Loss of function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2 inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in TCGA confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.

BRAF inhibitors are highly effective therapies for the treatment of BRAFV600-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.

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To accurately measure the vitreous chamber volume (VCV) in humans using high-resolution computed tomography (CT) scanning techniques combined with threedimensional analysis software. Potential relationships between age, axial length, and VCVs were also explored. Methods: In this retrospective study, the eyes of 100 healthy individuals were studied. Scans were acquired during clinical care and did not show any signs of orbital pathology. Exclusion criteria included any ocular history. CT scans were acquired with a slice thickness of 0.7 mm, and volumetric analysis was carried out using the MIMICS image analysis software version 19.0 (Materialise, Leuven, Belgium). Results: The final sample included 100 eyes from 50 patients (30 women, 20 men). The mean age was 48.67 ± 20.72 years, and the age range was 18 to 91 years. The mean VCV was 4.649.99 ± 0.426.54 mm 3 for women and 4.969.0 ± 0.465.20 mm 3 for men. We found a significant correlation between age and VCV (P < 0.001), axial length and VCV (P < 0.001), and age and axial length (P < 0.005). Conclusions: The VCV appears to be greater than the current consensus suggests. This work also suggests that the VCV is associated with age and axial length, indicating that it is dynamic and may change throughout adulthood. Translational Relevance: This information regarding the volume of the vitreous chamber is useful for our understanding of proper dosage and behavior of agents we commonly insert into the vitreous chamber.