Structure and chromosomal location of the bovine gene for the heart muscle isoform of cytochrome c oxidase subunit VIII

We have isolated the bovine COX8H gene for the heart/muscle isoform of cytochrome c oxidase (COX) subunit VIII from a library of bovine genomic DNA cloned into lambda EMBL3. Primer extension assays on bovine heart mRNA mapped the 5′ ends of COX8H transcripts to a CA dinucleotide 62-bp upstream from the ATG codon. The gene thus spans 1565-bp and comprises two exons and one large intron of 1227 bp. Exon 1 encodes the 5′ untranslated region, a 24-amino acid presequence, and the first 13 amino acids of the mature COX VIII-H protein. Exon 2 encodes the remainder of the cDNA: amino acids 14 to 46 plus the 66-bp 3′ untranslated region. The exon-intron boundaries matched the consensus splice junction sequences. Two protein polymorphisms were seen: an Ala/Val polymorphism at position-6 in the presequence and the previously noted Lys/Arg polymorphism at residue 7 of the mature protein. A Taq I polymorphism occurs in the intron. The COX8H gene was mapped by bovine x rodent somatic cell hybrid mapping panels to bovine (BTA) Chromosome (Chr) 25 with 100% concordancy. BTA25 is conserved relative to the long arm of human (HSA) Chr 11, which contains COX8, the gene for the single human COX VIII subunit that is homologous to the liver isoform.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47018/1/335_2004_Article_BF00303255.pd

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040