Citations

The ten‐member SLC26 gene family encodes anion transporters with a diversity of substrates and transport modes, functioning as electrogenic exchangers, anion sensors, and/or anion channels. Slc26a6 is perhaps the most versatile paralog, mediating electrogenic exchange of multiple divalent and monovalent anions. We have generated a cysteineless Slc26a6 for structure‐function studies, fully substituting 8 cysteines with threonine, serine, and alanine, as dictated by the functional data for single and compound mutants. Although absolute transport rates are reduced in the cysteineless Slc26a6 protein it exhibits equivalent anion specificity and electrophysiology (chloride‐bicarbonate exchange) to that of wild‐type. On Western blots, the oligomerization of wild‐type Slc26a6 is inhibited by dithiothreitol, suggesting a role for inter‐cysteine disulfide bonds; oligomerization is absent in the cysteineless protein. Co‐immunoprecipitation of FLAG‐ and MYC‐tagged Slc26a6 is easily detectable for wild‐type proteins but absent in the epitope‐tagged cysteineless proteins. The equivalent data for single and compound mutants implicate C‐terminal cytoplasmic cysteines in oligomerization of the transporter protein. In summary, the eight cysteines in Slc26a6 are dispensable for transport activity but appear to play a role in oligomerization of the transport protein.

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.