Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma.

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs ( P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs ( P = 0.026). The TT-genotype of Jo27T>C SNP ( P = 0.056) and GG-genotype of Jo31G>T ( P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.

Oxidative stress affects sperm performance and ejaculate redox status in subordinate house sparrows.

Oxidative stress is the result of random cellular damage caused by reactive oxygen species that leads to cell death, ageing or illness. Most physiological processes can result in oxidative stress, which in turn has been identified as a major cause of infertility. In promiscuous species, the fertilizing ability of the ejaculate partly determines the male reproductive success. When dominance determines access to fertile females, theory predicts that lower ranking males should increase resource investment into enhancing ejaculate quality. We hypothesized that subordinate males should thus prioritize antioxidant protection of their ejaculates to protect them from oxidative stress. We put this hypothesis to the test by chronically dosing wild house sparrows with diquat (∼1 mg kg-1), a herbicide that increases pro-oxidant generation. We found that, although they increased their antioxidant levels in the ejaculate, diquat-treated males produced sperm with reduced velocity. Importantly, and contrary to our hypothesis, males at the bottom of the hierarchy suffered the largest reduction in sperm velocity. We suggest that resource access hinders individuals' ability to cope with environmental hazards. Our results point at oxidative stress as a likely physiological mechanism mediating ejaculate quality, while individual ability to access resources may play a role in constraining the extent to which such resources can be allocated into the ejaculate.