Fibrosis is characterized by extracellular matrix (ECM) remodeling and stiffening. However, the functional contribution of tissue stiffening to noncancer pathogenesis remains largely unknown. Fibronectin (Fn) is an ECM glycoprotein substantially expressed during tissue repair. Here we show in advanced chronic liver fibrogenesis using a mouse model lacking Fn that, unexpectedly, Fn-null livers lead to more extensive liver cirrhosis, which is accompanied by increased liver matrix stiffness and deteriorated hepatic functions. Furthermore, Fnnull livers exhibit more myofibroblast phenotypes and accumulate highly disorganized/diffuse collagenous ECM networks composed of thinner and significantly increased number of collagen fibrils during advanced chronic liver damage. Mechanistically, mutant livers show elevated local TGF-␤ activity and lysyl oxidase expressions. A significant amount of active lysyl oxidase is released in Fn-null hepatic stellate cells in response to TGF-␤1 through canonical and noncanonical Smad such as PI3 kinase-mediated pathways. TGF-␤1-induced collagen fibril stiffness in Fn-null hepatic stellate cells is significantly higher compared with wild-type cells. Inhibition of lysyl oxidase significantly reduces collagen fibril stiffness, and treatment of Fn recovers collagen fibril stiffness to wild-type levels. Thus, our findings indicate an indispensable role for Fn in chronic liver fibrosis/cirrhosis in negatively regulating TGF-␤ bioavailability, which in turn modulates ECM remodeling and stiffening and consequently preserves adult organ functions. Furthermore, this regulatory mechanism by Fn could be translated for a potential therapeutic target in a broader variety of chronic fibrotic diseases.

Serum glutamic-oxaloacetic transaminase (GOT) levels were determined in 214 infants (133 males and 81 females) with atopic dermatitis during their first visit to the Department of Allergy, National Children’s Hospital, Tokyo, Japan. Compared with the normal hospital range, their levels were found to be significantly higher, a tendancy which was more conspicuous in lower age groups. We carried out a ¹³C-methacetin breath test (MBT), administering the stable-isotope-labeled compound to 11 children with higher serum GOT values and 5 within the normal range to investigate hepatic metablism of methacetin in infants with atopic dermatitis. ¹³C-methacetin was given orally, and the ¹³CO₂ level in the breath was determined immediately before and after administration, by mass spectrometry. Compared to the normal controls, the atopic infants demonstrated significantly lower ¹³CO₂ peak excretion and delayed peak time. The clearance rate of ¹³CO₂ was also decreased. These results suggest some relationship between atopic dermatitis and liver function in infants.

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Docetaxel-based chemotherapy prolongs life and relieves symptoms in patients with castration resistant prostate cancer. However, this needs to be improved because of limitations by lack of specificity, systemic toxicity, and progression of docetaxel-resistance. Nanotechnology has served a new role in medical sciences by a variety of nanotechnology platforms, leading to theranostics. Among these platforms, Fe3O4 magnetic nanoparticles (MgNPs) have potential applications in drug delivery, cancer diagnosis and hyperthermia. We have already shown that MgNPs would modify the effect of chemotherapy in prostate cancer cells based on the observations that MgNPs increased reactive oxygen species (ROS) production and induced oxidative DNA damage in prostate cancer cell lines. Combined treatment of docetaxel and MgNPs has also shown to suppress nuclear transcription factor kappa B expression in DU145 cells. In this study, we analyzed the combined effects of docetaxel-MgNPs with different surface modifications on a prostate cancer cell line, DU145 and their mechanisms. The combination treatment of docetaxel and carboxylic acid-modified MgNPs (MgNPs-COOH) more effectively inhibited cancer cell growth and induced apoptosis compared with docetaxel-MgNPs combination. While MgNPs produced ROS in a dose-dependent manner and inhibited cancer cell growth slightly, MgNPs-COOH did exert no ROS production, however cell membrane damage in a dose-dependent manner. In addition, MgNPs-COOH showed the involvement of the endoplasmic reticulum (ER) stress. These results suggest that MgNPs-COOH may induce different responses compared with MgNPs, and result in favorable development of current chemotherapy for the advanced disease and leading to new theranostics. Citation Format: Nao Furuta, Sou Yamaguchi, Ayumi Iwasaki, Daiki Okamoto, Akiko Sato, Yoshihiro Endo, Daisuke Kurioka, Tadashi Nittami, Hitoshi Ishiguro, Hiroji Uemura, Yoshinobu Kunota, Masatoshi Watanabe. Combined effects of docetaxel-magnetic nanoparticles with different surface modifications on prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5501. doi:10.1158/1538-7445.AM2014-5501