Renal cell carcinoma (RCC) is the major cause of death among patients with von Hippel-Lindau (VHL) disease. Resistance to therapies targeting tumor angiogenesis opens the question about the underlying mechanisms. Previously we have described that RWDD3 or RSUME (RWD domain-containing protein SUMO Enhancer) sumoylates and binds VHL protein and negatively regulates HIF degradation, leading to xenograft RCC tumor growth in mice. In this study, we performed a bioinformatics analysis in a ccRCC dataset showing an association of RSUME levels with VHL mutations and tumor progression, and we demonstrate the molecular mechanism by which RSUME regulates the pathologic angiogenic phenotype of VHL missense mutations. We report that VHL mutants fail to downregulate RSUME protein levels accounting for the increased RSUME expression found in RCC tumors. Furthermore, we prove that targeting RSUME in RCC cell line clones carrying missense VHL mutants results in decreased early tumor angiogenesis. The mechanism we describe is that RSUME sumoylates VHL mutants and beyond its sumoylation capacity, interacts with Type 2 VHL mutants, reduces HIF-2α-VHL mutants binding, and negatively regulates the assembly of the Type 2 VHL, Elongins and Cullins (ECV) complex. Altogether these results show RSUME involvement in VHL mutants deregulation that leads to the angiogenic phenotype of RCC tumors.

Bevacizumab is a humanized recombinant monoclonal antibody that blocks vascular endothelial growth factor (VEGF). Recently, its use has been related with osteneocrosis of the jaws (ONJ), a disease showing a histological pattern similar to bisphosphonate-related ONJ. The aim of this study is to describe an ONJ case-report following bevacizumab chemotherapy without bisphosphonate therapy. We monitored ONJ development associated with the use of bevacizumab in a 47-year-old male with primitive adenocarcinoma of the parotid gland. Our results could suggest a possible correlation between the eruption of the lower third molar tooth and ONJ development following bevacizumab therapy. Clinicians should be aware of the potential risk of bevacizumab-related ONJ complication; moreover, since there are no effective therapeutic protocols for ONJ treatment, it is very important that patients develop good oral hygiene habits and undergo regular dental status evaluation by dentists.

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In this animal model, surfactant administration through a preinserted feeding tube within the LMA lumen is safe and effective while providing the benefits of a minimally invasive approach. This technique reduces the need of PPV and may prevent its potential risks.