https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:46366 in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.]]> Wed 16 Nov 2022 08:57:15 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:39597 Wed 15 Jun 2022 12:54:03 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:18276 Wed 11 Apr 2018 12:33:19 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:12145 Wed 11 Apr 2018 09:48:47 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:34617 Wed 09 Feb 2022 15:55:15 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:45607 Wed 02 Nov 2022 14:14:14 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:50247 Tue 11 Jul 2023 14:16:11 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:644 T/R66X, was detected in one family and four sporadic patients. The majority of mutations (26/33) were located in exons 2 and 3 of the EFNB1 gene encoding the extracellular ephrin domain. The mutation spectrum includes frameshift, nonsense, missense, and splice site mutations, with a predominance of frameshift and nonsense mutations resulting in premature truncation codons. For the first time we describe mutations in exons 4 and 5 of EFNB1. Of particular interest are the frameshift mutations located in the last 25 codons of EFNI3 I encoding the carboxyterminal end of ephrin-B1. They result in an extension by 44 residues. These mutations disrupt the intracellular binding sites for Grb4 and PDZ-effector proteins involved in reverse signaling. We conclude that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor-ligand interaction, oligomerization, and ephrin-B1 reverse signaling.]]> Thu 25 Jul 2013 09:10:36 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:20908 Thu 01 Aug 2019 17:22:27 AEST ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:1474 4)-β-D-galactan side chains of rhamnogalacturonan I were internalized into BFA compartments. In contrast, Golgi-derived secretory (esterified up to 80%) homogalacturonan pectins localized to the cytoplasm in control cells and did not accumulate within characteristic BFA compartments. Latrunculin B-mediated depolymerization of F-actin inhibited internalization and accumulation of cell wall pectins within intracellular BFA compartments. Importantly, cold treatment and protoplasting prevented internalization of wall pectins into root cells upon BFA treatment. These observations suggest that cell wall pectins of meristematic maize root cells undergo rapid endocytosis in an F-actin-dependent manner.]]> Sat 24 Mar 2018 08:28:12 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:2267 Sat 24 Mar 2018 08:26:55 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:21428 50 ≈ 18 μM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC₅₀ values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC₅₀ values of 10, 6.9, 12, and 10 μM, respectively. Docking studies rationalized the structure–activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50 ≈ 6.9 μM, is the most potent clathrin terminal domain–amphiphysin inhibitor reported to date.]]> Sat 24 Mar 2018 08:05:47 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:17423 TM, was sufficient to abolish BoNT/A-Hc internalization and BoNT/A-induced SNAP25 cleavage in hippocampal neurons. Dyngo-4a also interfered with BoNT/A-Hc internalization into motor nerve terminals. Furthermore, Dyngo-4a afforded protection against BoNT/A-induced paralysis at the rat hemidiaphragm. A significant delay of >30% in the onset of botulism was observed in mice injected with Dyngo-4a. Dynamin inhibition therefore provides a therapeutic avenue for the treatment of botulism and other diseases caused by pathogens sharing dynamin-dependent uptake mechanisms.]]> Sat 24 Mar 2018 08:01:38 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:20084 Sat 24 Mar 2018 08:00:05 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:39 Sat 24 Mar 2018 07:42:13 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:28474 in silico docking studies. Docking studies predicted enhanced Pitstop® 2 family binding, not a loss of binding, within the Pistop® groove of the reported clathrin mutant invalidating recent assumptions of poor selectivity for this family of clathrin inhibitors.]]> Sat 24 Mar 2018 07:39:34 AEDT ]]> https://novaprd-lb.newcastle.edu.au/vital/access/ /manager/Repository/uon:50565 Fri 28 Jul 2023 11:27:49 AEST ]]>