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Chronic abdominal, groin, and perineal pain of visceral origin
Published in Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen, Clinical Pain Management, 2008
All clinical trials related to IC have been hampered by the inclusion of a likely heterogenous clinical population. This problem may become less problematic in the future with the advent of a diagnostic test that appears to have validity in the IC population. There is a presence of a specific peptide present within the urine of IC patients that impairs urothelial regrowth. Named the anti-proliferative factor (APF), this low molecular weight peptide is a member of the Frizzled 8 protein family and is present in bladder urine, but not renal pelvis urine of IC patients.81 It has been identified in over 90 percent of rigorously diagnosed IC patients, is not present in other disorders, and is therefore viewed as the best laboratory diagnostic test for IC. The test itself will likely become available widespread pending further validation as a diagnostic test. Whether APF is present due to rheumatological, immunological, infectious, genetic, or neurological causes has not been determined, but it has been demonstrated to produce a downregulation of genes that stimulate epithelial proliferation and upregulates genes that inhibit cell growth. Future clinical trials may finally have a tool that allows for appropriate inclusion and exclusion of appropriate subjects for study.
Structure, function and disease relevance of Wnt inhibitory factor 1, a secreted protein controlling the Wnt and hedgehog pathways
Published in Growth Factors, 2019
Krisztina Kerekes, László Bányai, Mária Trexler, László Patthy
Wnts and Hhs are palmitoleoylated and palmitoylated by porcupine and Hh acyltransferase, respectively; both enzymes are members of the membrane bound O-acyltransferase (MBOAT) family (Buglino and Resh 2012). Wnt proteins are palmitoleoylated in their N-terminal parts and this modification is essential for the signaling activity of these morphogens (Willert et al. 2003; Doubravska et al. 2011). Analysis of the structure of Wnt8 in complex with the ligand binding cysteine-rich Fz domain of the receptor, Frizzled-8, has provided an explanation for the importance of this lipid modification: the ligand-receptor interaction was found to be dominated by the palmitoleic acid side-chain of Wnt8 that is inserted into a deep groove of the ligand-binding Fz domain of the receptor (Janda et al. 2012; Figures 3(A) and 4(A)).
Hepatocellular carcinoma: an update on investigational drugs in phase I and II clinical trials
Published in Expert Opinion on Investigational Drugs, 2019
Anne Noonan, Timothy M. Pawlik
Integrative transcriptome analysis of HCC revealed a subgroup of HCC for which WNT signaling is important [16]. This was confirmed in the TCGA analysis [13]. Nuclear accumulation of β-catenin has been noted in approximately 40–70% of HCCs [20,21]. Several WNT inhibitors are in development. Ipafricept (OMP-54F28) is a potent antagonist of Wnt signaling, developed by OncoMed Pharmaceuticals and has been tested in phase I clinical trials. It is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. A phase I trial of ipafricept was done in solid tumors (NCT01608867) [22]. A phase Ib trial of ipafricept in combination with sorafenib in HCC is currently in progress (NCT02069145).