αvβ3 Antagonists(Technische Universität München)

Valvular interstitial cells (VICs) are integral to the progression of calcific aortic valve disease (CAVD). Dentin matrix protein-1 (DMP-1), a member of the Sibling family protein, is implicated in the calcification process. This study aims to investigate the role and mechanisms of DMP-1 in the osteogenic differentiation of VICs. Between April 2018 and December 2018, aortic valve tissues were collected from 14 patients undergoing aortic valve replacement or heart transplantation. DMP-1 expression was quantified in calcified valves versus normal controls. An in vitro model of VICs’ osteogenic differentiation was established to study the regulatory mechanism of DMP-1 on valvular calcification using immunoblot, immunohistochemistry, immunofluorescence, etc. The expression of DMP-1 was significantly increased in the calcified aortic valves patients ( P  < 0.01). DMP-1, both short and long arginine-glycine-aspartic acid (RGD) peptides, induced the osteogenic differentiation in VICs, an effect that was inhibited by an integrin αvβ3 antagonist ( P  < 0.05). Furthermore, the expression levels of RAF, RAS, MEK, and phosphorylated ERK1/2 were significantly elevated in VICs upon stimulation of DMP-1 ( P  < 0.05). DMP-1 is involved in the progression of valvular calcification and promotes the osteogenic differentiation of VICs via the integrin αvβ3 receptor. The combination of DMP-1 and integrin αvβ3 via its RGD domain activates the MAPK signaling pathway, leading to enhanced osteogenic gene expression in VICs. Clinical trial number: not applicable.

Integrin antagonist complex (IAC), a novel α v β 3 integrin antagonist peptidomimetic, has emerged as a promising agent for molecular imaging of tumor angiogenesis. This study evaluates the biodistribution and clinical efficacy of [ 68 Ga]Ga-DOTAGA-IAC PET/CT in detecting radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), comparing its diagnostic performance with [ 18 F]F-FDG PET/CT.

In this prospective pilot study, RAIR-DTC patients underwent whole-body imaging with [ 18 F] F-FDG PET/CT, followed by [ 68 Ga]Ga-DOTAGA-IAC PET/CT. Biodistribution patterns of [ 68 Ga]Ga-DOTAGA-IAC were assessed. Lesions with abnormal, nonphysiologic tracer uptake (showing activity exceeding mediastinal blood pool) were considered positive for disease. Imaging findings were compared between the two modalities, and quantitative metrics, including SUV max , metabolic tumor volume, and total lesion glycolysis, were analyzed statistically.

Among 30 patients with RAIR-DTC, [ 68 Ga]Ga-DOTAGA-IAC PET/CT revealed predominant physiological tracer uptake in the kidneys. [ 18 F]F-FDG PET/CT identified 97 lesions, predominantly nodal (73.2%), while [ 68 Ga]Ga-DOTAGA-IAC PET/CT detected 34 lesions, 50% of which were nodal. Few patients exhibited multiple lesions with varying uptake grades, with 20% showing coexisting higher-grade lesions (grade II or above) on [ 68 Ga]Ga-DOTAGA-IAC PET/CT.

Angiogenesis imaging using [ 68 Ga]Ga-DOTAGA-IAC PET/CT demonstrates limited sensitivity for lesion detection in patients with RAIR-DTC compared with [ 18 F]F-FDG PET/CT. However, the potential of [ 68 Ga]Ga-DOTAGA-IAC as a diagnostic tool for other cancers has been used in other cancers with positive imaging characteristics warranting further exploration.