Increased TIM-3 and galectin-9 serum levels in patients with advanced systemic mastocytosis.

BACKGROUND: Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. OBJECTIVE: We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. METHODS: Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from patients with systemic mastocytosis were stained to confirm expression. RESULTS: Serum levels of TIM-3 and galectin-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared with healthy controls. TIM-3 and galectin-9 levels were also found to correlate with other biomarkers of systemic mastocytosis, such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and galectin-9 in mastocytosis infiltrates in bone marrow. CONCLUSIONS: Together, our results demonstrate for the first time that serum levels of TIM-3 and galectin-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and galectin-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and galectin-9 as diagnostic markers and eventually therapeutic targets in systemic mastocytosis, particularly in advanced forms.

The discovery of the church of Rungholt, a landmark for the drowned medieval landscapes of the Wadden Sea World Heritage.

The UNESCO World Heritage Wadden Sea holds remains of a medieval cultural landscape shaped by interactions between man and natural forces. From the Netherlands to Denmark, human efforts of cultivating low-lying areas created a unique coastal landscape. Since the Middle Ages, storm floods widely drowned embanked cultural land and especially affected North Frisia (Germany), where once fertile marshland was permanently turned into tidal flats. One key region, the Edomsharde, was widely destroyed in 1362 AD. Medieval settlement remains still occur in the tidal flats around the island Hallig Südfall and are commonly associated with Edomsharde's trading centre Rungholt-ever since a symbol for the region's drowned landscapes and focus of this study. We present a first-time comprehensive reconstruction of this medieval settlement by means of new geophysical, geoarchaeological and archaeological data. Our results reveal remains of up to 64 newly found and rectified dwelling mounds, abundant drainage ditches, a seadike, and especially the discovery of Edomshardes's main church as important landmark in this former cultural landscape. These finds together with the documented imported goods confirm a thriving society, involved in transregional trade and thereby close a significant gap in medieval history not only for North Frisia, but the entire Wadden Sea region.