Rat gene mapping in the post-genome sequencing era: the continued utility of cell hybrids to localize rat genes (Cks2, Ephb4, Fabp5, Il13ra1, Rpl10, Ssr4)
CYTOGENETIC AND GENOME RESEARCH
Authors: Szpirer, C.; Van Vooren, P.; Riviere, M.; Szpirer, J.
Abstract
Finding the position of a gene is now easily done when the genome sequence is available: the gene position is generally found by a simple query of genomic databases such as those available at the Ensembl browser or the NCBI. We were interested in determining the position of 125 cancer-related rat genes and we found that the position of most of these genes (110) could indeed be identified in this manner. However, in 15 cases, the gene position was not available in these databases, or the results were ambiguous. We then explored a more specialized database, namely the Rat Genome Database, and experimentally mapped these genes using standard and radiation cell hybrids. The 15 genes in question could be localized unambiguously. In four cases, the radiation cell hybrids were indispensable: the sequence of these four genes could not be found in the rat genome sequence. On the basis of the sample we examined, it thus appears that a classical gene mapping method is still required to localize about 3% of the rat genes, as if 3% of the rat gene sequences were lacking in the current rat genome sequence. Copyright (c) 2007 S. Karger AG, Basel
RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis
GASTROENTEROLOGY
Authors: Hirano, Ikuo; Collins, Margaret H.; Assouline-Dayan, Yehudith; Evans, Larry; Gupta, Sandeep; Schoepfer, Alain M.; Straumann, Alex; Safroneeva, Ekaterina; Grimm, Michael; Smith, Heather; Tompkins, Cindy-ann; Woo, Amy; Peach, Robert; Frohna, Paul; Gujrathi, Sheila; Penenberg, Darryl N.; Li, Caiyan; Opiteck, Gregory J.; Olson, Allan; Aranda, Richard; Rothenberg, Marc E.; Dellon, Evan S.; Donnellan, Fergal; Iacucci, Marietta; Paterson, William; Schoepfer, Alain; Abonia, Pablo; Ayub, Kamran; Coates, Allan; Cohen, Sidney; Dellon, Evan; Desta, Taddese; Falk, Gary; Fein, Steven; Fernandez-Becker, Nielsen; Fleischer, David; Friedenberg, Keith; Ghishan, Fayez; Glover, Sarah; Goldstein, Gary; Gopal, Vikram; Gross, Craig; Nardi, Robert; Kugathasan, Subra; Lacy, Brian; Lewis, Jeffery; Menard-Katcher, Paul; Mitlyng, Benjamin; Moawad, Fouad; Perez, Rodney; Peterson, Kathryn; Ramirez, Francisco; Reeves-Darby, Vonda; Schey, Ron; Shad, Javaid; Vaezi, Michael; Wo, John; Zakko, Salam
Abstract
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1: 1: 1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 +/- 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 +/- 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 +/- 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. CONCLUSIONS: In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.