Suboptimal therapy controls clinically apparent disease but not subclinical progression of Vogt-Koyanagi-Harada disease

Purpose To evaluate clinical and angiographic differences in patients with Vogt-Koyanagi-Harada (VKH) disease during the early 4-month treatment phase with high- or medium-dose systemic corticosteroid therapy. Methods VKH patients treated at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland (n=4), or the Department of Ophthalmology, Tokyo Medical and Dental University, Tokyo, Japan (n=5), underwent a pre-treatment indocyanine green angiography (ICGA) and a follow-up ICGA four months after treatment began. Lausanne patients received high-dose, systemic corticosteroid therapy, with or without immunosuppressive therapy. Tokyo patients received medium-dose systemic corticosteroid therapy that included 3days of intravenous pulse methylprednisolone. ICGA signs including choroidal stromal vessel hyperfluorescence and leakage, hypofluorescent dark dots (HDD), fuzzy vascular pattern of large stromal vessels and disc hyperfluorescence were retrospectively compared. Results The pre-treatment ICGA demonstrated that each of the nine patients had choroidal inflammatory foci, as indicated by HDD. At 4-month follow-up, clinical and fluorescein findings had improved almost equally in both groups. HDD had resolved in the Lausanne group but persisted in the Tokyo group. Sunset glow fundus occurred in three of the Tokyo patients and none of the Lausanne patients. Conclusions Submaximal doses of inflammation suppressive therapy are sufficient to suppress clinically apparent disease but not the underlying lesion process. This explains the propensity for sunset glow fundus in seemingly controlled diseas

A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis.

Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent ("FGF1 decoy")

IL-17F Induces CCL20 in Bronchial Epithelial Cells

IL-17F plays a crucial role in airway inflammatory diseases including asthma, but its function has not been fully elucidated. CCL20 is also involved in allergic airway inflammation, while its regulatory mechanisms remain to be defined. To further identify a novel role of IL-17F, the expression of CCL20 by IL-17F in bronchial epithelial cells and the signaling mechanisms involved were investigated. Bronchial epithelial cells were stimulated with IL-17F, and the levels of CCL20 gene and protein measured, with the effects of the addition of various kinase inhibitors and siRNAs also investigated. IL-17F significantly induced the expression of CCL20 gene and protein. Pretreatment with inhibitors for MEK1/2, Raf1 and MSK1, and overexpression of a Raf1 dominant-negative mutant significantly diminished IL-17F-induced CCL20 production. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked CCL20 expression. These findings suggest that IL-17F is able to induce CCL20 via Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB signaling pathway in bronchial epithelial cells. The IL-17F/CCL20 axis may be a novel pharmacological target for asthma

Murine breast cancers disorganize the liver transcriptome in a zonated manner

がんが宿主の臓器に及ぼす悪影響を捉えた --がんをもつ個体における「肝機能の空間的制御」の破綻--. 京都大学プレスリリース. 2023-02-01.The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver

Extreme Nature of Four Blue-excess Dust-obscured Galaxies Revealed by Optical Spectroscopy

We report optical spectroscopic observations of four blue-excess dust-obscured galaxies (BluDOGs) identified by the Subaru Hyper Suprime-Cam. BluDOGs are a subclass of dust-obscured galaxies (DOGs; defined with the extremely red color (i − [22])AB ≥ 7.0; Toba et al., showing a significant flux excess in the optical g and r bands over the power-law fits to the fluxes at the longer wavelengths. Noboriguchi et al. have suggested that BluDOGs may correspond to the blowing-out phase involved in a gas-rich major-merger scenario. However, the detailed properties of BluDOGs are not understood because of the lack of spectroscopic information. In this work, we carry out deep optical spectroscopic observations of four BluDOGs using Subaru/FOCAS and VLT/FORS2. The obtained spectra show broad emission lines with extremely large equivalent widths, and a blue wing in the C iv line profile. The redshifts are between 2.2 and 3.3. The averaged rest-frame equivalent widths of the C iv lines are 160 \ub1 33 \uc5, ∼7 times higher than the average of a typical type 1 quasar. The FWHMs of their velocity profiles are between 1990 and 4470 km s−1, and their asymmetric parameters are 0.05 and 0.25. Such strong C iv lines significantly affect the broadband magnitudes, which are partly the origin of the blue excess seen in the spectral energy distribution of BluDOGs. Their estimated supermassive black hole masses are 1.1 7 108 < M BH/M ⊙ <5.5 7 108. The inferred Eddington ratios of the BluDOGs are higher than 1 (1.1 < λ Edd < 3.8), suggesting that the BluDOGs are in a rapidly evolving phase of supermassive black holes