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Purpose: To compare the haemostatic efficacy (i.e. efficacy to prevent access site complications) of the InnoSEAL haemostatic pad and Clo-Sur PLUS P.A.D. after femoral arterial puncture for transcatheter arterial chemoembolization (TACE). Material and methods: This randomized controlled trial compared the safety and efficacy of an InnoSEAL haemostatic pad (n = 48) and a Clo-Sur PLUS P.A.D. (n = 52) for haemostasis of arterial puncture sites after TACE with femoral arterial access using a 5-Fr sheath. Primary endpoints were incidence of major (necessitating surgery) and moderate access site complications (ASC) (necessitating blood transfusion/thrombin injection). Secondary endpoints were incidence of minor ASC (no therapy required) and time to haemostasis. Results: No major or moderate ASC was seen with either device. Minor ASC (6.3% [3/48] vs. 19.2% [10/52], p = 0.075) and ecchymosis (classified as minor ASC; 4.2% [2/48] vs. 17.3% [9/52]; p = 0.053, p-value cut-off after Bonferroni correction = 0.025) were less frequently observed with the InnoSEAL haemostatic pad. The time to haemostasis did not differ significantly between the 2 devices (5.6 ± 1.0 vs. 5.3 ± 0.7 minutes; p = 0.118). Multivariable logistic regression analysis showed a lower risk of ASC with the InnoSEAL pad (adjusted OR, 0.174; 95% CI: 0.034-0.890; p = 0.036). Conclusions: No major ASC was seen with either pad, and no significant difference of minor ASC was observed between 2 pads.

Background: Human epidermal γδ T cells are known to play crucial roles in the defense and homeostasis of the skin. However, their precise mechanism of action in skin inflammation remains less clear. Objective: In this study, we analyzed the cytokine expression profile of human epidermal γδ T cells and compared it to that of peripheral blood γδ T cells to investigate the specific activity of epidermal γδ T cells in modulating skin inflammation. Methods: We isolated γδ T cells from epidermal tissue or peripheral blood obtained from healthy volunteers. Isolated γδ T cells were stimulated using immobilized anti-CD3 antibody and interleukin-2 plus phytohaemagglutinin, and were then analyzed using a cytokine array kit. Results: Both epidermal and peripheral blood γδ T cells produced comparable levels of granulocyte-macrophage colony-stimulating factor, I-309, interferon-γ, macrophage migration inhibitory factor, macrophage inflammatory protein-1α, and chemokine (C-C) ligand 5. The epidermal γδ T cells produced significantly higher levels of interleukin-4, -8, -13, and macrophage inflammatory protein-1β than the peripheral blood γδ T cells did. Notably, the epidermal γδ T cells produced several hundred-fold higher levels of interleukin-13 than interleukin-4. Conclusion: These results suggest that the epidermal γδ T cells have a stronger potential to participate in the Th2-type response than the peripheral blood γδ T cells do. Furthermore, epidermal γδ T cells might play an important role in the pathogenesis of Th2-dominant skin diseases because of their active production of interleukin-13. (Ann Dermatol 26(3) 308∼313, 2014)

Skin diseases can be characterized by their predominant CD4-positive T-helper (Th) cell profiles. Chronic dermatological conditions often give rise to abnormal skin pigmentation. To understand the role of Th cells in pigmentation, the effects of the major Th cell cytokines, IFNγ, IL-4, and IL-17A, on melanogenesis were evaluated using cultured normal human melanocytes (NHMs) instead of relying on transformed melanoma cell lines. IL-4 directly inhibited melanogenesis in NHMs and downregulated both transcription and translation of melanogenesis-associated genes, such as microphthalmia-associated transcription factor (MITF) and dopachrome tautomerase. Despite the lack of a direct inhibition of melanin pigment synthesis, IFNγ and IL-17A increased the synthesis of an antimelanogenic cytokine IL-6 in NHMs. IFNγ activated signal transducers and activators of transcription 1 (STAT1) and STAT3 phosphorylation in NHMs, and IL-4 increased the STAT3 and STAT6 phosphorylation. The differential phosphorylation profile of STAT proteins between IFNγ and IL-4 may explain the difference in their effect on melanogenesis in NHMs. The IL-4-induced downregulation of melanogenesis was inhibited by treating NHMs with a JAK2 inhibitor AG490 or STAT6 siRNA. In conclusion, the involvement of the IL-4-induced JAK2–STAT6 signaling and the IFNγ- or IL-17A-dependent antimelanogenic IL-6 production should be considered as one of the mechanisms explaining the association with hypopigmention in skin diseases.

Melanoblasts are derived from the neural crest and migrate to the dermal/epidermal border of skin and hair bulges. Although melanoblast migration during embryogenesis has been well investigated, there are only a few reports regarding the migration of mature melanocytes. Here, we demonstrate that a chemokine, stromal-derived factor-1 (SDF1, also known as CXCL12), and one of its receptor CXCR7 regulate normal human epidermal melanocyte (NHEM) migration. We found that SDF1 induces the directional migration of NHEMs. Interestingly, although both CXCR4 and CXCR7 are expressed in NHEMs, blockade of CXCR4 using a CXCR4-specific neutralizing antibody did not exert any influence on the SDF1-induced migration of NHEMs, whereas blockade of CXCR7 using a CXCR7-specific neutralizing antibody did influence migration. Furthermore, SDF1-induced NHEMs migration exhibited the early hallmark events of CXCR7 signaling associated with MAP kinase activation. It is known that the phosphorylation of ERK through CXCR7 signaling is mediated by β-arrestins. The treatment of NHEMs with SDF1 resulted in the phosphorylation of ERK in a β-arrestin 2-dependent manner. These results suggest that melanocytes may have a unique mechanism of migration via SDF1/CXCR7 signaling that is different from that of other cell types.

Background Kojic acid is a fungal metabolite widely used in medicinal and cosmetic formulations as a skin-lightening agent based on its de-pigmenting activity. Although in human clinical studies kojic acid has been shown to be effective in the treatment of hyper-pigmentation disorders such as melasma, the reasons for its apparent lack of anti-melanogenic activity in cultured mammalian melanocytes are unclear. Objectives This study was aimed to elucidate pharmacological mechanisms of the in vivo anti-melanogenic activity of kojic acid in human skin. Methods A primary human melanocyte and keratinocyte co-culture system was used to evaluate whether kojic-acid-induced changes in keratinocytes were associated with anti-melanogenic activities in melanocytes. The cytokine secretion profiles in response to kojic acid were analyzed. Results Kojic acid increased interleukin (IL)-6 and IL-8 production in melanocyte/keratinocyte co-cultures; however, IL-6 directly inhibited melanogenesis whereas IL-8 did not. In melanocyte monocultures, kojic acid did not increase IL-6 production whereas in keratinocyte monocultures it significantly up-regulated IL-6 gene and protein expression. Therefore, the up-regulation of IL-6 in melanocyte/keratinocyte co-cultures seems to be originated from kojic acid-induced changes in keratinocytes. Anti-IL-6 antibody treatment antagonized the anti-melanogenic effect of kojic acid on the co-cultures. Conclusions The pharmacological mechanism of kojic acid to explain clinically effective anti-melanogenic activity on hyper-pigmented skin is associated with the kojic acid-induced IL-6 production in keratinocytes. The cross-talk between melanocytes and keratinocytes should be determined in future studies on the pharmacological mechanisms of clinically effective dermatological drugs acting on the epidermis.

Sphingosylphosphorylcholine (SPC) mediates various inflammatory and behavioral responses in atopic dermatitis. Recent studies have shown that dysfunction of the epidermal permeability barrier itself plays a primary role in the etiology of atopic dermatitis. However, the effects of SPC on major proteins essential to the development of the epidermal permeability barrier such as filaggrin, loricrin, involucrin, keratin 1, keratin 10 and small proline-rich proteins are still unclear. In this study, we demonstrated that SPC significantly reduces filaggrin gene transcription, implying that SPC plays a pivotal role in impairment of the epidermal permeability barrier in atopic dermatitis lesional skin. In cultured normal human keratinocytes (NHKs), SPC increases the intracellular level of reactive oxygen species (ROS) and up-regulates NADPH oxidase 5 (NOX5) gene transcription. SPC also stimulates prostaglandin (PG) E(2) production by increasing cyclooxygenase (COX)-2 expression in NHK. The effects of the prostanoid EP receptor agonists, limaprost, butaprost, and sulprostone on filaggrin gene expression in NHK suggest that the prostanoid EP2 receptor plays a significant role in the PGE(2)-mediated filaggrin down-regulation. In contrast, limaprost and butaprost do not affect NOX5 expression in NHK, implying that the NOX5-regulated ROS pathway stimulated by SPC may be upstream of the COX-2 pathway. We propose that the increase in SPC levels further aggravates dermatological symptoms of atopic dermatitis through SPC-induced down-regulation of filaggrin in NHK.

Skin irritation caused by retinol and retinoic acid results in mild erythema called as retinoid dermatitis. To develop compounds modulating the retinoid dermatitis, we tried to establish the screening method for retinoid dermatitis. At first we examined the inflammatory cytokine profile in neonatal human dermal fibroblasts which are known to be one of main site of retinoid action. As a result, interleukin-8 (IL-8) and monocytes chemoattractant protein-1 (MCP-1) were significantly produced by all trans retinoic acid (ATRA) and all trans retinol (ATROL) in dermal fibroblasts. Especially the production of MCP-1 was more than that of IL-8. The production of MCP-1 by retinoid was dose-dependently increased, continuing up to 24 hrs. After then using ethacrynic acid (ECA) known to reduce mouse ear edema induced by ATRA, we checked whether ECA suppressed the production of MCP-1. As a result, ECA effectively suppressed the production of MCP-1 in the ATRA- or ATROL-treated-fibroblasts. These results suggested that screening method effectively reflects the in vivo anti-inflammatory activity of ECA. It was reported that citral inhibited the enzyme involved in the conversion of ATROL to ATRA. We showed that citral suppressed the production of MCP-1 in ATROL-treated fibroblasts. We expect these finding might be helpful to find useful compounds modulating the side effects of retinoid or retinoid dermatitis.

OBJECTIVE. Portal vein embolization (PVE) has been widely used to facilitate major liver resection; however, curative surgery even after PVE may not be possible mainly because of inadequate hypertrophy of remnant liver or disease progression. For these patients, transcatheter arterial chemoembolization (TACE) is the next therapeutic option. We evaluated the safety and efficacy of TACE after PVE in 25 patients with hepatocellular carcinoma (HCC).CONCLUSION. TACE using a single chemotherapeutic agent can be performed safely and effectively in HCC patients who previously underwent PVE. TACE after PVE allowed two of the patients to be downstaged so they could undergo surgical resection.

Background and purpose: Recently, we reported that 12(S)-HPETE (12(S)-hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid) induces scratching in ICR mice. We hypothesized that 12(S)-HPETE might act as an agonist of the low-affinity leukotriene B4 receptor BLT2. To confirm the involvement of the BLT2 receptor in 12(S)-HPETE-induced scratching, we studied the scratch response using the BLT2 receptor agonists compound A (4′-{[pentanoyl (phenyl) amino]methyl}-1,1′-biphenyl-2-carboxylic acid) and 12(S)-HETE (12(S)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid). Experimental approach: A video recording was used to determine whether the BLT2 receptor agonists caused itch-associated scratching in ICR mice. Selective antagonists and several chemicals were used. Key results: Both 12(S)-HETE and compound A dose dependently induced scratching in the ICR mice. The dose–response curve for compound A showed peaks at around 0.005–0.015 nmol per site. Compound A- and 12(S)-HETE-induced scratching was suppressed by capsaicin and naltrexon. We examined the suppressive effects of U75302 (6-[6-(3-hydroxy-1E,5Z-undecadienyl)-2-pyridinyl]-1,5-hexanediol, the BLT1 receptor antagonist) and LY255283 (1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]-ethanone, the BLT2 receptor antagonist) on the BLT2 agonist-induced scratching. LY255283 suppressed compound A- and 12(S)-HETE-induced scratching, but U75302 did not. LY255283 required a higher dose to suppress the compound A-induced scratching than it did to suppress the 12(S)-HETE-induced scratching. One of the BLT2 receptor agonists, 12(R)-HETE (12(R)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid), also induced scratching in the ICR mice. Conclusions and implications: Our present results corroborate the hypothesis that the BLT2 receptor is involved in 12(S)-lipoxygenase-product-induced scratching in ICR mice. We also confirmed that this animal model could be a valuable means of evaluating the effects of BLT2 receptor antagonists. British Journal of Pharmacology (2008) 154, 1073–1078; doi:10.1038/bjp.2008.220; published online 9 June 2008

Sphingosylphosphorylcholine (SPC) is upregulated in the stratum corneum of atopic dermatitis patients by sphingomyelin deacylase. We conducted an investigation, both to confirm that intradermal injection of SPC elicits scratching in mice, and to elucidate the detailed mechanism of the SPC-induced itch–scratch response. Intradermal administration of SPC increased the incidence of scratching behavior in a dose-dependent manner. SPC-induced scratching could be suppressed, significantly, by the μ-opoid receptor antagonist, naltrexon, the vaniloid receptor agonist, capsaicin, and the histamine H 1 receptor antagonist ketotifen. d - erythro SPC, one of the SPC stereotypes, could elicit the scratch response, but not l - threo SPC. Y-27632 (1 mg/kg, an inhibitor of Rho-associated protein kinase (ROCK)), was found to suppress SPC-induced scratching. Both the stereospecificity of SPC and the involvement of the Rho/ROCK pathway suggested that SPC-induced scratching is related to the receptor.

The Her-2/neu oncogene, which encodes a growth factor receptor, was implicated in the malignancy of human adenocarcinomas. Antibodies directed to this molecule have been previously shown to have an antitumor effect in vivo. In an attempt to understand the mechanisms of the antitumor activity, we generated 2 monoclonal antibodies (mAbs), HRO G1 and HRT G1, that recognize different epitopes on Her-2/neu. Both of the mAbs bound HER2/neu on the tumor surface, resulting in phosphorylation of HER2/neu. We also generated IgG2a and IgG2b mAbs from these 2 mAbs, respectively. The results of in vitro studies showed that these anti-Her-2/neu mAbs could not inhibit the growth of the tumor cells that express Her-2/neu molecules by themselves. However, in an antibody-dependent cellular cytotoxicity study using mouse splenocytes as effector cells, HRT mAbs had antitumor activities superior to those of HRO mAbs, indicating that the epitope specificity may also partake in antibody-dependent cellular cytotoxicity with antibody isotype. In a complement-dependent cytotoxicity study, the IgG2a and IgG2b mAbs showed stronger effects than IgG1 isotype mAbs irrespective of the epitope specificities. The results of in vivo studies also showed that HRT mAbs had superior antitumor activity to those of HRO mAbs. The antitumor activity was most prominent in the HRT G2b isotype among HRT mAbs. HRT G1 also showed a moderate antitumor effect, while HRT G2a showed only slight inhibition effect. These data indicate that both the epitope specificity and the differences in Fc region of mAbs could play important roles in the antitumor activities. © 2002 Wiley-Liss, Inc.

Ginsenoside F1 (GF1) is a metabolite of ginsenoside Rg1. Although GF1 has several benefits for skin physiology, the effect of GF1 on skin pigmentation has not been reported. We found that a cream containing 0.1% GF1 showed a significant whitening effect on artificially tanned human skin after 8 weeks of application. However, GF1 did not inhibit mRNA expression of tyrosinase or dopachrome tautomerase (DCT) in normal human epidermal melanocytes (NHEMs) or cocultured NHEMs/normal human epidermal keratinocytes. Interestingly, GF1 enhanced production of interleukin 13 (IL-13) from human epidermal γδ T cells. IL-13 significantly reduced the mRNA expression and protein amount of both tyrosinase and DCT and reduced melanin synthesis activities in NHEMs, resulting in visible brightening of NHEM pellet. These results suggest that enhancement of IL-13 production by GF1 from epidermal γδ T cells might play a role in the skin-whitening effect of GF1 via the suppression of tyrosinase and DCT.

The interaction of 4-1BB and its ligand plays an important role in the regulation of T-cell-mediated immune responses. In this study, the authors examined the effect of a humanized anti--4-1BB monoclonal antibody (H4B4) on ovalbumin-induced immune responses in baboons. Previously, a mouse monoclonal antibody, 4B4 against the human 4-1BB molecule, was generated and characterized. Based on this antibody, a humanized version of 4B4 monoclonal antibody was constructed and the resultant antibody, H4B4, showed full recovery of the binding activity of the original antibody 4B4: a 1.5-fold increase in affinity for 4-1BB. In addition, H4B4 mediated antibody-dependent cellular cytotoxicity of activated human peripheral blood T cells and CEM cells in a dose-dependent manner. Weekly administration of H4B4 at doses of 1 or 4 mg/kg could suppress immunoglobulin G production against ovalbumin. This was not a result of the overall immune suppression, because the numbers of B and T cells and the total immunoglobulin G production were not altered during treatment with H4B4. These findings suggest that treatment with H4B4 may be a valid therapeutic approach to control unwanted immune responses in persons with autoimmune diseases.

Oral administration of antigen induces an antigen-specific immunologic tolerance and many studies are being carried out to apply this phenomenon to the treatment of autoimmune diseases. In this study, we investigated long-term Th1 and Th2 tolerance in mice given a high dose of orally administered Ovalbumin (OVA). Feeding OVA to BALB/c mice suppressed OVAspecific IgG response and the degree of inhibition was dose-dependent in the range of 2.5∼250 mg. Moreover, the state of tolerance established by prior feeding of high dose of OVA was present after 26 weeks. Interestingly, even though both Th subsets were tolerized significantly for a short period, the tolerizing effect was more pronounced and persistent in Th2-mediated immune responses. Thus we speculate that oral administration of a single high dose of OVA induces Th1- and Th2-tolerance by different mechanisms. Our findings could be important in the development of therapeutics for the treatment of autoimmune disease and allergy.

Evidence from clinical and experimental studies of human and chimpanzees suggests that hepatitis C virus (HCV) envelope glycoprotein E2 is a key antigen for developing a vaccine against HCV infection. To identify B-cell epitopes in HCV E2, six murine monoclonal antibodies (MAbs), CET-1 to -6, specific for HCV E2 protein were generated by using recombinant proteins containing E2t (a C-terminally truncated domain of HCV E2 [amino acids 386 to 693] fused to human growth hormone and glycoprotein D). We tested whether HCV-infected sera were able to inhibit the binding of CET MAbs to the former fusion protein. Inhibitory activity was observed in most sera tested, which indicated that CET-1 to -6 were similar to anti-E2 antibodies in human sera with respect to the epitope specificity. The spacial relationship of epitopes on E2 recognized by CET MAbs was determined by surface plasmon resonance analysis and competitive enzyme-linked immunosorbent assay. The data indicated that three overlapping epitopes were recognized by CET-1 to -6. For mapping the epitopes recognized by CET MAbs, we analyzed the reactivities of CET MAbs to six truncated forms and two chimeric forms of recombinant E2 proteins. The data suggest that the epitopes recognized by CET-1 to -6 are located in a small domain of E2 spanning amino acid residues 528 to 546.

The interaction between CD40 ligand (CD40L) and its counter-receptor CD40 is critically important in T- and B-cell costimulation and generation of the humoral immune response. But several questions still remain unsolved, particularly in the human in vivo system. To clarify the precise function of CD40L and develop an immunosuppressive agent, we have generated a murine monoclonal antibody (MAb), 2B2 specific for human CD40L. The specificity of this MAb for human CD40L was verified by enzyme-linked immunoadsorbent assay (ELISA) and flow cytometry. MAb 2B2 immunoprecipitated proteins of molecular weight 35 and 28 kD on human peripheral blood lymphocytes (PBLs) stimulated with phorbol 12-myristate-13-acetate (PMA) plus ionomycin. Then we have studied the biological effect of MAb 2B2 in severe combined immunodeficiency (SCID) mice reconstituted with human PBLs. The data showed that this MAb strongly suppressed human IgG production of human B cells transplanted in SCID mice, indicating that this MAb 2B2 could be used to regulate unwanted immune responses associated with autoimmune disease. Then we analyzed the sequence of MAb 2B2. The 2B2 heavy chain variable region (VH) and light chain variable region (VL) genes were cloned using PCR. The cloned VH gene coded for 123 amino acid residues and belonged to the subgroup III(D). The VL gene coded for 126 amino acid and belonged to the subgroup V. Collectively, these results will be used to develop an immunosuppressive chimeric or humanized anti-CD40L antibody.

This study evaluated the feasibility and efficacy of covered retrievable stent placement compared with drainage catheter placement for treating biliary anastomotic strictures following living donor liver transplantation (LDLT). In 39 of 59 patients who underwent LDLT, balloon dilation of strictures and subsequent interposition of 14-French indwelling catheters were performed (group 1), whereas in 20 patients, 29 covered retrievable stents were percutaneously placed (group 2). The drainage catheters were positioned above the stricture after at least 12 weeks of internal drainage or following stent removal after at least 8 weeks of stent placement. The drainage catheters were removed when the follow-up cholangiogram revealed free passage of contrast media. In the presence of residual stricture, either of the following was performed: (1) balloon dilation of the stricture and replacement of the indwelling catheter or (2) placement of another covered retrievable stent for at least 12 weeks. Technical success was achieved in all recipients. Clinical success was higher in group 1 (95%) than in group 2 (70%) (P = 0.005), whereas the duration of treatment was significantly shorter in group 2 (197 ± 89 days) than in group 1 (278 ± 115 days) (P = 0.018). All stents were successfully removed at a median of 14 weeks after placement, except for 1 patient in whom early stent removal was inevitable and a second patient in whom the stent migrated completely. Stent migration rate was 24% (7 of 29 stents). In conclusion, treatment of biliary anastomotic strictures following LDLT is feasible using covered retrievable stents and has an acceptable clinical success rate with shorter treatment duration.

The mechanisms of 12(S)-hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid (12(S)-HPETE)-induced scratching were studied in ICR mice. In a recent paper, we demonstrated that the 12(S)-HPETE-induced scratching was reduced not by U75302 (BLT(1) receptor antagonist), but by LY255283 (BLT(2) receptor antagonist). In the present study, we tested various compounds to elucidate the mechanism of 12(S)-HPETE-induced scratching relating to transient receptor potential vanilloid type-1 (TRPV1), histamine receptor (H(1)) and several serotonin receptors (5-HT(1), 5-HT(2), and 5-HT(3)). As a result, 12(S)-HPETE-induced scratching was suppressed by capsaicin (TRPV1 receptor agonist), but not by capsazepine (TRPV1 receptor antagonist). Additionally, chlopheniramine (H(1) receptor antagonist) did not suppress 12(S)-HPETE-induced scratching, but cyproheptadine (H(1) receptor and serotonin 5-HT(2) receptor antagonist) potently suppressed the same response. Therefore, we tested several serotonin receptor antagonists to explain the detailed mechanisms relating to serotonin receptors. The scratching was reduced by WAY100635 (5-HT(1) receptor antagonist), or ketanserin (5-HT(2) receptor antagonist), but not by ondansetron (5-HT(3) receptor antagonist), after intradermal injection of 12(S)-HPETE. These results suggest that serotonin 5-HT(1/2) receptors are implicated in 12(S)-HPETE-induced scratching in ICR mice and that the TRPV1 receptor might not be directly related to 12(S)-HPETE-induced scratching.

The itch-associated responses evoked by intradermal injection of 12( S )-HPETE and leukotriene B 4 were compared in ICR-mice. 12( S )-HPETE and leukotriene B 4 (0.01–0.2 nmol/site) induced scratching of the injected site, respectively; the dose-responses were a peak at 0.05 nmol/site (12( S )-HPETE) or 0.03 nmol/site (leukotriene B 4 ). The scratching response by 12( S )-HPETE (0.05 nmol/site) started within 1 min, peaked in the first 10 min period, had almost subsided by 25 min whereas the effect of leukotriene B 4 peaked in the second 10 min. The effect of leukotriene B 4 is slightly stronger than that of 12( S )-HPETE in 40 min of count. The scratching induced by 12( S )-HPETE was inhibited by capsaicin, naltrexon, and LY255283. These results suggest the possibility that 12-lipoxygenase product can be added to a new member of an endogenous itch mediator in the skin.

4-1BB(CD137) is a member of the tumour necrosis factor receptor superfamily and is expressed on activated T cells, monocytes and natural killer (NK) cells. The interaction of 4-1BB and 4-1BB ligand provides a costimulatory signal leading to T-cell activation. The expression of 4-1BB has been known to be activation dependent. Interestingly, we found that expression of 4-1BB increased in human peripheral blood mononuclear cells after exposure to mitomycin C. Thus, we tested whether the treatment with other DNA-damaging agents, such as doxorubicin, bleomycin, and gamma-irradiation, could induce 4-1BB expression. The data indicated that 4-1BB expression increased dose-dependently by these agents reaching maximum at 2-3 days after the exposure. We found that the major 4-1BB-expressing population was CD3+ T cells, although a moderate number of CD14+ cells and a few NKB1+ cells also expressed 4-1BB. The levels of 4-1BB expression induced by anticancer drugs, were relatively lower than that induced by CD3 ligation. Interestingly, at subcytotoxic concentrations, doxorubicin and bleomycin considerably enhanced 4-1BB expression induced by CD3 ligation in CEM cells. The ligation of the damage-induced 4-1BB by monoclonal antibody enhanced the viability and proliferating capacity of the cells. In conclusion, the expression of 4-1BB might be one of the cellular responses of the immune cells against various genotoxic stresses.

Ann Dermatol Vol. 26, No. 3, 2014 http://dx.doi.org/10.5021/ad.2014.26.3.308 In this paper, the ACKNOWLEDGMENT was given incorrectly. The authors have supplied the following corrected version of ACKNOWLEDGMENT. This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant No. HN10C0009) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012R1A1A1015784). This study was conducted under a research agreement with AmorePacific Corporation, Republic of Korea. We apologize for any inconvenience that this may have caused.

Fulminant hepatic failure (FHF) is a clinical syndrome resulting from massive death of liver cells or sudden and severe impairment of liver function. The causes of FHF are diverse and the overall mortality is very high. Recently, it became clear that apoptosis of hepatocytes is the critical cause of acute hepatic failure in FHF. It is well known that a family of cysteine proteases called caspase is one of the key mediators of the apoptotic pathway. Thus, caspases are attractive potential targets for the treatment of disorders resulting from excessive apoptosis. In this report, we examined the activity of a new caspase inhibitor, Xyz 033 mp. This nonpeptide inhibitor showed broad-spectrum caspase-inhibiting activity and protected primary rat hepatocytes from apoptotic death. In a mouse model of FHF induced by concavalin A (Con A), Xyz 033 mp suppressed elevated AST and ALT and specifically reduced IL-1 beta concentration. Also, Xyz 033 mp rescued mice from lethal experimental hepatitis induced by Con A. In addition, histological examinations indicated that Xyz 033 mp protected hepatocytes from the fatal apoptogenic effect of Con A. These results suggest that Xyz 033 mp may be a candidate therapeutic agent for FHF caused by massive apoptotic death of hepatocytes.

Purpose: The purpose of this study was to test the effects of tailored diabetic education on blood glucose control and self-care for patients with type 2 diabetes on insulin therapy. Methods: The participants were 60 patients (experimental group: 30, control group: 30) with type 2 diabetes on insulin therapy. The patients were being seen at a university hospital in Seoul, Korea. Group diabetic education and tailored diabetic education were given to the experiment group while group diabetic education only was given to the control group. Data were collected before and three months after the education. 2 test, t-test, and ANCOVA were used to analyze the data. Results: No significant differences in postprandial (PP2hrs) glucose and HbA1c levels were found between the two groups. Participants in the experiment group showed statistically significant differences in the area of self-glucose test, management of insulin injection, and life style change compared to those in the control group. Conclusion: The results indicate that tailored education for patients with diabetes on insulin therapy improve self-glucose test, management of insulin injection, and life style. Therefore it is suggested that tailored education can be applied in diabetic education to improve self-care.