Genetic alterations in BRAF, NRAS and NF1 that activate the ERK cascade, account for over 80% of metastatic melanomas. However, ERK cascade inhibitors have been proven beneficial almost exclusively for BRAF mutant melanomas. One of the hallmarks of the ERK cascade is the nuclear translocation of ERK1/2, which is important mainly for the induction of proliferation. This translocation can be inhibited by the NTS-derived peptide (EPE) that blocks the ERK1/2-importin7 interaction, inhibits the nuclear translocation of ERK1/2, and arrests active ERK1/2 in the cytoplasm. In this study, we found that the EPE peptide significantly reduced the viability of not only BRAF, but also several NRAS and NF1 mutant melanomas. Importantly, combination of the EPE peptide and trametinib showed synergy in reducing the viability of some NRAS mutant melanomas, an effect driven by the partial preservation of negative feedback loops. The same combination significantly reduced the viability of other melanoma cells, including those resistant to mono-treatment with EPE peptide and ERK cascade inhibitors. Our study indicates that targeting the nuclear translocation of ERK1/2, in combination with MEK inhibitors can be used for the treatment of different mutant melanomas.
To present four female-to-male (FTM) transgender patients on testosterone therapy diagnosed with idiopathic intracranial hypertension (IIH).Methods: The authors report 4 consecutive FTM transgender patients on exogenous testosterone diagnosed with IIH at a single institution.Results: Patient 1 presented with progressive blurred vision and a central scotoma 10 weeks after starting testosterone cypionate injections for hormonal gender transition. Bilateral grade 5 papilledema was present; the patient underwent bilateral optic nerve sheath fenestration with improved vision and resolution of edema. Patient 2 presented with transient vision loss, pulsatile tinnitus, and blurred vision 13 months after starting testosterone cypionate injections. The patient had grade 4 and 3 disc edema of the right and left eyes, respectively. Patient 3 presented with headaches and pulsatile tinnitus and was on testosterone injections at an unknown dose. The examination revealed grade 1 and 2 disc edema of the right and left eyes, respectively. Patient 4 presented with decreased vision, transient visual obscurations, and daily migraines while using topical testosterone gel every other day. Color vision was reduced, and lumbar puncture revealed elevated intracranial pressure. All patients had neuroimaging findings consistent with increased intracranial pressure.Conclusions: Testosterone therapy plays an essential role in FTM hormonal transitioning and may play a role in IIH. Patients undergoing testosterone therapy for gender transition should be informed of the possibility of developing IIH while on treatment, with obesity possibly increasing this risk. Comprehensive eye examinations should be considered in these patients before initiating hormone therapy.
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