Thymus And Activation-regulated Chemokine Research Articles

Circulating thymus and activation-regulated chemokine/CC chemokine ligand 17 is a strong candidate diagnostic marker for interstitial lung disease in patients with malignant tumors: a result from a pilot study.

IntroductionSerum Krebs von den Lungen-6 (KL-6) level is an established diagnostic marker of interstitial lung disease (ILD). However, it is also elevated in patients with non-small cell lung cancer (NSCLC). The significance of circulating thymus and activation-regulated chemokine (TARC)/CC chemokine ligand 17 (CCL17) in malignant diseases remains unknown.MethodsWe measured circulating TARC/CCL17 and KL-6 using enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay, respectively, in 26 patients with malignant disease and six patients with benign lung disease (BLD). The cutoff levels were 500 U/mL for KL-6 and 450 pg/mL for TARC/CCL17. The significance of the markers was evaluated in relationship to the presence of ILD (n=10). The statistical significance was set at P<0.05.ResultsThe KL-6 positive ratio was significantly higher in the patients with NSCLC (n=17) than in those with BLD. There was a significant difference in the KL-6 positive ratio between the patients with NSCLC without ILD and those with BLD without ILD. However, there were no significant differences in the TARC/CCL17 positive ratio between the patients with NSCLC and BLD or between those with NSCLC without ILD and those with BLD without ILD. The TARC/CCL17 positive ratio was significantly higher in the patients with malignancy and ILD than in those without ILD. There was also a significant difference in the TARC/CCL17 positive ratio between the patients with NSCLC without ILD and those with ILD.ConclusionTARC/CCL17 may be useful for the diagnosis of ILD in patients with malignancies. Confirmation of the results is warranted through a large-scale study.

Cosmetic Activities of Nyasol from the Rhizomes of Anemarrhena asphodeloide

The rhizomes of Anemarrhena asphodeloide was extracted with 100% ethanol and concentrated subfractions were separated with medium pressure liquid chromatography-based activity profiling. One compound was isolated from the subfraction 10 through the repeated preparative high performance liquid chromatography (prep-HPLC). According to physico-chemical and spectroscopic data including NMR and MS, the chemical structures of the compound was determined as nyasol (1). Nyasol was exhibited potent inhibitory activity for NO (IC50: 12.5 µg/mL), tyrosinase (IC50: 12.5 µg/mL), melanin contents (IC50: 12.5 µg/mL), thymus and activation-regulated chemokine (TARC) production (IC50: 6.25 µg/mL). As a result, nyasol has an excellent inflammation- dependent anti-whitening and TARC production activity. It could be used to a large range of functional cosmetics.

New Developments in Biomarkers for Atopic Dermatitis.

The application of biomarkers in medicine is evolving. Biomarkers do not only give us a better understanding of pathogenesis, but also increase treatment efficacy and safety, further enabling more precise clinical care. This paper focuses on the current use of biomarkers in atopic dermatitis, new developments and future perspectives. Biomarkers can be used for many different purposes, including the objective determination of disease severity, confirmation of clinical diagnosis, and to predict response to treatment. In atopic dermatitis, many biomarkers have been investigated as a marker for disease severity. Currently serum thymus and activation-regulated chemokine (TARC) is the superior biomarker for assessing disease severity. However, we have recently shown that the use of a panel of serum biomarkers is more suitable for assessing disease severity than an individual biomarker. In this overview, we will discuss alternative sources for biomarkers, such as saliva and capillary blood, which can increase the user friendliness of biomarkers in atopic dermatitis (AD). Both methods offer simple, non-invasive and cost effective alternatives to venous blood. This provides great translational and clinical potential. Biomarkers will play an increasingly important role in AD research and personalized medicine. The use of biomarkers will enhance the efficacy of AD treatment by facilitating the individualization of therapy targeting the patients’ specific biological signature and also by providing tools for predicting and monitoring of therapeutic response.

A novel mechanism for improvement of dry skin by dietary milk phospholipids: Effect on epidermal covalently bound ceramides and skin inflammation in hairless mice

BackgroundDietary milk phospholipids (MPLs) increase hydration of the stratum corneum and reduced transepidermal water loss (TEWL) in hairless mice fed a standard diet. However, the mechanism by which MPLs improve skin barrier functions has yet to be established. ObjectiveThis study was designed to examine the mechanism by which MPLs may affect covalently bound ceramides and markers of skin inflammation and improve the skin barrier defect in hairless mice fed a magnesium-deficient (HR-AD) diet. MethodsFour-week-old female hairless mice were randomized into four groups (n=10/group), and fed a standard (control) diet, the HR-AD diet, the HR-AD diet supplemented with either 7.0g/kg MPLs (low [L]-MPL) or 41.0g/kg MPLs (high [H]-MPL). ResultsDietary MPLs improved the dry skin condition of hairless mice fed the HR-AD diet. MPLs significantly increased the percentage of covalently bound ω-hydroxy ceramides in the epidermis, and significantly decreased both thymus and activation-regulated chemokine (TARC) mRNA and thymic stromal lymphopoietin (TSLP) mRNA levels in skin, compared with the HR-AD diet. Furthermore, the MPL diets significantly decreased serum concentrations of immunoglobulin-E, TARC, TSLP, and soluble P-selectin versus the HR-AD diet. ConclusionOur study showed for the first time that dietary MPLs may modulate epidermal covalently bound ceramides associated with formation of lamellar structures and suppress skin inflammation, resulting in improved skin barrier function.

Identification of CCL17 neutraligands targeting atopic diseases

Introduction Chemokines constitute a family of small cytokines that attract and activate leukocytes during the inflammatory response. Among them, the β-chemokine CCL17 formerly known as thymus- and activation regulated chemokine (TARC), is involved in the development of atopic disorders such as asthma and atopic dermatitis. This chemokine exerts its biological effects by binding to and activating the CCR4 cell-surface receptor that belongs to the Gi-protein-coupled receptor family. Enhanced expression of CCL17 as well as elevated recruitment of CCR4+ Th2 cells have been observed in asthma and atopic dermatitis. To date, most therapeutic strategies have focused on disrupting the chemokine/receptor interaction through use of chemokine receptor antagonists. We have discovered a novel class of small chemical molecules called “neutraligands” that bind to the chemokine itself, not to the receptor, and neutralize its biological activity. The concept has already been fully validated with the discovery of “chalcone 4”, a small chemical that binds CXCL12, thereby preventing bronchial inflammation and hyperresponsiveness in animal models of asthma (Hachet-Haas et al., JBC 2008; Galzi et al., Pharmacol Ther 2010; Gasparik et al., ACS Med Chem Lett 2012; Daubeuf et al., JBC 2013). Our aim was to identify new CCL17 neutraligands, and evaluate their in vivo activity in mouse models of cutaneous and respiratory Th2-driven allergic inflammation. Methods We have set up a cell-based high throughput assay to identify new CCL17 neutraligands. HEK293 cells were transfected with the CCL17 receptor, CCR4, together with the G protein Gαqi5 that will increase the intracellular Ca2+ response (FlexStation3) upon activation with CCL17. A library of pure natural substances, as well as a subset of the academic library of Strasbourg (1000 compounds) was screened. The hits were tested in two Th2-driven murine models: – an 8-day model of allergic hypereosinophilia to ovalbumin; – a model of allergic dermatitis to MC903 (calcipotriol). Results Two hit molecules were selected from the HTS assay, compounds A and B, with CCL17-neutralizing activity: when preincubated with the chemokine, they blocked CCL17-induced Ca2+ responses (2 μg/mL; IC50s = 5 and 8 μM, respectively); by contrast, when preincubated with the cells, i.e. with the CCR4 receptor, the Ca2+ responses were not affected, indicating the compounds were CCL17 neutraligands and not CCR4 receptor antagonists. We show that compounds A and B (350 μmol/kg, I.P.) significantly reduced the number of cells collected in broncho-alveolar lavage fluid, in particular eosinophils (40 and 60% inhibition, respectively) in the model of allergic hypereosinophilia. In addition, compounds A and B (350 μmol/kg) administered topically prevented MC903-induced ear redness and thickness, and decreased plasma IgE levels (by 90%). Conclusion Our results show successful identification of CCL17 neutraligands that efficiently control Th2 inflammation, and will help understand the role of CCL17 in asthma and atopic dermatitis.

Gamisasangja-tang suppresses pruritus and atopic skin inflammation in the NC/Nga murine model of atopic dermatitis

Ethnopharmacological relevanceGamisasangja-tang (GST) is a traditional herbal formula prescribed for patients with intractable pruritus in association with various inflammatory skin diseases. To evaluate the effects of GST on pruritic skin inflammation and investigate its cellular and molecular mechanisms. Materials and methodsWe orally administered GST to NC/Nga (NC) mice, an animal model of atopic dermatitis. Scratching frequency and the dermatitis index were evaluated, and histological examination was performed using hematoxylin and eosin and toluidine blue staining. The levels of interleukin (IL)-31 and T-helper cell type 2 (TH2) cytokines were determined in both the dorsal skin and cultured splenocytes by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum levels of chemokines and immunoglobulin E (IgE) were determined by ELISA. Changes in the inflammatory cell population were analyzed by a hemocytometer. ResultsGST significantly lowered scratching frequency and inhibited increases in dermatitis index, thickness of epidermis/dermis and infiltration of chemokine (C-C motif) receptor 3 (CCR3)+ and cluster of differentiation (CD)117+/FcεRIα (Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide)+ cells in atopic skin. Both IL-31 mRNA expression and production were significantly reduced by GST, which was accomrease in the levels of IL-4, IL-5, and IL-13. Further, GST treatment suppressed the secretion of eotaxin, TARC (thymus and activation-regulated chemokine), IgE, and increases in the number of basophils and eosinophils in the blood. ConclusionGST may have potential as an effective treatment for pruritic skin disease such as atopic dermatitis.

Up-Regulation of CysLT2 Receptor Expression and Cysteinyl Leukotrienes-Induced Calcium Signaling By Th2 Cytokines in Human Endothelial Cells

FEBRUARY 2015 AB60 Abstracts S A T U R D A Y 191 Serum Zinc and Secretory IgA Levels Are Important Factors in Children with Food Allergy Yosuke Baba, MD, PhD, Reina Yokota, MD, Hiromi Yagisawa, MD, Susumu Yamazaki, MD, Asuka Ishida, MD, Eisuke Inage, MD, PhD, Mari Mori, MD, PhD, Yoshikazu Ohtsuka, MD, PhD, Toshiaki Shimizu, MD, PhD; Department of Pediatrics and Adolescent Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan, Department of Pediatrics, Juntendo University Shizuoka Hospital, Shizuoka, Japan. RATIONALE: Zinc is an essential nutrient and its deficiency causes malnutrition and results in defects in innate and acquired immune responses. Also, zinc is important for highly proliferating cells, especially in the immune system and influences both innate and acquired immune functions. However, the precise roles and molecular mechanisms of zinc’s function in allergic response have not been clarified. On the other hand, the IgA antibody is massively produced in the intestinal Peyer’s patches, and the secretory IgA (sIgA) plays an important role on mucosal immune responses. It is considered that sIgA regulates the cause of allergic reactions. We studied serum zinc levels and sIgA levels in children with food allergies and studied their relationship with allergy symptoms. METHODS: It is a retrospective study using medical records of infants (from 6 months to 6 years old) who had been admitted to our hospitals. We classified the groups according to the results of physical examinations with or without allergic symptom (eczema, wheezing, food allergy). In addition, we investigated thewhite blood cell counts (eosinophils and basophils) and the serum levels of specific IgE, total IgA, sIgA, TARC (thymus and activation-regulated chemokine), and zinc. RESULTS: Children who were low levels in sIgA and serum zinc have past histories of atopic dermatitis, and their serum levels of specific IgE was significantly higher (p50.013) but their serum IgA level was significantly lower (p50.038) compared with children who does not have allergic symptoms. CONCLUSIONS: Secretory IgA levels and zinc levels are also important to the onset of allergic reactions.

T Helper 2 Polarization in Senile Erythroderma with Elevated Levels of TARC and IgE

Background: Some cases of senile erythroderma tend to be diagnosed as senile atopic dermatitis (AD) based on elevated levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). However, there are few studies that describe the detailed characteristics of senile erythroderma and senile AD. Objective: We examined the association of erythroderma with AD. Methods: In this retrospective observational study, 68 patients over 65 years of age who presented with erythroderma at Osaka University Hospital were enrolled. Patient data were collected through medical records and descriptive statistics. Results: 47% of the patients were classified as having idiopathic erythroderma and 53% as having secondary erythroderma. In both idiopathic and secondary senile erythroderma patients, serum IgE and TARC levels were elevated. 84% of idiopathic erythroderma patients fulfilled the Japanese Dermatological Associations criteria for AD; however, only 4 patients were finally definitely diagnosed with senile AD. Conclusion: Many senile erythroderma patients showed AD-like symptoms due to T helper 2 polarization.

Traditional herbal formula Jakyakgamcho-tang (Paeonia lactiflora and Glycyrrhiza uralensis) impairs inflammatory chemokine production by inhibiting activation of STAT1 and NF-κB in HaCaT cells

A traditional herbal formula Jakyakgamcho-tang (JYGCT; Paeonia lactiflora and Glycyrrhiza uralensis) has been used for treatment of backache, muscle pain, acute abdominal pain, neuralgia, bronchial asthma, and painful peripheral neuropathy in Oriental medicine. We report on our experiments using the HaCaT human keratinocyte cell line showing that a traditional herbal formula JYGCT has inhibitory effects on inflammatory responses in skin.Stimulation with tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) caused a significant increase in the production of the following chemokines: thymus- and activation-regulated chemokine (TARC)/CCL17; macrophage-derived chemokine (MDC)/CCL22; regulated on activation, normal T-cell expressed and secreted (RANTES)/CCL5; and interleukin-8 (IL-8) in HaCaT cells. By contrast, treatment with JYGCT extract significantly reduced the production of TARC, MDC, RANTES, and IL-8, but caused no cytotoxicity, compared with TNF-α and IFN-γ-treated control cells. Consistently, JYGCT extract downregulated the mRNA expression of TARC, MDC, RANTES, and IL-8 induced by TNF-α and IFN-γ in a dose-dependent manner. In addition, TNF-α and IFN-γ markedly increased the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and the nuclear translocation of nuclear factor kappa B (NF-κB) in HaCaT cells. By contrast, TNF-α and IFN-γ-induced activation of STAT1 and NF-κB activation was inhibited by JYGCT treatment in a dose-dependent manner.Our data indicate that JYGCT attenuates TNF-α and IFN-γ-mediated chemokine production by targeting the STAT1 and NF-κB signalling in keratinocytes. Our findings suggest that JYGCT has potential as a therapeutic drug candidate for the treatment of inflammatory skin diseases.

Practical evaluation of serum thymus and activation regulated chemokine (TARC) measurement using the fully automated enzyme immunoassay analyzer HISCL-2000i

Practical evaluation of serum thymus and activation regulated chemokine (TARC) measurement using the fully automated enzyme immunoassay analyzer HISCL-2000i

Study of pruritus in chronic hepatitis C patients

To investigate the occurrence and severity of pruritus in chronic hepatitis C patients treated with or without interferon (IFN) therapy. A total of 89 patients with chronic hepatitis C and 55 control (non-hepatitis) patients were asked to rate their experience of diurnal and nocturnal pruritus in the preceding week using a visual analogue scale (VAS) and a five-point scale, respectively. Blood samples were taken and serum thymus and activation-regulated chemokine (TARC) levels were measured by enzyme-linked immunosorbent assay. A significantly greater proportion of chronic hepatitis C patients experienced nocturnal pruritus compared with control (58.4% vs 5.5%, P < 0.0001). Chronic hepatitis C patients also had more severe pruritus compared with control patients, indicated by the higher mean VAS scores in both the IFN-treated and non-IFN-treated groups. In particular, patients who received combined peginterferon alfa-2b and ribavirin had significantly higher mean VAS scores than those receiving peginterferon alfa-2a or no IFN treatment. Serum TARC levels did not correlate with pruritus scores, and no significant differences in TARC levels were observed between the IFN-treated and non-IFN-treated groups. Patients with chronic hepatitis C experience pruritus more than those without. Serum TARC levels do not correlate with pruritus severity in chronic hepatitis C patients.

Decrease of Serum TARC Levels As Predictive Biomarkers of Response to Targeted Therapy with Kinase Inhibitors in Refractory/Relapsed Hodgkin Lymphoma Patients

INTRODUCTION: Identification of predictive biomarkers of response to new agents represents a challenging issue. Thymus and Activation-Regulated Chemokine (TARC) is a protein highly expressed by Reed-Sternberg cells in Hodgkin lymphoma (HL) and has been demonstrated to be a prognostic biomarker in HL patients treated with chemotherapy. We investigated the correlation between clinical response and early variation of serum TARC levels in patients with refractory/relapsed HL treated with kinase inhibitors. Patients were enrolled in two consecutive phase II trials evaluating activity and safety of the multikinase inhibitor Sorafenib (Nexavar®, Bayer) used as single agent, or in combination with the AKT inhibitor Perifosine (Æterna Zentaris GmBH, Germany).METHODS: Between July 2008 and November 2011, 30 patients (19 males and 11 females; median age 30 years, range, 17-73 years) with relapsed (n = 3) or refractory (n = 27) HL were analyzed. In one trial, patients received Sorafenib alone (400 mg BID, per os), and in the second trial Perifosine (50 mg BID, per os) for 4 weeks followed by combination therapy of Perifosine plus Sorafenib (400 mg BID, per os) until disease progression or clinically significant toxicity. Tumor responses were assessed according to the revised response criteria for malignant lymphoma of the International Working Group. Serum samples collected prior to therapy initiation and monthly thereafter were analyzed for TARC by ELISA. Early variation in TARC levels was calculated as percentage difference between values at baseline and at day 60 after starting therapy. Comparison of variation of TARC between different groups of patients was calculated using the Mann-Whitney Test, correlation between clinical response and TARC reduction was calculated using Fisher’s exact text and presented also as relative risk (RR). The study was approved by the Institutional Ethical CommitteeRESULTS: Nine out of 30 patients (30%) achieved clinical responses, including complete response (CR, n = 1) and partial response (PR, n = 8), 12/30 patients achieved stable disease (SD), and 9/30 patients experienced progressive disease (PD). Median overall survival (OS), progression-free survival (PFS) and duration of response (DOR) were 18, 4.5 and 3 months, respectively. Data of TARC at baseline and during therapy were available for all 30 patients but only 29 patients were evaluated. The patient achieving CR who showed baseline and 60-day values below 500 pg/ml (212 pg/ml and 368 pg/ml, respectively) was in fact excluded from analysis. At baseline, the median TARC level for the whole population was 13451 pg/ml (range, 1010 - 89877). No differences in baseline TARC levels were detected between patients achieving PR, SD and PD as best response. The median percentage variation of TARC levels after 60 days of therapy in PR, SD and PD patients was -57% (IQ range, -79% to -28%), -15% (IQ range, -78% to +8%) and +6% (IQ range, -49% to >100%). Variation of TARC observed among PR patients was significantly different from variation detected in PD group (p=0.005), whereas no differences were observed between PR and SD patients. A decrease of TARC levels at day 60 was observed in 17 patients, median percentage reduction was 49% (range, 8% – 94%). TARC reduction discriminated patients sensitive to treatment, in fact 15/17 patients (88%) with evidence of a reduction achieved PR (n=7) or SD (n=8), whereas 7/12 patients showing no change or increasing values of TARC experienced PD (p=0.014). The chance of obtaining PR and SD was greater in patients with evidence of TARC reduction than in patients with stable or increasing values (RR 3.37, 95%CI, 0.97 – 11.7). When we considered the median percentage reduction of 49% as cut-off, this value didn’t discriminate PR from SD patients. Similarly, deeper reduction in TARC levels was not correlated to longer PFS or DOR in responding patients.CONCLUSIONS: Analysis of TARC in HL patients treated with perifosine and sorafenib allowed to identify a biomarker predicting response to treatment with kinase inhibitors. Early reduction of TARC seems to be a useful tool for selecting patients who will receive a clinical benefit from therapy. However, correlation observed between early reduction and clinical response need to be validated in larger studies. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Role of the CD68+ Cell Count and Early Response Evaluation with Interim-PET and Levels of Plasma Thymus and Activation-Regulated Chemokine (TARC) in ABVD-Treated Classical Hodgkin Lymphoma

▪Prognostication in classical Hodgkin lymphoma (cHL) has mainly explored three areas of interest beyond the use of clinical risk factors in recent years: I. Early response evaluation with positron emission tomography scan (“interim PET”) after 2 cycles of treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has become the most interesting functional imaging technique to accurately predict treatment response in cHL. II. An increased number of tumor-infiltrating macrophages stained with the CD68 antigen in the microenvironment of cHL has been shown to be a simple tissue biomarker with an adverse impact on outcome. III. Among circulating biomarkers, early changes in plasma levels of the chemokine TARC during therapy have been proposed as alternative biomarker for response evaluation.The aim of our study was to evaluate plasma levels of TARC at diagnosis and at interim PET in combination with the tissue biomarker CD68 and interim PET as predictors of outcome in cHL. We included 84 patients diagnosed with cHL (45 limited stage, 39 advanced stage) between 2007 and 2013 who were treated with ABVD in our department. Median age was 34 years (range 15-73), 43 patients were males and 41 females. PET-CT scan was performed at baseline and after two courses of chemotherapy. Interim PET results were assessed using the Deauville five-point scale. Treatment changed according to the PET result in 2 patients only. Plasma TARC levels were measured using ELISA (Human CCL-17/TARC DuoSet, R&D Systems Inc), and CD68+ cells were stained using the PGM1 antibody.When compared to normal individuals? (n=63), plasma TARC levels were elevated above the normal range (upper limit 162 U/ml) at diagnosis in 89% (73/82) patients with cHL. Significantly higher TARC levels were observed in patients with advanced stage disease (p=0.05) and patients with bulky disease (p<0.001). There was no significant association to the CD68+ cell count in the tumor tissue (>5% vs <5%, p=0.09). After 2 cycles of ABVD, interim PET according to Deauville criteria was negative (score 0-3) in 67 (85%) patients and positive (score 4-5) in 12 patients (15%). At interim PET, TARC levels were elevated (>162 U/ml) in 18% of patients and were significantly associated with a positive PET result (p=0.007). Progression-free survival (PFS) at a median observation of 28 months was 76% (95% CI, 65-84%). Strong predictors for PFS were a negative interim PET (86% vs 25% , p<0.0001) and CD68+ cell count <5% (88% vs 66%, p<0.03). Limited stage of disease (p=0.005) and age < 45 years (p<0.05) were favorable prognostic factors. TARC levels (with different cut-off levels and as continuous variable) both at diagnosis and at interim evaluation, were not associated to prognosis. The multivariate analysis including interim PET, CD68 count , stage and age, showed that only a positive interim PET and CD68+ cell count >5% remained independent predictive parameters for PFS (Hazard ratio 11.3, 95% C.I, 3.3-38.4, p<0.001; and hazard ratio 5.8, 95% C.I. 1.4-25, p<0.02, respectively).In conclusion, baseline TARC levels are elevated in the vast majority of patients with classical HL in relation to tumor burden, and turn to normal in most patients after 2 courses of ABVD. Persistent elevated levels of TARC associate with a positive interim PET, but cannot substitute for it as outcome predictor. Interim PET and CD68+ cell counts in the microenvironment maintain their prognostic significance both in univariate and multivariate analysis. DisclosuresNo relevant conflicts of interest to declare.

Clinical significance of serum thymus and activation-regulated chemokine in gastric cancer: potential as a serum biomarker.

Thymus and activation-regulated chemokine (TARC) can stimulate cancer cell proliferation and migration. The present study evaluated the clinical significance of serum TARC in gastric cancer (GC). We measured serum TARC, macrophage-derived chemokine, monocyte chemotactic protein-1 and stem cell factor (SCF) levels using a chemiluminescent immunoassay along the GC carcinogenesis (normal, high-risk, early GC [EGC] and advanced GC [AGC]) in both training (N = 25 per group) and independent validation datasets (90 normal, 30 high-risk, 50 EGC and 50 AGC). Serum levels were compared among groups using one-way analysis of variance. To evaluate the diagnostic potential of serum TARC for GC, receiver operating characteristic curve and logistic regression analyses were performed. Correlations between serum TARC and GC clinicopathological features were analyzed using Spearman's correlation. In the training dataset, serum TARC correlated with serum MDC, MCP-1 and SCF. However, only serum TARC and SCF were significantly higher in cancer groups than non-cancer groups (P < 0.001). In the validation dataset, serum TARC also increased along the GC carcinogenesis; the AGC group (167.2 ± 111.1 ng/mL) had significantly higher levels than the EGC (109.1 ± 67.7 ng/mL), the high-risk (66.2 ± 47.7 ng/mL) and the normal (67.5 ± 36.2 ng/mL) groups (Bonferroni, all P < 0.001). Receiver operating characteristic curves and logistic regression demonstrated the remarkable diagnostic potential of serum TARC as a single marker (72.0% sensitivity and 71.1% specificity; cutoff point, 0.37; logistic regression) and in a multiple-marker panel (72.6% sensitivity and 88.2% specificity; cutoff point, 0.54). Spearman's correlation showed that serum TARC was closely correlated with tumor size (γs = 0.227, P = 0.028), T-stage (γs = 0.340, P = 0.001), N-stage (γs = 0.318, P = 0.002) and M-stage (γs = 0.346, P = 0.001). Serum TARC is a promising serum biomarker for GC.

Inhibitory Effects of Camellia sinensis Extract on the Development of Atopic Dermatitis-like Lesions in NC/Nga Mice

Atopic dermatitis (AD) syndrome is one of the most common and severe skin diseases in Korea; a large population has this disease. We examined the effects of the extract from the leaf and sprig of Camellia sinensis on the development of AD by using NC mice as a model of atopic dermatitis. Oral administration of the extract to NC/Nga mice treated with 2,4?dinitrochlorobenzene (DNCB) inhibited the development of AD-like skin lesions as shown by a significant decrease in the skin symptoms of the disease and a decrease in ear thickness and levels of immunoglobulin E (IgE) and thymus-and activation-regulated chemokine (TARC) level in the skin. Administration of the extract markedly suppressed the DNCB-induced mRNA expression of interleukin 4 (IL-4) and tumor necrosis factor <TEX>${\alpha}$</TEX> (TNF-<TEX>${\alpha}$</TEX>). The findings suggest that transdermal application of the extract may modulate in the skin of NC/Nga mice. The extract was effective for the prevention and treatment of AD.

Expression of thymus and activation-regulated chemokine (TARC) by human dermal cells, but not epidermal keratinocytes

BackgroundSerum levels of thymus and activation-regulated chemokine (TARC/CCL17) have served as a reliable biomarker of disease progression of atopic dermatitis (AD). However, it remains to be scientifically explained why serum TARC levels correlate well with the degree of AD progression. ObjectiveWe hypothesized that dermal cells, but not epidermal keratinocytes, are major cellular sources of TARC and thus responsible for subclinical skin inflammation. This study aimed to identify the skin cells that can produce TARC protein. MethodsPrimary normal human epidermal keratinocytes (NHEK), dermal microvascular endothelial cells (HMVEC-dBl) and dermal fibroblasts (NHDF) were stimulated with TNF-α and IL-4, alone and in combination. TARC mRNA and protein levels were quantified by qPCR and ELISA, respectively. We also investigated the effects of such immunosuppressants as a corticosteroid (dexamethasone) and tacrolimus (FK506) on TARC production, and used various signaling inhibitors to evaluate the signaling pathways involved in TARC expression. ResultsAlthough neither TNF-α nor IL-4 alone induced TARC production by any of the tested cell types, together they induced expression of TARC mRNA and appreciable amounts of TARC protein by HMVEC-dBl and NHDF, but not by NHEK. TARC production by those dermal cells was not inhibited by dexamethasone or FK506. TARC production by HMVEC-dBl was completely inhibited by NF-κB and p38 MAPK inhibitors, but not by an ERK inhibitor. ConclusionDermal cells, but not epidermal keratinocytes, may be important cellular sources of TARC in AD skin. Therefore, even if epidermal eczematous lesions seem to be improved, complete inhibition of inflammation in the dermis is thought to be particularly important for suppressing both the TARC blood level and progression of AD. However, immunosuppressants did not directly inhibit TARC production by the dermal cells. Anti-inflammatory therapy may decrease TARC blood levels in AD patients indirectly, via its inhibitory effects on TNF-α- and/or IL-4-producing cells in the dermis.

Serum Thymus and Activation-Regulated Chemokine Level Monitoring May Predict Disease Relapse Detected by PET Scan after Reduced-Intensity Allogeneic Stem Cell Transplantation in Patients with Hodgkin Lymphoma

Patients with relapsed and refractory Hodgkin lymphoma (HL) may experience long-term survival after allogeneic stem cell transplantation (alloSCT), but disease recurrence represents the main cause of treatment failure. Positron-emission tomography (PET)–positive patients after alloSCT have a dismal outcome. Serum thymus and activation-regulated chemokine (TARC) is produced by Reed-Sternberg cells and may be a marker of disease. Our study aimed at assessing whether TARC levels after alloSCT correlated with disease status and whether TARC monitoring could increase the ability to predict relapse. Twenty-four patients were evaluated in a prospective observational study. TARC serum level and PET were assessed before and after alloSCT during the follow-up (median, 30 months; range, 2 to 54). Before alloSCT, the median TARC level was 721 pg/mL (range, 209 to 1332) in PET-negative patients and 2542 pg/mL (range, 94 to 13,870) in PET-positive patients. After alloSCT, TARC was 620 pg/mL (range, 12 to 4333) in persistently PET-negative patients compared with 22,397 pg/mL (range, 602 to 106,578) in PET-positive patients (P < .0001). In 7 patients who relapsed after alloSCT, TARC level increased progressively even before PET became positive, with a median fold increase of 3.19 (range, 1.66 to 7.11) at relapse. The cut-off value of 1726 pg/mL had a sensitivity of 100% and a specificity of 71% for PET positivity. Patients with at least 1 TARC value above 1726 pg/mL during the first year after alloSCT had a worse progression-free survival (P = .031). In conclusion, TARC was correlated with disease status and its monitoring may be able to predict PET positivity after alloSCT, thus potentially allowing an early immune manipulation.

Periostin levels correlate with disease severity and chronicity in patients with atopic dermatitis

Recent findings indicate that periostin, an extracellular matrix protein induced by T helper 2 cytokines, plays a critical role in the pathogenesis of atopic dermatitis (AD). To determine whether serum periostin level is associated with clinical phenotype in adult patients with AD. An enzyme-linked immunosorbent assay was performed to determine serum periostin levels in 257 adult patients with AD, 66 patients with psoriasis vulgaris (PV) as a disease control and 25 healthy controls. Serum periostin levels were analysed together with clinical characteristics and laboratory parameters, including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophil count and total IgE. Immunohistochemical analysis evaluated the expression of periostin in association with various clinical phenotypes of AD. The effect of treatment on serum periostin level was also assessed. Serum periostin was significantly higher in patients with AD than in patients with PV and healthy controls. Periostin level was found to be positively correlated with disease severity, TARC level, LDH level and eosinophil count, but not with IgE level. Higher serum periostin level was observed in patients with extrinsic AD compared with patients with intrinsic AD; the positive correlation of disease severity disappeared in patients with intrinsic AD. Robust expression of periostin was detected in the dermis of patients with AD with erythroderma, lichenification and, to a lesser extent, scaly erythema. Serial measurement of serum periostin revealed decreased levels of periostin after treatment for AD. Periostin may play a critical role in disease severity and chronicity in the pathogenesis of AD.

Anti-CCR4 monoclonal antibody KW-0761 (mogamulizumab) or investigator’s choice of chemotherapy in subjects with relapsed or refractory adult T-cell leukemia-lymphoma (ATL).

TPS8622 Background: The receptor for macrophage derived chemokine (MDC) and thymus- and activation-regulated chemokine (TARC) CC chemokine receptor 4 (CCR4) is over expressed in several T-cell mali...

Determination of Toll-Like Receptor-Induced Cytokine Profiles in the Blood and Cerebrospinal Fluid of Chikungunya Patients

Background: Chikungunya infection caused by Chikungunya virus (CHIKV) is an inflammatory disease affecting the joints and may also lead to neurological complications. We investigated a panel of human Toll-like receptor (TLR)-induced cytokines in Chikungunya patients with and without neurological complications. Methods: In a case-control study, a panel of 12 cytokines and chemokines, TNF-α, IFN-α, IL-1β, IL-6, IL-12, IL-17A, IL-8, monocyte chemotactic protein (MCP)-1, RANTES, interferon (IFN)-γ-induced protein (IP)-10, monokine induced by IFN-γ (MIG) and thymus and activation-regulated chemokine (TARC), was analysed using a conventional ELISA protocol in the serum samples of Chikungunya patients without neurological complications and in the cerebrospinal fluid (CSF) and paired serum samples of Chikungunya patients with neurological complications. Results: The levels of 3 cytokines, IL-1β, IL-17A and IL-8, and 4 chemokines, MCP-1, RANTES, IP-10 and TARC, were raised in serum samples of Chikungunya patients without neurological complications, whereas, 4 cytokines, TNF-α, IFN-α, IL-6 and IL-8, and 4 chemokines, MCP-1, RANTES, MIG and TARC, were elevated in CSF samples of Chikungunya patients with neurological complications. Moreover, the levels of IL-6 and IL-8 cytokines were significantly elevated in the CSF compared to paired serum samples in Chikungunya patients with neurological complications. Conclusions: In CHIKV infection, multiple cytokines are elevated in serum and CSF. The elevation in IL-6 and IL-8 cytokines in CSF correlates with neurological involvement.