Crucial Roles of SATB1 in Regulation of Thymocyte Migration after Positive Selection.

Double-positive thymocytes that have passed positive selection migrate from the cortex to the medulla, where negative selection and the development of thymic regulatory T cells (tTregs) take place. Medullary thymic epithelial cells (mTECs) play important roles in these selections, and their differentiation and maintenance depend on interaction with positively selected CD4+ single-positive cells. Therefore, migration and differentiation after positive selection must be coordinated to establish immune tolerance. However, the regulatory mechanisms of these processes are not fully understood. SATB1 is a genome organizer highly expressed in double-positive thymocytes, and SATB1 deletion causes various defects in T-cell development, including impaired positive and negative selection and tTreg differentiation. Here, we show that SATB1 is critical for temporally coordinated thymocyte trafficking after positive selection in mice. Satb1 knockout (ΔSatb1) led to precocious thymic egress caused by augmented S1pr1 upregulation in positively selected thymocytes, accompanied by lower induction of Ccr7, Tnfsf11, and Cd40lg. Altered thymocyte trafficking and functionality affected the differentiation of mTECs and, in turn, tTreg differentiation. Thus, SATB1 is required to establish immune tolerance, at least in part, by ensuring timely thymic egress and mTEC differentiation.

Light irradiation for treatment of acute carbon monoxide poisoning: an experimental study.

BACKGROUND: Because treatment modalities for carbon monoxide (CO) poisoning, especially normobaric oxygen and hyperbaric oxygen therapies, have limited effects and hyperbaric oxygen is not available at the scene where treatment is most needed, we conducted a study to determine and compare rates of carboxyhemoglobin (COHb) dissociation achieved in human in vitro blood samples under light radiation emitted at three levels of illuminance. This was done with a view toward eventual on-site application. METHODS: We drew blood from 10 volunteers, prepared 10 red blood cell solutions, and subjected each solution to a CO bubbling procedure to increase the COHb saturation. Samples of each bubbled solution were then divided between 3 beakers (beakers A, B, and C) for a total of 30 beakers. The solution in each beaker was exposed to a continuous flow of oxygen at 50 mL/min, and simultaneously for a period of 15 min, the beaker A and B solutions were irradiated with light emitted at 500,000 and 100,000 lux, respectively, from a halogen light source. The beaker C solutions were exposed to room light. At 3, 6, 9, 12, and 15 min, a 50-µL sample was pipetted from each of the 30 beakers for determination of its light absorbance and the COHb dissociation rate. RESULTS: Under each of the experimental conditions, dissociation progressed but at different rates, and starting at 3 min, the differences in rates between conditions were significant (P < 0.01). The dissociation rate was greatest with light emitted at 500,000 lux. CONCLUSIONS: Our results point toward the possibility of readily performed, acute photodissociation therapy for patients with CO poisoning.

Angiomodulin, a marker of cancer vasculature, is upregulated by vascular endothelial growth factor and increases vascular permeability as a ligand of integrin αvß3.

Angiomodulin (AGM) is a member of insulin-like growth factor binding protein (IGFBP) superfamily and often called IGFBP-rP1 or IGFBP-7. AGM was originally identified as a tumor-derived cell adhesion factor, which was highly accumulated in blood vessels of human cancer tissues. AGM is also overexpressed in cancer-associated fibroblasts (CAFs) and activates fibroblasts. However, some studies have shown tumor-suppressing activity of AGM. To understand the roles of AGM in cancer progression, we here investigated the expression of AGM in benign and invasive breast cancers and its functions in cancer vasculature. Immunohistochemical analysis showed that AGM was highly expressed in cancer vasculature even in ductal carcinoma in situ (DCIS) as compared to normal vasculature, while its expression in CAFs was more prominent in invasive carcinomas than DCIS. In vitro analyses showed that AGM was strongly induced by vascular endothelial cell growth factor (VEGF) in vascular endothelial cells. Although AGM stimulated neither the growth nor migration of endothelial cells, it supported efficient adhesion of endothelial cells. Integrin αvß3 was identified as a novel major receptor for AGM in vascular endothelial cells. AGM retracted endothelial cells by inducing actin stress fibers and loosened their VE-cadherin-mediated intercellular junction. Consequently, AGM increased vascular permeability both in vitro and in vivo. Furthermore, AGM and integrin αvß3 were highly expressed and colocalized in cancer vasculature. These results suggest that AGM cooperates with VEGF to induce the aberrant functions of cancer vasculature as a ligand of integrin αvß3.