study was to determine the prevalence and types of anti-ganglioside antibodies in Korean GBS patients, and to identify their clinical significance.
Serum was collected from patients during the acute phase of GBS at 20 university-based hospitals in Korea. The clinical and laboratory findings were reviewed and compared with the detected types of anti-ganglioside antibody.
Among 119 patients, 60 were positive for immunoglobulin G (IgG) or immunoglobulin M antibodies against any type of ganglioside (50%). The most frequent type was IgG anti-GM1 antibody (47%), followed by IgG anti-GT1a (38%), IgG anti-GD1a (25%), and IgG anti-GQ1b (8%) antibodies. Anti-GM1-antibody positivity was strongly correlated with the presence of preceding gastrointestinal infection, absence of sensory symptoms or signs, and absence of cranial nerve involvement. Patients with anti-GD1a antibody were younger, predominantly male, and had more facial nerve involvement than the antibody-negative group. Anti-GT1a-antibody positivity was more frequently associated with bulbar weakness and was highly associated with ophthalmoplegia when coupled with the coexisting anti-GQ1b antibody. Despite the presence of clinical features of acute motor axonal neuropathy (AMAN), 68% of anti-GM1- or anti-GD1a-antibody-positive cases of GBS were diagnosed with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) by a single electrophysiological study.
Anti-ganglioside antibodies were frequently found in the serum of Korean GBS patients, and each antibody was correlated strongly with the various clinical manifestations. Nevertheless, without an anti-ganglioside antibody assay, in Korea AMAN is frequently misdiagnosed as AIDP by single electrophysiological studies.
PMCID: PMC4017025  PMID: 24829594
Guillain-Barré syndrome; ganglioside; antibodies; Korea; acute motor axonal neuropathy
3.  Differential Diagnosis of Patients with Inconclusive Parkinsonian Features Using [18F]FP-CIT PET/CT 
It is often difficult to differentiate parkinsonism, especially when patients show uncertain parkinsonian features. We investigated the usefulness of dopamine transporter (DAT) imaging for the differential diagnosis of inconclusive parkinsonism using [18F]FP-CIT PET.
Twenty-four patients with inconclusive parkinsonian features at initial clinical evaluation and nine healthy controls were studied. Patients consisted of three subgroups: nine patients whose diagnoses were unclear concerning whether they had idiopathic Parkinson’s disease or drug-induced parkinsonism (‘PD/DIP’), nine patients who fulfilled neither the diagnostic criteria of PD nor of essential tremor (‘PD/ET’), and six patients who were alleged to have either PD or atypical parkinsonian syndrome (‘PD/APS’). Brain PET images were obtained 120 min after injection of 185 MBq [18F]FP-CIT. Imaging results were quantified and compared with follow-up clinical diagnoses.
Overall, 11 of 24 patients demonstrated abnormally decreased DAT availability on the PET scans, whereas 13 were normal. PET results could diagnose PD/DIP and PD/ET patients as having PD in six patients, DIP in seven, and ET in five; however, the diagnoses of all six PD/APS patients remained inconclusive. Among 15 patients who obtained a final follow-up diagnosis, the image-based diagnosis was congruent with the follow-up diagnosis in 11 patients. Four unsolved cases had normal DAT availability, but clinically progressed to PD during the follow-up period.
[18F]FP-CIT PET imaging is useful in the differential diagnosis of patients with inconclusive parkinsonian features, except in patients who show atypical features or who eventually progress to PD.
PMCID: PMC4028478  PMID: 24900150
Parkinsonism; Inconclusive parkinsonian features; Dopamine transporter; [18F]FP-CIT; Positron emission tomography
4.  TRPA1-Dependent Pruritus in IL-13-Induced Chronic Atopic Dermatitis 
Chronic debilitating pruritus is a cardinal feature of a topic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In the present study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13 transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from normal subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1+ dermal afferent nerves and TRPA1+ mast cells in a Th2-dominated inflammatory environment.
PMCID: PMC4175413  PMID: 24140646
5.  A Disease Modification Effect of APOE E4 on the Association between Urinary Albumin Excretion and Cognition in Korean Adults 
Disease Markers  2014;2014:724281.
Background. No previous study examined a disease modifying effect of APOE E4 status on the association between the urinary albumin-to-creatinine ratio (UACR) and cognition. This study aimed to investigate whether APOE E4 modified the association in Korean adults. Methods. We performed a cross-sectional study in adults aged 45 to 74 who were living in Namwon City, Republic of Korea. Cognitive function was measured with the Korean version of modified Mini-Mental State Examination (K-mMMSE) and cognitive impairment was defined as scores falling below the 25th percentile of the K-mMMSE according to age, sex, and educational attainments. Results. A total of 10,190 participants (4006 men and 6184 women) were analyzed in the present study. Of these, 1698 subjects (16.7%) were APOE E4 carriers. The UACR values were negatively associated with the K-mMMSE scores, even after adjusting for potential confounders including age, sex, education, and vascular risk factors. APOE E4 modified the association significantly, resulting in a steeper decline of cognitive function with the increase in UACR in E4 carriers (P for interaction = 0.021). Conclusion. Higher UACR values were significantly associated with cognitive dysfunction in the general Korean population, with cognition in APOE E4 carriers being more severely affected by increased UACR.
PMCID: PMC4230004  PMID: 25530658
6.  The Type III TGF-β receptor regulates filopodia formation via a Cdc42-mediated IRSP53: NWASP interaction in epithelial cells 
The Biochemical journal  2013;454(1):79-89.
Cell adhesion and migration are tightly controlled by regulated changes in the actin cytoskeleton. Previously we reported that the TGF-β superfamily coreceptor, the type III TGF-β receptor (TβRIII/betaglycan), regulates cell adhesion, migration and invasion and suppresses cancer progression in part, through activation of the small GTPase, Cdc42, and Cdc42-dependent alterations to the actin cytoskeleton. Here we demonstrate that TβRIII specifically promotes filopodial formation and extension in MCF10A and HMEC mammary epithelial cells. Mechanistically, cell surface TβRIII and Cdc42 colocalize to filopodial structures and co-complex in a β-arrestin2 dependent, and a TβRI/TβRII independent manner. The β-arrestin2-mediated interaction between TβRIII and Cdc42 increases complex formation between the Cdc42 effectors, IRSp53 with N-WASP, to increase filopodial formation. We demonstrate a function link between filopodial structures and epithelial cell adhesion as regulated by the TβRIII-Cdc42 interaction. These studies identify TβRIII as a novel regulator of IRSP53/NWASP via Cdc42 to regulate filopodial formation and cell adhesion.
PMCID: PMC4082962  PMID: 23750457
TβRIII; filopodia; Cdc42; β-arrestin2; IRSp53
7.  Regulation of Nasal Airway Homeostasis and Inflammation in Mice by SHP-1 and Th2/Th1 Signaling Pathways 
PLoS ONE  2014;9(8):e103685.
Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev) mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ) and Th2 (IL-4 and IL-13) cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs) were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13), chemokines (eotaxin), and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.
PMCID: PMC4121172  PMID: 25090641
8.  The Balance of Cell Surface and Soluble Type III TGF-β Receptor Regulates BMP Signaling in Normal and Cancerous Mammary Epithelial Cells1 
Neoplasia (New York, N.Y.)  2014;16(6):489-500.
Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily that are over-expressed in breast cancer, with context dependent effects on breast cancer pathogenesis. The type III TGF-β receptor (TβRIII) mediates BMP signaling. While TβRIII expression is lost during breast cancer progression, the role of TβRIII in regulating BMP signaling in normal mammary epithelium and breast cancer cells has not been examined. Restoring TβRIII expression in a 4T1 murine syngeneic model of breast cancer suppressed Smad1/5/8 phosphorylation and inhibited the expression of the BMP transcriptional targets, Id1 and Smad6, in vivo. Similarly, restoring TβRIII expression in human breast cancer cell lines or treatment with sTβRIII inhibited BMP-induced Smad1/5/8 phosphorylation and BMP-stimulated migration and invasion. In normal mammary epithelial cells, shRNA-mediated silencing of TβRIII, TβRIII over-expression, or treatment with sTβRIII inhibited BMP-mediated phosphorylation of Smad1/5/8 and BMP induced migration. Inhibition of TβRIII shedding through treatment with TAPI-2 or expression of a non-shedding TβRIII mutant rescued TβRIII mediated inhibition of BMP induced Smad1/5/8 phosphorylation and BMP induced migration and/or invasion in both in normal mammary epithelial cells and breast cancer cells. Conversely, expression of a TβRIII mutant, which exhibited increased shedding, significantly reduced BMP-mediated Smad1/5/8 phosphorylation, migration, and invasion. These data demonstrate that TβRIII regulates BMP-mediated signaling and biological effects, primarily through the ligand sequestration effects of sTβRIII in normal and cancerous mammary epithelial cells and suggest that the ratio of membrane bound versus sTβRIII plays an important role in mediating these effects.
PMCID: PMC4198744  PMID: 25077702
BMP, bone morphogenetic protein; TβRIII, type III TGF-β receptor; sTβRIII, soluble type III TGF-β receptor CM, conditioned media; TAPI-2, N-(R)-[2-(Hydroxyaminocarbonyl)methyl]-4-methylpentanoyl-L-t-butyl-alanyl-L-alanine 2-aminoethyl Amide, TNF-α Protease Inhibitor-2; EV, empty vector; ∆shed-TβRIII, non-shedding TβRIII mutant; SS-TβRIII, super shedding TβRIII mutant
9.  Differential Diagnosis of Patients with Inconclusive Parkinsonian Features Using [18F]FP-CIT PET/CT 
It is often difficult to differentiate parkinsonism, especially when patients show uncertain parkinsonian features. We investigated the usefulness of dopamine transporter (DAT) imaging for the differential diagnosis of inconclusive parkinsonism using [18F]FP-CIT PET.
Twenty-four patients with inconclusive parkinsonian features at initial clinical evaluation and nine healthy controls were studied. Patients consisted of three subgroups: nine patients whose diagnoses were unclear concerning whether they had idiopathic Parkinson’s disease or drug-induced parkinsonism (‘PD/DIP’), nine patients who fulfilled neither the diagnostic criteria of PD nor of essential tremor (‘PD/ET’), and six patients who were alleged to have either PD or atypical parkinsonian syndrome (‘PD/APS’). Brain PET images were obtained 120 min after injection of 185 MBq [18F]FP-CIT. Imaging results were quantified and compared with follow-up clinical diagnoses.
Overall, 11 of 24 patients demonstrated abnormally decreased DAT availability on the PET scans, whereas 13 were normal. PET results could diagnose PD/DIP and PD/ET patients as having PD in six patients, DIP in seven, and ET in five; however, the diagnoses of all six PD/APS patients remained inconclusive. Among 15 patients who obtained a final follow-up diagnosis, the image-based diagnosis was congruent with the follow-up diagnosis in 11 patients. Four unsolved cases had normal DAT availability, but clinically progressed to PD during the follow-up period.
[18F]FP-CIT PET imaging is useful in the differential diagnosis of patients with inconclusive parkinsonian features, except in patients who show atypical features or who eventually progress to PD.
PMCID: PMC4028478  PMID: 24900150
Parkinsonism; Inconclusive parkinsonian features; Dopamine transporter; [18F]FP-CIT; Positron emission tomography
10.  Is it Feasible to Use the Commercially Available Autoquantitation Software for the Evaluation of Myocardial Viability on Small-Animal Cardiac F-18 FDG PET Scan? 
To evaluate the reliability of quantitation of myocardial viability on cardiac F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scans with three different methods of visual scoring system, autoquantitation using commercially available autoquantitation software, and infarct-size measurement using histogram-based maximum pixel threshold identification on polar-map in rat hearts.
A myocardial infarct (MI) model was made by left anterior descending artery (LAD) ligation in rat hearts. Eighteen MI rats underwent cardiac FDG-PET-computed tomography (CT) twice within a 4-week interval. Myocardium was partitioned into 20 segments for the comparison, and then we quantitated non-viable myocardium on cardiac FDG PET-CT with three different methods: method A—infarct-size measurement using histogram-based maximum pixel threshold identification on polar-map; method B—summed MI score (SMS) by a four-point visual scoring system; method C—metabolic non-viable values by commercially available autoquantitation software. Changes of non-viable myocardium on serial PET-CT scans with three different methods were calculated by the change of each parameter. Correlation and reproducibility were evaluated between the different methods.
Infarct-size measurement, visual SMS, and non-viable values by autoquantitation software presented proportional relationship to each other. All the parameters of methods A, B, and C showed relatively good correlation between each other. Among them, infarct-size measurement (method A) and autoquantitation software (method C) showed the best correlation (r = 0.87, p < 0.001). When we evaluated the changes of non-viable myocardium on the serial FDG-PET-CT- however, autoquantitation program showed less correlation with the other methods. Visual assessment (method B) and those of infarct size (method A) showed the best correlation (r = 0.54, p = 0.02) for the assessment of interval changes.
Commercially available quantitation software could be applied to measure the myocardial viability on small animal cardiac FDG-PET-CT scan. This kind of quantitation showed good correlation with infarct size measurement by histogram-based maximum pixel threshold identification. However, this method showed the weak correlation when applied in the measuring the changes of non-viable myocardium on the serial scans, which means that the caution will be needed to evaluate the changes on the serial monitoring.
PMCID: PMC4041970  PMID: 24900090
Myocardial viability; FDG PET; Autoquantitation; Myocardial infarct model
11.  Feasibility of PET Template-Based Analysis on F-18 FP-CIT PET in Patients with De Novo Parkinson’s Disease 
The aim of this study was to evaluate the feasibility of FP-CIT PET template-based quantitative analysis on F-18 FP-CIT PET in patients with de novo Parkinson’s disease (PD), compared with MR-based and manual methods. We also assessed the correlation of quantitative parameters of those methods with clinical severity of the disease.
Forty patients with de novo PD underwent both MRI and F-18 FP-CIT PET. Images were spatially normalized to a standardized PET template. Mean counts of 4 ROIs: putamen, caudate, occipital cortex and cerebellum, were obtained using the quantification program, Korean Statistical Probabilistic Anatomical Map (KSPAM). Putamen-to-caudate ratio (PCR), asymmetry index (ASI), specific-to-nonspecific ratios with two different references: to occipital cortex (SOR) and cerebellum (SCR) were compared. Parameters were also calculated from manually drawn ROI method and MR-coregistrated method.
All quantitative parameters showed significant correlations across the three different methods, especially between the PET-based and manual methods. Among them, PET-based SOR and SCR values showed an excellent correlation and concordance with those of manual method. In relationship with clinical severity, only ASI achieved significantly inverse correlations with H&Y stage and UPDRS motor score. There was no significant difference between the quantitative parameters of both occipital cortex and cerebellum in all three methods, which implied that quantitation using PET-based method could be reproducible regardless of the reference region.
Quantitative parameters using FP-CIT PET template-based method correlated well with those using laborious manual method with excellent concordance. Moreover, PET-based quantitation was less influenced by the reference region than MR-based method. It suggests that PET-based method can provide objective and quantitative parameters quickly and easily as a feasible analysis in place of conventional method.
PMCID: PMC4041974  PMID: 24900086
Parkinson’s disease; F-18 FP-CIT PET; Template-based quantitative analysis; Korean statistical probabilistic anatomical map (KSPAM); Dopamine transporter (DAT)
12.  Plasma Bacterial and Mitochondrial DNA Distinguish Bacterial Sepsis from Sterile SIRS and Quantify Inflammatory Tissue Injury in Nonhuman Primates 
Shock (Augusta, Ga.)  2013;39(1):55-62.
Systemic inflammatory response syndrome (SIRS) is a fundamental host response common to bacterial infection and sterile tissue injury. SIRS can cause organ dysfunction and death but its mechanisms are incompletely understood. Moreover, SIRS can progress to organ failure or death despite being sterile or after control of the inciting infection. Biomarkers discriminating between sepsis, sterile SIRS and post-infective SIRS would therefore help direct care. Circulating mitochondrial DNA (mtDNA) is a damage-associated molecular pattern (DAMP) reflecting cellular injury. Circulating bacterial 16S-DNA (bDNA) is a pathogen-associated pattern (PAMP) reflecting ongoing infection. We developed qPCR assays to quantify these markers and predicted their plasma levels might help distinguish sterile injury from infection. To study these events in primates we assayed banked serum from papio baboons that had undergone a brief challenge of intravenous Bacillus anthracis deltaSterne (modified to remove toxins) followed by antibiotics (anthrax) that causes organ failure and death. To investigate the progression of sepsis to “severe” sepsis and death we studied animals where anthrax was pretreated with drotrecogin alfa (aPC), which attenuates sepsis in baboons. We also contrasted lethal anthrax bacteremia against non-lethal E.coli bacteremia and against sterile tissue injury from Shiga-like toxin-1 (Stx1). bDNA and mtDNA levels in timed samples were correlated with blood culture results and assays of organ function. Sterile injury by Stx1 increased mtDNA but bDNA was undetectable: consistent with the absence of infection. The bacterial challenges caused parallel early bDNA and mtDNA increases, but bDNA detected pathogens even after bacteria were undetectable by culture. Sub-lethal E.coli challenge only caused transient rises in mtDNA consistent with a self-limited injury. In lethal anthrax challenge (n=4) bDNA increased transiently but mtDNA levels remained elevated until death, consistent with persistent septic tissue damage after bacterial clearance. Critically, aPC pre-treatment (n=4) allowed mtDNA levels to decay after bacterial clearance with sparing of organ function and survival. In summary, host tissue injury correlates with mtDNA whether infective or sterile. mtDNA and bDNA PCRs can quantify tissue injury incurred by septic or sterile mechanisms and suggest the source of SIRS of unknown origin.
PMCID: PMC3537509  PMID: 23247122
Sepsis; Inflammation; Bacteremia; Systemic Inflammatory Response Syndrome; Trauma
13.  Detectability of T-Measurable Diseases in Advanced Gastric Cancer on FDG PET-CT 
Usefulness of FDG PET-CT in monitoring response in locally advanced gastric cancer has been reported. The purpose of this study was to evaluate the related factors to detect measurable diseases in advanced gastric cancer on FDG PET-CT.
We retrospectively reviewed 38 patients diagnosed as having advanced gastric cancer. We defined the measurable diseases when there was visualized tumor of which maximum standardized uptake value (SUVmax) was higher than 1.35*SUVmax of liver + 2*SD of liver SUV. We evaluated what kinds of factors from the clinicopathologic features were related to identifying measurable diseases.
Of 38 patients with advanced gastric cancer, 18 (50 %) had measurable tumors on FDG PET-CT. Measurable tumors were significantly more frequent in well or moderately differentiated adenocarcinoma (70.5 % vs 35.3 %, p < 0.05), in the tumors located at antrum or angle (66.7 % vs 29.4 %, p < 0.05) and in the elderly group (age of 55 years old or more, 72.0 % vs 8.3 %, p < 0.001) than the others, respectively. By multivariate analysis, age at diagnosis was the only independent predictor for the measurable disease on FDG PET-CT.
We found that age at diagnosis, as well as histologic types and location of tumors, were the affecting factors to detect measurable disease on FDG PET-CT in patients with advanced gastric cancer. Our study suggests that elderly patients of age of 55 years old or more can frequently have T-measurable disease on FDG PET-CT in advanced gastric cancer and FDG PET-CT will be helpful to monitor measurable disease.
PMCID: PMC4043066  PMID: 24900073
Advanced gastric cancer; Measurable disease; FDG PET-CT; Age at diagnosis; Affecting factor
14.  The clinical course and genetic defect in the PCFT gene in a 27-year old woman with hereditary folate malabsorption 
The Journal of pediatrics  2008;153(3):10.1016/j.jpeds.2008.04.009.
Two sequential homozygous mutations are demonstrated in the recently cloned proton-coupled folate transporter (PCFT) gene resulting in the absence of this protein in a 27 year old woman with hereditary folate malabsorption, who is normal in all respects and has completed higher education, following treatment with parenteral 5-formyltetrahydrofolate since infancy.
PMCID: PMC3835188  PMID: 18718264
Intestinal folate absorption; folate transport; low pH folate transporter; proton-coupled folate transporter; RFC; reduced folate carrier
15.  SHP-1 Regulation of Mast Cell Function in Allergic Inflammation and Anaphylaxis 
PLoS ONE  2013;8(2):e55763.
Allergic inflammation and severe allergic reactions (anaphylaxis) are important in allergen induced diseases. Bacterial products such as lipopolysaccharide (LPS) are ubiquitous and can facilitate allergen induced Th2 immune responses. Phosphatase SHP-1 is critical in regulating immunological homeostasis and in allergen induced Th2 immune responses in the lung. However, the mechanisms underlying the initiation of allergic inflammation and allergen induced anaphylaxis are still not completely elucidated and it is unclear whether SHP-1 plays any role in LPS-induced airway inflammation and in allergen-induced anaphylaxis. In this study we tested the hypothesis that phosphatase SHP-1 plays an important role in allergic inflammation and anaphylaxis and determined whether its effects are through regulation of mast cell functions. SHP-1 deficient (mev/+ and mev/mev) and mast cell deficient (KitW-sh) mice were examined in their responses to LPS airway stimulation and to ovalbumin (OVA) allergen induced systemic anaphylaxis. Compared to wild type mice, mev/+ mice had significantly enhanced LPS induced airway inflammation and OVA induced anaphylactic responses, including hypothermia and clinical symptoms. These changes were mast cell dependent as KitW-sh mice had reduced responses whereas adoptive transfer of mast cells restored the responses. However, T and B cells were not involved and macrophages did not play a significant role in LPS induced airway inflammation. Interestingly, basophil differentiation from SHP-1 deficient bone marrow cells was significantly reduced. These findings provided evidence that through regulation of mast cell functions SHP-1 plays a critical role as a negative regulator in allergic inflammation and in allergen induced anaphylaxis. In addition, SHP-1 seems to be required for normal basophil development.
PMCID: PMC3563592  PMID: 23390550
16.  IL-13 Induces Skin Fibrosis in Atopic Dermatitis by Thymic Stromal Lymphopoietin 
Skin fibrotic remodeling is a major feature in human atopic dermatitis (AD). Inflammation and tissue fibrosis are common consequences of Th2 responses. Elevated IL-13 and thymic stromal lymphopoietin (TSLP) have been found in the AD skin lesions. Fibrocytes can be recruited to inflamed tissues to promote wound healing and fibrosis. Dermal transgenic expression of IL-13 causes an AD-like phenotype with fibrosis and increased TSLP. However, the role of TSLP in fibrotic remodeling is unknown. In this study, we investigated the role of TSLP and fibrocytes in the generation of IL-13–induced skin fibrosis. In AD lesion, cessation of IL-13 transgene expression resulted in reduced skin inflammation but with no effect on further progression of fibrosis. This was accompanied by markedly increased CD34+/procollagen 1+ fibrocytes. Furthermore, fibrocytes express TSLP receptor (TSLPR), and TSLP directly promotes PBMC-derived fibrocytes to produce collagen. Neutralization of TSLP or genetic deletion of TSLPR in IL-13 transgenic mice resulted in a significant reduction in fibrocytes and in skin fibrosis. Furthermore, reduction of fibrosis by depletion of TSLP was independent of IL-13. Interestingly, the number of fibrocytes was highly increased in the skin samples of AD patients. These data indicate that the progression of skin fibrosis in IL-13–induced AD occurs via TSLP/TSLPR-dependent but IL-13–independent novel mechanisms by promoting fibrocyte functions.
PMCID: PMC3399513  PMID: 21576506
17.  Vascular Endothelial Growth Factor Is a Key Mediator in the Development of T Cell Priming and Its Polarization to Type 1 and Type 17 T Helper Cells in the Airways 
Chronic inflammatory airway diseases including asthma are characterized by immune dysfunction to inhaled allergens. Our previous studies demonstrated that T cell priming to inhaled allergens requires LPS, which is ubiquitously present in household dust allergens. In this study, we evaluated the role of vascular endothelial growth factor (VEGF) in the development of T cell priming and its polarization to Th1 or Th17 cells when exposed to LPS-contaminated allergens. An asthma mouse model was induced by airway sensitization with LPS-contaminated allergens and then challenged with allergens alone. Therapeutic intervention was performed during allergen sensitization. The present study showed that lung inflammation induced by sensitization with LPS-contaminated allergens was decreased in mice with homozygous disruption of the IL-17 gene; in addition, allergen-specific Th17 immune response was abolished in IL-6 knockout mice. Meanwhile, in vivo production of VEGF was up-regulated by airway exposure of LPS. In addition, airway sensitization of allergen plus recombinant VEGF induced both type 1 and type 17 Th cell (Th1 and Th17) responses. Th1 and Th17 responses induced by airway sensitization with LPS-contaminated allergens were blocked by treatment with a pan-VEGF receptor (VEGFR; VEGFR-1 plus VEGFR-2) inhibitor during sensitization. These effects were accompanied by inhibition of the production of Th1 and Th17 polarizing cytokines, IL-12p70 and IL-6, respectively. These findings indicate that VEGF produced by LPS plays a key role in activation of naive T cells and subsequent polarization to Th1 and Th17 cells.
PMCID: PMC3385973  PMID: 19786548
18.  Spontaneous Eosinophilic Nasal Inflammation in a Genetically-Mutant Mouse: Comparative Study with an Allergic Inflammation Model 
PLoS ONE  2012;7(4):e35114.
Eosinophilic inflammation is a hallmark of chronic rhinosinusitis with nasal polyps. To model this disease process experimentally, nasal sensitization of mice with ovalbumin or aspergillus has been described. Here, we describe a genetically mutant mouse that develops robust spontaneous nasal eosinophilic inflammation. These mice lack the enzyme SHP-1 that down-regulates the IL-4Rα/stat6 signaling pathway. We compared nasal inflammation and inflammatory mediators in SHP-1 deficient mice (mev) and an ovalbumin-induced nasal allergy model.
A novel technique of trans-pharyngeal nasal lavage was developed to obtain samples of inflammatory cells from the nasal passages of allergic and mev mice. Total and differential cell counts were performed on cytospin preparations. Expression of tissue mRNA for IL-4, IL-13, and mouse beta-defensin-1 (MBD-1) was determined by quantitative PCR. Eotaxin in the lavage fluid was assessed by ELISA.
Allergic and mev mice had increased total cells and eosinophils compared with controls. Expression of IL-4 was similarly increased in both allergic and mev mice, but expression of IL-13 and eotaxin was significantly greater in the allergic mice than mev mice. Eotaxin was significantly up-regulated in both allergic rhinitis and mev mice. In both models of eosinophilic inflammation, down-regulation of the innate immune marker MBD-1 was observed.
The mev mice display spontaneous chronic nasal eosinophilic inflammation with potential utility for chronic rhinosinusitis with nasal polyps research. The eosinophilic infiltrate is more robust in the mev mice than allergic mice, but Th2 cytokine expression is not as pronounced. Decreased MBD-1 expression in both models supports the concept that Th2-cytokines down-regulate sinonasal innate immunity in humans, and suggests a role for mouse models in investigating the interaction between adaptive and innate immunity in the sinonasal mucosa.
PMCID: PMC3324406  PMID: 22509389
19.  Cbl-b Regulates Airway Mucosal Tolerance to Aeroallergen 
As an E3 ubiquitin ligase and a molecular adaptor, Cbl-b controls the activation threshold of the antigen receptor and negatively regulates CD28 co-stimulation, functioning as an intrinsic mediator of T cell anergy that maintains tolerance. However, the role of Cbl-b in the airway immune response to aeroallergens is unclear.
To determine the contribution of Cbl-b in tolerance to aeroallergens, we examined ovalbumin (OVA)-induced lung inflammation in Cbl-b deficient mice.
Cbl-b-/- mice and wildtype (WT) C57BL/6 mice were sensitized and challenged with OVA intranasally, a procedure normally tolerated by WT mice. We analyzed lung histology, BAL total cell counts and differential, cytokines and chemokines in the airway, and cytokine response by lymphocytes after re-stimulation by OVA antigen.
Compared with WT mice, OVA challenged Cbl-b-/- mice showed significantly increased neutrophilic and eosinophilic infiltration in the lung and mucus hyperplasia. The serum levels of IgG2a and IgG1, but not IgE, were increased. The levels of inflammatory mediators IFN-γ, IL-10, IL-12, IL-13, IP-10, MCP-1, MIP-1α, Eotaxin, and RANTES, but not IL-17A or IL-6, were elevated in the airway of Cbl-b-/- mice. Lymphocytes from Cbl-b-/-mice released increased amount of IFN-γ, IL-10, IL-13, and IP-10 in response to OVA re-stimulation. However, no significant changes were noted in the CD4+CD25+ Treg cell populations in the lung tissues after OVA stimulation and there was no difference between WT and Cbl-b-/- mice.
These results demonstrate that Cbl-b deficiency leads to a breakdown of tolerance to OVA allergen in the murine airways, probably through increased activation of T effector cells, indicating that Cbl-b is a critical factor in maintaining lung homeostasis upon environmental exposure to aeroallergens.
PMCID: PMC2994994  PMID: 20738317
Cbl-b; Ubiquitin E3 Ligase; Aeroallergen; Allergic inflammation; Asthma
20.  Usefulness of Bremsstrahlung Images after Intra-arterial Y-90 Resin Microphere Radioembolization for Hepatic Tumors 
Y-90 resin microsphere radioembolization is used to treat inoperable hepatic tumors. After injection of Y-90 resin microsphere, the only method to visualize the distribution of Y-90 is the scintigraphic imaging of bremsstrahlung radiation. The purpose of this study was to evaluate the characteristics and usefulness of bremsstrahlung imaging in Y-90 resin microsphere treatment.
Twenty patients (22 administrations) underwent intra-arterial Y-90 resin microsphere treatment. For pre-treatment planning, images of Tc-99m albumin macroaggregate (MAA) arterial injection and hepatic contrast angiography were obtained. Post-treatment bremsstrahlung images were taken and compared with pre-treatment images. The extrahepatic activity was evaluated on bremsstrahlung images. To correlate the size and vascularity of the tumors with tumor visualization on bremsstrahlung images, the individual tumors were grouped according to visualization on each image and compared with one another by size and tumor-to-normal ratio.
All post-therapeutic bremsstrahlung images showed similar contours of the liver with pre-treatment angiography. No extrahepatic activity was seen in all cases. The visualized tumors on bremsstrahlung images were significantly larger than the non-visualized tumors. Tumor-to-normal ratios of the visualized tumors on bremsstrahlung images were significantly higher than those of the non-visualized tumors.
Bremsstrahlung images after intra-arterial Y-90 resin microsphere treatment are useful in evaluating the intrahepatic distribution of radioisotope and detecting possible extrahepatic activity.
PMCID: PMC4042949  PMID: 24899979
Y-90; microsphere; Radioembolization; Bremsstrahlung; Hepatocellular carcinoma; Liver malignancy
21.  Radiation Safety Issues in Y-90 Microsphere Selective Hepatic Radioembolization Therapy: Possible Radiation Exposure from the Patients 
The purpose of this study was to estimate the possible external radiation dose to other individuals from patients treated with Y-90 resin microspheres for unresectable hepatocellular carcinoma.
We designed the study prospectively to estimate the possible radiation dose to other individuals from patients who had been treated with Y-90 microspheres for unresectable hepatocellular carcinoma. We estimated the total effective dose equivalent (TEDE) using two methods: ‘theoretical’ TEDEs according to the administered activity and ‘measured’ TEDE based on the ‘measured’ ambient radiation exposure rate. We compared the results from each method to determine when we can release patients from confinement at the earliest time complying with the patient release criteria.
A total of 20 administrations of Y-90 resin microspheres were done in 18 patients. The average administered activity was 1.2 ± 0.77 (0.28–2.97) GBq. The ‘theoretical’ TEDEs were in the range of 0.8–10 μSv. The ‘measured’ TEDEs were in the range of 2.31–185 μSv. The measured TEDEs tend to be higher than the theoretical TEDEs. The values of theoretical and measured TEDE were both far less than 1 mSv, the upper limit at which the licensee can release a patient without any written documents.
The effective dose equivalent caused by the Y-90 microsphere administered patient is very low. It is safe in terms of radiation safety to the other individuals when Y-90 microsphere radioembolization therapy is done with dose less than 3 GBq. Because the measured TEDE tends to be higher than the theoretical TEDE, it is recommended to use ‘measured’ TEDE for determining patient release.
PMCID: PMC4042917  PMID: 24899961
Radiation safety; Y-90 microsphere; Selective hepatic radio-embolization therapy; Liver tumor; Hepatocellular carcinoma
22.  Rescue From Lethal Shiga Toxin 2-induced Renal Failure With A Cell-Permeable Peptide 
Pediatric nephrology (Berlin, Germany)  2011;26(11):2031-2039.
Intestinal infection with Shiga toxin (Stx)-producing E.coli is a leading cause of hemolytic uremic syndrome and acute renal injury in otherwise healthy children in the US. Antibiotics are contraindicated and a therapeutic priority is agents that act intracellularly against the bacterial toxins which drive kidney injury. Our aim was to evaluate whether intravenous administration of a cell-permeable peptide (TVP) that binds to Stx2 will reduce disease severity and rescue juvenile baboons from a lethal Stx2 dose (50ng/kg).
TVP (5mg/kg) was delivered i.v. simultaneously with toxin (prevention protocol) or at 6 or 24 hours after toxin with daily 1mg/kg supplements up to Day 4 (rescue protocols). Biomarkers were monitored in blood and urine up to 28 days.
Results and Conclusions
TVP therapy resulted in either absence of clinical signs of acute kidney injury and normal urine output (prevention), or delayed and reduced BUN and creatinine levels (rescue) with concomitant survival. Delayed peptide administration significantly reduced thrombocytopenia, but surprisingly did not alter anemia even when monitored for 28 days in rescued survivors. This is the first successful cell-permeable therapeutic that counteracts Stx2 lethality in an animal model which recapitulates many of the human responses to enteric infection.
PMCID: PMC3179571  PMID: 21603905
Shiga toxins; enterohemorrhagic E.coli; hemolytic uremic syndrome; nonhuman primate; acute renal injury
23.  Roles for the Type III TGF-β Receptor in Human Cancer 
Cellular signalling  2010;22(8):1163-1174.
Transforming growth factor β (TGF-β) superfamily ligands have important roles in regulating cellular homeostasis, embryonic development, differentiation, proliferation, immune surveillance, angiogenesis, motility, and apoptosis in a cell type and context specific manner. TGF-β superfamily signaling pathways also have diverse roles in human cancer, functioning to either suppress or promote cancer progression. The TGF-β superfamily co-receptor, the type III TGF-β receptor (TβRIII, also known as betaglycan) mediates TGF-β superfamily ligand dependent as well as ligand independent signaling to both Smad and non-Smad signaling pathways. Loss of TβRIII expression during cancer progression and direct effects of TβRIII on regulating cell migration, invasion, proliferation, and angiogenesis support a role for TβRIII as a suppressor of cancer progression and/or as a metastasis suppressor. Defining the physiological function and mechanism of TβRIII action and alterations in TβRIII function during cancer progression should enable more effective targeting of TβRIII and TβRIII mediated functions for the diagnosis and treatment of human cancer.
PMCID: PMC2875339  PMID: 20153821
TβRIII; TGF-β; BMP; cancer; receptor
24.  Tyrosine phosphatase SHP-1 in allergic and anaphylactic inflammation 
Immunologic research  2010;47(1-3):3-13.
Protein tyrosine phosphatase SHP-1 is an essential regulatory molecule in many different signaling pathways. The biological importance of SHP-1 is underscored by the motheaten mutant mouse strains with immunological disorders involving multiple organs and by the close association of aberrant SHP-1 expression with several human diseases. Recent studies provided some compelling evidence that supports a role of SHP-1 in regulating mast cell development and function and also in regulating type 2 allergic inflammatory responses in both innate and adaptive immune responses. In this article, we summarize the recent advancement of our understanding of this interesting phosphatase in the important area of allergic inflammation.
PMCID: PMC2954886  PMID: 20077161
Phosphatase; Mast cells; Th2 cytokines; Allergic inflammatory response; Allergy; Asthma
25.  Peritoneal Lymphomatosis Imaged by F-18 FDG PET/CT 
Peritoneal lymphomatosis is uncommon, but when encountered is associated with aggressive histological subtypes of high-grade lymphoma, such as small-cell, large-cell, mixed large and small cell, non-cleaved, lymphoblastic Burkitt-like, and diffuse large B cell lymphomas. The CT findings of peritoneal lymphomatosis are linear or nodular peritoneal thickening, retroperitoneal lymphadenopathy, omental and mesenteric involvement with streak-like infiltrations or a bulky mass, bowel wall thickening, hepatosplenomegaly, and ascites. The authors report the first FDG PET/CT images of diffuse large B-cell lymphoma of small bowel origin associated with peritoneal lymphomatosis in a 69-year-old man. The lesions demonstrated intense FDG uptake in PET/CT images.
PMCID: PMC4079784  PMID: 25013531
Peritoneal lymphomatosis; Lymphoma; FDG; PET

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