Novel elucidation and treatment of pancreatic chronic graft-versus-host disease in mice

Chronic graft-versus-host disease (cGVHD) is a severe complication of allogeneic haematopoietic stem cell transplantation. There is a growing understanding of cGVHD, and several effective therapies for cGVHD have been reported. However, pancreatic cGVHD is a potentially untapped study field. Our thought-provoking study using a mouse model of cGVHD suggested that the pancreas could be impaired by cGVHD-induced inflammation and fibrosis and that endoplasmic reticulum (ER) stress was augmented in the pancreas affected by cGVHD. These findings urged us to treat pancreatic cGVHD through reduction of ER stress, and we used 4-phenylbutyric acid (PBA) as an ER stress reducer. A series of experiments have indicated that PBA can suppress cGVHD-elicited ER stress in the pancreas and accordingly alleviate pancreatic cGVHD. Furthermore, we focused on a correlation between epithelial to mesenchymal transition (EMT) and fibrosis in the cGVHD-affected pancreas, because EMT was conceivably implicated in various fibrosis-associated diseases. Our investigation has suggested that the expression of EMT markers was increased in the cGVHD-disordered pancreas and that it could be reduced by PBA. Taken together, we have provided a clue to elucidate the pathogenic process of pancreatic cGVHD and created a potentially effective treatment of this disease using the ER stress alleviator PBA

Steady‐State and Time‐Resolved Optical Properties of Multilayer Film of Titanium Dioxide Sandwiched by Gold Nanoparticles and Gold Thin Film

We proposed metal-insulator (MI) and metal-insulator-metal (MIM) structures of titanium dioxide (TiO2) sandwiched by gold nanoparticles (AuNPs) layer and gold sputtered thin film (only for the MIM film) to couple localized plasmon mode of AuNP with multi-reflection mode and/or cavity resonator mode of TiO2. The optical extinctions of MI and MIM with differing TiO2 thickness were studied theoretically by finite-element method simulation and experimentally by optical spectrometry. The extinction peaks of MI and MIM shifted by exchanging the surrounding medium from air to TiO2. The interference of TiO2 in MI structure also affected the extinction spectra showing the oscillation along the spectrum of AuNP in TiO2. Then, the extinction degree of MIM was higher than that of MI because of the coupling between cavity resonance mode with localized plasmon mode and interband transition in AuNPs. In addition, the cross section of MI and MIM films were observed by scanning electron microscopy. The surface of thinner film was rough because TiO2 heterogeneously grew from AuNP. The irregular growth of TiO2 might have induced the wide-range extinction in 300-2500 nm after Au thin film deposition. The transient absorption spectra using a femtosecond laser were also carried out under the condition of 800 nm for excitation laser and 950 nm for probe laser. The long-lived electron (~1 ns) was observed in thick MIM film as a result of hot electron transfer from the gold nanostructure in the film

A Case of Pancreatic Carcinoma with Bilateral Hilar 18F-FDG and 67Ga Hyperaccumulation

Article信州医学雑誌 66(2): 151-155(2018)journal articl

“Input/output cytokines” in epidermal keratinocytes and the involvement in inflammatory skin diseases

Considering the role of epidermal keratinocytes, they occupy more than 90% of the epidermis, form a physical barrier, and also function as innate immune barrier. For example, epidermal keratinocytes are capable of recognizing various cytokines and pathogen-associated molecular pattern, and producing a wide variety of inflammatory cytokines, chemokines, and antimicrobial peptides. Previous basic studies have shown that the immune response of epidermal keratinocytes has a significant impact on inflammatory skin diseases. The purpose of this review is to provide foundation of knowledge on the cytokines which are recognized or produced by epidermal keratinocytes. Since a number of biologics for skin diseases have appeared, it is necessary to fully understand the relationship between epidermal keratinocytes and the cytokines. In this review, the cytokines recognized by epidermal keratinocytes are specifically introduced as "input cytokines", and the produced cytokines as "output cytokines". Furthermore, we also refer to the existence of biologics against those input and output cytokines, and the target skin diseases. These use results demonstrate how important targeted cytokines are in real skin diseases, and enhance our understanding of the cytokines

Elevated expression of interleukin-6 (IL-6) and serum amyloid A (SAA) in the skin and the serum of recessive dystrophic epidermolysis bullosa: Skin as a possible source of IL-6 through Toll-like receptor ligands and SAA

The effect of persistent skin inflammation on extracutaneous organs and blood is not well studied. Patients with recessive dystrophic epidermolysis bullosa (RDEB), a severe form of the inherited blistering skin disorder, have widespread and persistent skin ulcers, and they develop various complications including anaemia, hyperglobulinaemia, hypoalbuminaemia and secondary amyloidosis. These complications are associated with the bioactivities of IL-6, and the development of secondary amyloidosis requires the persistent elevation of serum amyloid A (SAA) level. We found that patients with RDEB had significantly higher serum levels of IL-6 and SAA compared to healthy volunteers and patients with psoriasis or atopic dermatitis. Both IL-6 and SAA were highly expressed in epidermal keratinocytes and dermal fibroblasts of the skin ulcer lesions. Keratinocytes and fibroblasts surrounding the ulcer lesions are continuously exposed to Toll-like receptor (TLR) ligands, pathogen-associated and damage-associated molecular pattern molecules. In vitro, TLR ligands induced IL-6 expression via NF-κB in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs). SAA further induced the expression of IL-6 via TLR1/2 and NF-κB in NHEKs and NHDFs. The limitation of this study is that NHEKs and NHDFs were not derived from RDEB patients. These observations suggest that TLR-mediated persistent skin inflammation might increase the risk of IL-6-related systemic complications, including RDEB

Photocatalytic Activity Enhancement of Anatase/Rutile-Mixed Phase TiO2 Nanoparticles Annealed with Low-Temperature O2 Plasma

Photodecomposition and photobactericidal activities of anatase/rutile-mixed phase TiO2 nanoparticles annealed with low-temperature O2 plasma were clarified by comparing them with those annealed in ambient air. The photocatalytic activities of plasma-assisted-annealed sample greatly enhanced as compared with the untreated sample, under not only ultraviolet irradiation but also visible-light irradiation. The photocatalytic activities of air-annealed samples did not enhance under ultraviolet irradiation but enhanced under visible-light irradiation. The enhanced photocatalytic activities due to the plasma-assisted annealing (PAA) originated from the increased photoexcited carrier concentration. This enhancement was discussed from PAA-induced characteristic factors. PAA facilitated the phase transformation to anatase, contributing directly to extending the photoexcited carrier lifetime. PAA introduced more oxygen vacancies, contributing to trapping more photogenerated electrons. PAA also introduced more bridging/terminal oxygen groups adsorbed on the surface, increasing the upward band-bending, the depletion layer width at the surface, and the charge transfer from rutile to anatase. These two introductions contributed to facilitating the separation of photoexcited carriers. Furthermore, PAA reduced the aggregate size of TiO2 nanoparticles formed on the surface, contributing to increasing optical absorptions. More reactive oxygen species produced from the bridging/terminal oxygen groups by the photoexcited carriers would also enhance the photocatalytic activities

The protective effect of CD40 ligand–CD40 signalling is limited during the early phase of Plasmodium infection

Abstractγδ T cells are essential for eliminating Plasmodium berghei XAT. Because administration of the agonistic anti-CD40 antibody can induce elimination of P. berghei XAT parasites in γδ T cell-deficient mice, we considered that γδ T cells might activate dendritic cells via CD40 signalling during infection. Here we report that administration of the anti-CD40 antibody to γδ T cell-deficient mice 3–10days post-P. berghei XAT infection could eliminate the parasites. Our data suggest that dendritic cell activation via γδ T cells expressing CD40 ligand is critical during the early phase of infection

A fatal case of acute exacerbation of interstitial lung disease in a patient with rheumatoid arthritis during treatment with tocilizumab.

A 68-year-old man, who was a patient with established rheumatoid arthritis (RA) with RA-associated interstitial lung disease (RA-ILD) and pulmonary emphysema, began taking tocilizumab. Subsequently, he developed dyspnea parallel to improvement of RA. At 10 months after the administration of tocilizumab, he was urgently admitted because of exacerbation of ILD. He died despite receiving steroid pulse therapy and antibiotic therapy on a respirator. This is the first case report to describe the exacerbation of ILD during treatment with tocilizumab in the postmarketing surveillance (PMS) period