Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.
Mitochondrial function is critical for energy homeostasis and should shape how genetic variation in metabolism is transmitted through levels of biological organization to generate stability in organismal performance. Mitochondrial function is encoded by genes in two distinct and separately inherited genomes - the mitochondrial genome and the nuclear genome - and selection is expected to maintain functional mito-nuclear interactions. The documented high levels of polymorphism in genes involved in these mito-nuclear interactions and wide variation for mitochondrial function demands an explanation for how and why variability in such a fundamental trait is maintained. Potamopyrgus antipodarum is a New Zealand freshwater snail with coexisting sexual and asexual individuals and, accordingly, contrasting systems of separate vs. co-inheritance of nuclear and mitochondrial genomes. As such, this snail provides a powerful means to dissect the evolutionary and functional consequences of mito-nuclear variation. The lakes inhabited by P. antipodarum span wide environmental gradients, with substantial across-lake genetic structure and mito-nuclear discordance. This situation allows us to use comparisons across reproductive modes and lakes to partition variation in cellular respiration across genetic and environmental axes. Here, we integrated cellular, physiological, and behavioral approaches to quantify variation in mitochondrial function across a diverse set of wild P. antipodarum lineages. We found extensive across-lake variation in organismal oxygen consumption and behavioral response to heat stress and differences across sexes in mitochondrial membrane potential but few global effects of reproductive mode. Taken together, our data set the stage for applying this important model system for sexual reproduction and polyploidy to dissecting the complex relationships between mito-nuclear variation, performance, plasticity, and fitness in natural populations.
1Mitochondrial function is critical for energy homeostasis and should shape how genetic variation 2 in metabolism is transmitted through levels of biological organization to generate stability in 3 organismal performance. Mitochondrial function is encoded by genes in two distinct and 4 separately inherited genomes -the mitochondrial genome and the nuclear genome -and selection 5 is expected to maintain functional mito-nuclear interactions. Nevertheless, high levels of 6 polymorphism in genes involved in these mito-nuclear interactions and variation for 7 mitochondrial function are nevertheless frequently observed, demanding an explanation for how 8 and why variability in such a fundamental trait is maintained. Potamopyrgus antipodarum is a 9New Zealand freshwater snail with coexisting sexual and asexual individuals and, accordingly, 10 contrasting systems of separate vs. co-inheritance of nuclear and mitochondrial genomes. As 11 such, this snail provides a powerful means to dissect the evolutionary and functional 12 consequences of mito-nuclear variation. The lakes inhabited by P. antipodarum span wide 13 environmental gradients, with substantial across-lake genetic structure and mito-nuclear 14 discordance. This situation allows us to use comparisons across reproductive modes and lakes to 15 partition variation in cellular respiration across genetic and environmental axes. Here, we 16 integrated cellular, physiological, and behavioral approaches to quantify variation in 17 mitochondrial function across a diverse set of wild P. antipodarum lineages. We found 18 extensive across-lake variation in organismal oxygen consumption, mitochondrial membrane 19 potential, and behavioral response to heat stress, but few global effects of reproductive mode or 20 sex. Taken together, our data set the stage for applying this important model system for sexual 21 reproduction and polyploidy to dissecting the complex relationships between mito-nuclear 22 variation, performance, plasticity, and fitness in natural populations. 23 3 24 KEYWORDS 25 asexual reproduction, JC-1, mitochondria, oxygen consumption, Potamopyrgus antipodarum, 26 sexual reproduction 27
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