Optimal age to discontinue long-term surveillance of intraductal papillary mucinous neoplasms: comparative cost-effectiveness of surveillance by age.

OBJECTIVE: Current guidelines recommend long-term image-based surveillance for patients with low-risk intraductal papillary mucinous neoplasms (IPMNs). This simulation study aimed to examine the comparative cost-effectiveness of continued versus discontinued surveillance at different ages and define the optimal age to stop surveillance. DESIGN: We constructed a Markov model with a lifetime horizon to simulate the clinical course of patients with IPMNs receiving imaging-based surveillance. We calculated incremental cost-effectiveness ratios (ICERs) for continued versus discontinued surveillance at different ages to stop surveillance, stratified by sex and IPMN types (branch-duct vs mixed-type). We determined the optimal age to stop surveillance as the lowest age at which the ICER exceeded the willingness-to-pay threshold of US$100 000 per quality-adjusted life year. To estimate model parameters, we used a clinical cohort of 3000 patients with IPMNs and a national database including 40 166 patients with pancreatic cancer receiving pancreatectomy as well as published data. RESULTS: In male patients, the optimal age to stop surveillance was 76-78 years irrespective of the IPMN types, compared with 70, 73, 81, and 84 years for female patients with branch-duct IPMNs <20 mm, =20-29 mm, ≥30 mm and mixed-type IPMNs, respectively. The suggested ages became younger according to an increasing level of comorbidities. In cases with high comorbidity burden, the ICERs were above the willingness-to-pay threshold irrespective of sex and the size of branch-duct IPMNs. CONCLUSIONS: The cost-effectiveness of long-term IPMN surveillance depended on sex, IPMN types, and comorbidity levels, suggesting the potential to personalise patient management from the health economic perspective.

Physical Activity and Mammographic Density in Japanese Women.

BACKGROUND: Dense breast is one of the strong risk factors for breast cancer among women. While it has been established that physical activity is associated with decreased risk for breast cancer, results have been inconsistent in terms of mammographic density. Thus, we examined physical activity in relation to mammographic density among Japanese women in Tokyo. METHODS: We used 123,026 records from 33,698 Japanese women without a history of breast cancer who got mammograms at St. Luke's International Hospital in Tokyo, Japan from 2004 to 2019. Mammographic density was classified according to the Breast Imaging Reporting and Data System (BI-RADS), and women self-reported their physical activity level over the past year. ORs were estimated using logistic generalized estimating equations after adjusting for age, body mass index, menopausal status, parity, family history of breast or ovarian cancer, hormone therapy use, smoking status, alcohol consumption, and year. RESULTS: We observed inverse associations of physical activity with dense breasts. Adjusted ORs were 0.96 (95% confidence interval: 0.91-1.00) for women with physical exercise for 1-2 days per week, 0.94 (0.88-0.99) for those with physical exercise for 3-5 days per week, and 0.91 (0.84-0.99) for those with daily physical exercise when compared with those reported seldom physical exercise. CONCLUSIONS: Higher levels of physical activity may be associated with decreased mammographic density levels in Japanese women. IMPACT: Increasing physical activity may serve as a reasonable intervention to reduce mammographic density, and thereby, to mitigate the risk of breast cancer in Asian women.

The microRNA-mediated gene regulatory network in the hippocampus and hypothalamus of the aging mouse.

Aging leads to time-dependent functional decline of all major organs. In particular, the aging brain is prone to cognitive decline and several neurodegenerative diseases. Various studies have attempted to understand the aging process and underlying molecular mechanisms by monitoring changes in gene expression in the aging mouse brain using high-throughput sequencing techniques. However, the effect of microRNA (miRNA) on the post-transcriptional regulation of gene expression has not yet been comprehensively investigated. In this study, we performed global analysis of mRNA and miRNA expression simultaneously in the hypothalamus and hippocampus of young and aged mice. We identified aging-dependent differentially expressed genes, most of which were specific either to the hypothalamus or hippocampus. However, genes related to immune response-related pathways were enriched in upregulated differentially expressed genes, whereas genes related to metabolism-related pathways were enriched in downregulated differentially expressed genes in both regions of the aging brain. Furthermore, we identified many differentially expressed miRNAs, including three that were upregulated and three that were downregulated in both the hypothalamus and hippocampus. The two downregulated miRNAs, miR-322-3p, miR-542-3p, and the upregulated protein-encoding coding gene C4b form a regulatory network involved in complement and coagulation cascade pathways in the hypothalamus and hippocampus of the aging brain. These results advance our understanding of the miRNA-mediated gene regulatory network and its influence on signaling pathways in the hypothalamus and hippocampus of the aging mouse brain.

Mitochondrial nucleic acids in innate immunity and beyond.

Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the innate immune response to viral infection. Recently, studies have revealed that mitochondrion-derived DNAs and RNAs are recognized as non-self molecules and act as immunogenic ligands. More importantly, the cytosolic release of these mitochondrial nucleic acids (mt-NAs) is closely associated with the pathogenesis of human diseases accompanying aberrant immune activation. The release of mitochondrial DNAs (mtDNAs) via BAX/BAK activation and/or VDAC1 oligomerization activates the innate immune response and inflammasome assembly. In addition, mitochondrial double-stranded RNAs (mt-dsRNAs) are sensed by pattern recognition receptors in the cytosol to induce type I interferon expression and initiate apoptotic programs. Notably, these cytosolic mt-NAs also mediate adipocyte differentiation and contribute to mitogenesis and mitochondrial thermogenesis. In this review, we summarize recent studies of innate immune signaling pathways regulated by mt-NAs, human diseases associated with mt-NAs, and the emerging physiological roles of mt-NAs.

A Novel Interaction between MFN2/Marf and MARK4/PAR-1 Is Implicated in Synaptic Defects and Mitochondrial Dysfunction.

As cellular energy powerhouses, mitochondria undergo constant fission and fusion to maintain functional homeostasis. The conserved dynamin-like GTPase, Mitofusin2 (MFN2)/mitochondrial assembly regulatory factor (Marf), plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, is not clearly understood. Here, we identified a novel interaction between MFN2/Marf and microtubule affinity-regulating kinase 4 (MARK4)/PAR-1. In the Drosophila larval neuromuscular junction, muscle-specific overexpression of MFN2/Marf decreased the number of synaptic boutons, and the loss of MARK4/PAR-1 alleviated the synaptic defects of MFN2/Marf overexpression. Downregulation of MARK4/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2/Marf overexpression in the Drosophila muscles as well as in the cultured cells. In addition, knockdown of MARK4/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2/Marf overexpression in mammalian cells. Together, our results indicate that the interaction between MFN2/Marf and MARK4/PAR-1 is fine-tuned to maintain synaptic integrity and mitochondrial homeostasis, and its dysregulation may be implicated in neurologic pathogenesis.

H19X-encoded microRNAs induced by IL-4 in adipocyte precursors regulate proliferation to facilitate differentiation.

Adipose tissue, an organ critical for systemic energy homeostasis, is influenced by type 2 immunity in its development and function. The type 2 cytokine interleukin (IL)-4 induces the proliferation of bipotential adipocyte precursors (APs) in white fat tissue and primes these cells for differentiation into beige adipocytes, which are specialized for thermogenesis. However, the underlying mechanisms have not yet been comprehensively examined. Here, we identified six microRNA (miRNA) genes upregulated upon IL-4 stimulation in APs, miR-322, miR-503, miR-351, miR-542, miR-450a, and miR-450b; these are encoded in the H19X locus of the genome. Their expression is positively regulated by the transcription factor Klf4, whose expression also increases upon IL-4 stimulation. These miRNAs shared a large set of target genes, of which 381 genes were downregulated in mRNA expression upon IL-4 stimulation and enriched in Wnt signaling pathways. Two genes with downregulated expression, Ccnd1 and Fzd6, were repressed by H19X-encoded miRNAs. Additionally, the Wnt signaling activator LiCl downregulated the expression of this group of miRNAs in APs, indicating that Wnt signaling-related genes and these miRNAs form a double-negative feedback regulatory loop. This miRNA/Wnt feedback regulation modulated the elevated proliferation of APs induced by IL-4 stimulation and contributed to priming them for beige adipocyte differentiation. Moreover, the aberrant expression of these miRNAs attenuates the differentiation of APs into beige adipocytes. Collectively, our results suggest that H19X-encoded miRNAs facilitate the transition of APs from proliferation to differentiation in the IL-4-mediated regulation.

Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity.

Introduction: Breast tumor development is regulated by a sub-population of breast cancer cells, termed cancer stem-like cells (CSC), which are capable of self-renewing and differentiating, and are involved in promoting breast cancer invasion, metastasis, drug resistance and relapse. CSCs are highly adaptable, capable of reprogramming their own metabolism and signaling activity in response to stimuli within the tumor microenvironment. Recently, the nutrient sensor O-GlcNAc transferase (OGT) and O-GlcNAcylation was shown to be enriched in CSC populations, where it promotes the stemness and tumorigenesis of breast cancer cells in vitro and in vivo. This enrichment was associated with upregulation of the transcription factor Kruppel-like-factor 8 (KLF8) suggesting a potential role of KLF8 in regulating CSCs properties. Methods: Triple-negative breast cancer cells were genetically modified to generate KLF8 overexpressing or KLF8 knock-down cells. Cancer cells, control or with altered KLF8 expression were analyzed to assess mammosphere formation efficiency, CSCs frequency and expression of CSCs factors. Tumor growth in vivo of control or KLF8 knock-down cells was assessed by fat-pad injection of these cell in immunocompromised mice. Results: Here, we show that KLF8 is required and sufficient for regulating CSC phenotypes and regulating transcription factors SOX2, NANOG, OCT4 and c-MYC. KLF8 levels are associated with chemoresistance in triple negative breast cancer patients and overexpression in breast cancer cells increased paclitaxel resistance. KLF8 and OGT co-regulate each other to form a feed-forward loop to promote CSCs phenotype and mammosphere formation of breast cancer cells. Discussion: These results suggest a critical role of KLF8 and OGT in promoting CSCs and cancer progression, that may serve as potential targets for developing strategy to target CSCs specifically.

In vivo profiling of the Zucchini proximal proteome in the Drosophila ovary.

PIWI-interacting RNAs (piRNAs) are small RNAs that play a conserved role in genome defense. The piRNA processing pathway is dependent on the sequestration of RNA precursors and protein factors in specific subcellular compartments. Therefore, a highly resolved spatial proteomics approach can help identify the local interactions and elucidate the unknown aspects of piRNA biogenesis. Herein, we performed TurboID proximity labeling to investigate the interactome of Zucchini (Zuc), a key factor of piRNA biogenesis in germline cells and somatic follicle cells of the Drosophila ovary. Quantitative mass spectrometry analysis of biotinylated proteins defined the Zuc-proximal proteome, including the well-known partners of Zuc. Many of these were enriched in the outer mitochondrial membrane (OMM), where Zuc was specifically localized. The proximal proteome of Zuc showed a distinct set of proteins compared with that of Tom20, a representative OMM protein, indicating that chaperone function-related and endomembrane system/vesicle transport proteins are previously unreported interacting partners of Zuc. The functional relevance of several candidates in piRNA biogenesis was validated by derepression of transposable elements after knockdown. Our results present potential Zuc-interacting proteins, suggesting unrecognized biological processes.

Development of a Fast Onset Proton Pump Inhibitor: Comparison of Fixed-Dose Combination of Rabeprazole and Sodium Bicarbonate (YPI-011) to the Conventional Enteric-Coated Rabeprazole.

Purpose: Proton pump inhibitors (PPIs) are the first-line therapy for gastroesophageal reflux disorder (GERD). Unlike conventional PPIs, non-enteric coated PPIs with antacid salt enable a faster acid suppression through the rapid absorption of the PPI. YPI-011 is a newly developed fixed-dose combination of a rabeprazole with sodium bicarbonate (NaHCO3). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of YPI-011 to the conventional enteric-coated rabeprazole (Pariet®). Materials and Methods: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with two different doses (10 and 20 mg) and 44 subjects in each group. They randomly received either a test or reference treatment for 7 days in the first period and the other treatment in the second period. Blood samples for the PK analysis were taken after the single- and multiple-dose. Intragastric pH monitoring for the PD analysis was implemented for baseline and after the single- and multiple-dose. Results: Gastric acid suppression evaluated by the percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the multiple-dose was similar between the treatments in both dose groups. The systemic exposure of rabeprazole at steady state after the multiple-dose was also similar between the treatments in both dose groups. The time to reach the maximum rabeprazole concentration was faster in the test treatment. The PK-PD relationship of PPI is well known, and the faster absorption of rabeprazole resulted in a more rapid mode of action in acid suppression. Conclusion: The fixed dose combination of rabeprazole with NaHCO3 showed a faster absorption and consequently, a more rapid gastric acid suppression with a similar systemic exposure of rabeprazole at steady state compared to the conventional enteric-coated rabeprazole.

An association between mammographic breast density and fine particulate matter among postmenopausal women.

Increasing breast density is a risk factor for breast cancer. Geographic variations in breast density may be due to differences in lifestyle and diet, as well as environmental factors such as air pollution exposure. However, these environmental contributors have not been established. In this study, we evaluated an association between air pollution and mammographic breast density. The study population for this study was postmenopausal women who had undergone screening mammography at the Center for Preventive Medicine, St. Luke's International Hospital, from April 2004 to September 2018. Individual mammography results were obtained from electronic charts. The ambient air pollution (PM2.5) density of the locations of interest, namely, the patients' residential areas during the study period, was obtained. The mean PM2.5 exposure levels for 1, 3, 5, and 7 years were determined. A generalized estimating equations model was used to examine the association between air pollution density and dense breast. A total of 44,280 mammography results were included in this study, and 29,135 were classified in the non-dense breast group and 15,145 in the dense breast group. There was a 3% increase in the odds of having dense breasts after 1 year (OR = 1.027, 95% confidence interval (CI) 1.019-1.034) and 3 years of PM2.5 exposure (OR = 1.029, 95% CI 1.022-1.036). This further increased to 4% at 5-year exposure (OR = 1.044, 95% CI 1.037-1.052) and 5% at 7-year exposure (OR = 1.053, 95% CI 1.044-1.063). The risk for dense breasts increased if the factors of smoking, family history of breast and/or ovarian cancer, and history of childbirth were present.

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines in vitro. Here, we created constitutive Rarres1 knockout (Rarres1-/-) mouse models to study RARRES1 function in vivo. Rarres1-/- embryonic fibroblasts regulated tubulin glutamylation, cell metabolism, and survival, recapitulating RARRES1 function in immortalized cell lines. In two mouse strains, loss of Rarres1 led to a markedly increased dose-dependent incidence of follicular lymphoma (FL). Prior to lymphoma formation, Rarres1-/- B cells have compromised activation, maturation, differentiation into antibody-secreting plasma cells, and cell cycle progression. Rarres1 ablation increased B cell survival and led to activation of the unfolded protein response (UPR) and heat shock response (HSR). Rarres1 deficiency had differential effects on cellular metabolism, with increased bioenergetic capacity in fibroblasts, and minor effects on bioenergetics and metabolism in B cells. These findings reveal that RARRES1 is a bona fide tumor suppressor in vivo and the deletion in mice promotes cell survival, and reduces B cell differentiation with B cell autonomous and non-autonomous functions.

NOX2-Induced High Glycolytic Activity Contributes to the Gain of COL5A1-Mediated Mesenchymal Phenotype in GBM.

The alteration of the cellular metabolism is a hallmark of glioma. The high glycolytic phenotype is a critical factor in the pathogenesis of high-grade glioma, including glioblastoma multiforme (GBM). GBM has been stratified into three subtypes as the proneural, mesenchymal, and classical subtypes. High glycolytic activity was found in mesenchymal GBM relative to proneural GBM. NADPH oxidase 2 (NOX2) has been linked to cellular metabolism and epithelial-mesenchymal transition (EMT) in tumors. The role of NOX2 in the regulation of the high glycolytic phenotype and the gain of the mesenchymal subtype in glioma remain unclear. Here, our results show that the levels of NOX2 were elevated in patients with GBM. NOX2 induces hexokinase 2 (HK2)-dependent high glycolytic activity in U87MG glioma cells. High levels of NOX2 are correlated with high levels of HK2 and glucose uptake in patients with GBM relative to benign glioma. Moreover, NOX2 increases the expression of mesenchymal-subtype-related genes, including COL5A1 and FN1 in U87MG glioma cells. High levels of NOX2 are correlated with high levels of COL5A1 and the accumulation of extracellular matrix (ECM) in patients with GBM relative to benign glioma. Furthermore, high levels of HK2 are correlated with high levels of COL5A1 in patients with GBM relative to benign glioma. Our results suggest that NOX2-induced high glycolytic activity contributes to the gain of the COL5A1-mediated mesenchymal phenotype in GBM.

ROS-induced PADI2 downregulation accelerates cellular senescence via the stimulation of SASP production and NFκB activation.

Cellular senescence is closely related to tissue aging including bone. Bone homeostasis is maintained by the tight balance between bone-forming osteoblasts and bone-resorbing osteoclasts, but it undergoes deregulation with age, causing age-associated osteoporosis, a main cause of which is osteoblast dysfunction. Oxidative stress caused by the accumulation of reactive oxygen species (ROS) in bone tissues with aging can accelerate osteoblast senescence and dysfunction. However, the regulatory mechanism that controls the ROS-induced senescence of osteoblasts is poorly understood. Here, we identified Peptidyl arginine deiminase 2 (PADI2), a post-translational modifying enzyme, as a regulator of ROS-accelerated senescence of osteoblasts via RNA-sequencing and further functional validations. PADI2 downregulation by treatment with H2O2 or its siRNA promoted cellular senescence and suppressed osteoblast differentiation. CCL2, 5, and 7 known as the elements of the senescence-associated secretory phenotype (SASP) which is a secretome including proinflammatory cytokines and chemokines emitted by senescent cells and a representative feature of senescence, were upregulated by H2O2 treatment or Padi2 knockdown. Furthermore, blocking these SASP factors with neutralizing antibodies or siRNAs alleviated the senescence and dysfunction of osteoblasts induced by H2O2 treatment or Padi2 knockdown. The elevated production of these SASP factors was mediated by the activation of NFκB signaling pathway. The inhibition of NFκB using the pharmacological inhibitor or siRNA effectively relieved H2O2 treatment- or Padi2 knockdown-induced senescence and osteoblast dysfunction. Together, our study for the first time uncover the role of PADI2 in ROS-accelerated cellular senescence of osteoblasts and provide new mechanistic and therapeutic insights into excessive ROS-promoted cellular senescence and aging-related bone diseases.

Photochemical oxidants and ambulance dispatches for asthmatic symptoms in Tokyo.

While photochemical oxidants (Ox = O3+ NO2) are known to increase asthma flare-ups, there is a paucity of studies of the Japanese population, especially for Tokyo residents. We used data on asthma cases (n = 7,455) from ambulance dispatches in Tokyo, 2015-2016. Variables included date and time of incidence, age, sex, occurrence location at the ward (ku) level, and the symptom/cause of dispatch as recorded by paramedics. Ox data were obtained from the nearest air quality monitoring station to the occurrence location, then linked them with the outcomes based on occurrence date. We directly incorporated a distributed lag model into a bi-directional case-crossover study design controlling for ambient temperature and day of week. A 10-ppb increase in Ox for lag days 0-3 was associated with a 5.51% (95% CI: 0.13 to 11.18) increase in ambulance dispatches related to asthma. The association was strongest on lag day 1 (4.67%, 95% CI: 0.51 to 9.00). Exposure to high levels of Ox was associated with increased ambulance dispatches related to asthma exacerbations in Tokyo, Japan.

Correction: Tumor suppressor RARRES1 links tubulin deglutamylation to mitochondrial metabolism and cell survival.

[This corrects the article DOI: 10.18632/oncotarget.26600.].

Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy.

Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates FGF signaling. Various FGFR2 alterations are detected in breast cancer, yet it remains unclear if activation of FGFR2 signaling initiates tumor formation. In an attempt to answer this question, a mouse model berrying an activation mutation of FGFR2 (FGFR2-S252W) in the mammary gland is generated. It is found that FGF/FGFR2 signaling drives the development of triple-negative breast cancer accompanied by epithelial-mesenchymal transition that is regulated by FGFR2-STAT3 signaling. It is demonstrated that FGFR2 suppresses BRCA1 via the ERK-YY1 axis and promotes tumor progression. BRCA1 knockout in the mammary gland of the FGFR2-S252W mice significantly accelerated tumorigenesis. It is also shown that FGFR2 positively regulates PD-L1 and that a combination of FGFR2 inhibition and immune checkpoint blockade kills cancer cells. These data suggest that the mouse models mimic human breast cancers and can be used to identify actionable therapeutic targets.

PM2.5 and Diabetes in the Japanese Population.

Growing evidence suggests that PM2.5 is associated with diabetes mellitus (DM). Although DM is a major public health concern, there has not yet been a study of this association in Japan. We used health examination data from 66,885 individuals in Tokyo, Japan 2005-2019. Cox proportional hazards models were used to evaluate an association between annual exposure to PM2.5 and glycated hemoglobin A1c (HbA1c), or fasting plasma glucose (FPG). An increase of 1 µg/m3 in the annual average of PM2.5 concentration was associated (HR = 1.029; 95% CI = 1.004-1.055) with an increase in diabetes (incident + prevalent). For incident DM, a greater PM2.5 level was associated with more DM (HR = 1.029; 95% CI, 1.003-1.055). Compared to HbA1c, FPG showed a stronger association with the annual exposure to PM2.5 (HR = 1.065; 95% CI, 1.040-1.091). We found that greater exposure to PM2.5 in the long-term was associated with an increased risk of diabetes, and that the magnitude of association became stronger as the exposure duration increased. Omorogieva Ojo.

miR-542-3p Contributes to the HK2-Mediated High Glycolytic Phenotype in Human Glioma Cells.

(1) Background: The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear; (2) Methods: We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis; (3) Results: We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database; (4) Conclusions: miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.

Effects of conditioned media from human umbilical cord blood-derived mesenchymal stem cells in the skin immune response.

Atopic dermatitis (AD) is an inflammatory skin disease in which type 2 allergic inflammation plays a critical role. In this study, the anti-inflammatory effect of conditioned media from human umbilical cord blood-derived mesenchymal stem cells (USC-CM) was investigated in order to apply it as an effective treatment with a low risk of side effects that can overcome the limitations of AD treatment which is currently in use. We found that USC-CM has various growth factors and cytokines associated with anti-inflammatory effect. RT-PCR and ELISA analysis showed that USC-CM inhibited the levels of type 2 cytokine and chemokine Thymus and activation-regulated chemokine (TARC), TNF-α and IL-6 in TNF-α/IFN-γ-stimulated HaCaT cells. In addition, USC-CM inhibited IL-4 and IL-13 levels in Th2 cells. Therefore, the results of our study demonstrated that USC-CM has anti-inflammatory effect in TNF-α/IFN-γ-stimulated HaCaT cells which associated with the inhibition of the immunoglobulin (IgE) secretion by activating B cell line. Our In vivo results showed that when the USC-CM was applied to lesions of patients with the mild AD for 4 weeks, the skin barrier was strengthened by increasing the level of Corneometer and decreasing the value of transepidermal water loss (TEWL). In conclusion, the results suggest that USC-CM may have therapeutic effect for AD as cosmetics and drug materials.