Rappaport Faculty of Medicine

About: Rappaport Faculty of Medicine is a based out in . It is known for research contribution in the topics: Population & Heparanase. The organization has 3205 authors who have published 3915 publications receiving 114533 citations.

Identification of Novel Class of Triazolo-Thiadiazoles as Potent Inhibitors of Human Heparanase and their Anticancer Activity

Abstract: Expression and activity of heparanase, an endoglycosidase that cleaves heparan sulfate (HS) side chains of proteoglycans, is associated with progression and poor prognosis of many cancers which makes it an attractive drug target in cancer therapeutics. In the present work, we report the in vitro screening of a library of 150 small molecules with the scaffold bearing quinolones, oxazines, benzoxazines, isoxazoli(di)nes, pyrimidinones, quinolines, benzoxazines, and 4-thiazolidinones, thiadiazolo[3,2-a]pyrimidin-5-one, 1,2,4-triazolo-1,3,4-thiadiazoles, and azaspiranes against the enzymatic activity of human heparanase. The identified lead compounds were evaluated for their heparanase-inhibiting activity using sulfate [35S] labeled extracellular matrix (ECM) deposited by cultured endothelial cells. Further, anti-invasive efficacy of lead compound was evaluated against hepatocellular carcinoma (HepG2) and Lewis lung carcinoma (LLC) cells. Among the 150 compounds screened, we identified 1,2,4-triazolo-1,3,4-thiadiazoles bearing compounds to possess human heparanase inhibitory activity. Further analysis revealed 2,4-Diiodo-6-(3-phenyl-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazol-6yl)phenol (DTP) as the most potent inhibitor of heparanase enzymatic activity among the tested compounds. The inhibitory efficacy was demonstrated by a colorimetric assay and further validated by measuring the release of radioactive heparan sulfate degradation fragments from [35S] labeled extracellular matrix. Additionally, lead compound significantly suppressed migration and invasion of LLC and HepG2 cells with IC50 value of ~5 μM. Furthermore, molecular docking analysis revealed a favourable interaction of triazolo-thiadiazole backbone with Asn-224 and Asp-62 of the enzyme. Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer.

Resolution of orofacial granulomatosis with amalgam removal

Abstract: A 61-year-old woman presented with a 2-year history of an abnormal erythematous swelling on the upper lip and cheek. Upon examination there were no other physical findings. Histological examination found discreet sarcoidal granulomas in the lower dermis. Routine laboratory studies, chest radiographs and pulmonary functions were all normal. Clinical presentation and histological findings were, therefore, compatible with the diagnosis of orofacial granulomatosis (OFG). The patient was patch tested with an extended standard series that included metal-salt, dental prosthesis, bakery and corticosteroids series. The patch test was positive (score ++) after 48 and 72 h for mercury in the metal-salt and dental prosthesis series. During the past decade the patient had received amalgam fillings of several dental cavities, including one adjacent to the swollen cheek. The unilateral localization of the soft tissue swelling adjacent to the amalgam tooth fillings, along with the positive patch test for mercury, raised the possibility that the OFG was part of a delayed hypersensitive reaction to the fillings. The patient therefore underwent a total amalgam replacement procedure; complete disappearance of the swelling overlying the right cheek was observed within 7 weeks and the swelling of the upper lip subsided completely within 6 months. We propose that mercury in amalgam tooth fillings is another cause of OFG and suggest appropriate patch testing in patients who do not have an apparent cause of OFG.