Summary Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an anti-tumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and expanding a single cell clone, we generated a mutagenized model that exhibits high somatic mutation burden. When inoculated at low cell numbers in immunocompetent C57BL/6J mice, YUMMER1.7 (YUMM Exposed to Radiation) regresses after a brief period of growth. This regression phenotype is dependent on T cells as YUMMER1.7 tumors grow significantly faster in immunodeficient Rag1−/− mice and C57BL/6J mice depleted of CD4 and CD8 T cells. Interestingly, regression can be overcome by injecting higher cell numbers of YUMMER1.7, which results in tumors that grow without effective rejection. Mice that have previously rejected YUMMER1.7 tumors develop immunity against higher doses of YUMMER1.7 tumor challenge. In addition, escaping YUMMER1.7 tumors are sensitive to anti-CTLA-4 and anti-PD-1 therapy, establishing a new model for the evaluation of immune checkpoint inhibition and anti-tumor immune responses.

The phosphatidylinositol-3,4,5-triphosphate (PIP3) binding function of pleckstrin homology (PH) domain is essential for the activation of oncogenic Akt/PKB kinase. Following the PIP3-mediated activation at the membrane, the activated Akt is subjected to other regulatory events, including ubiquitination-mediated deactivation. Here, by identifying and characterizing an allosteric inhibitor, SC66, we show that the facilitated ubiquitination effectively terminates Akt signaling. Mechanistically, SC66 manifests a dual inhibitory activity that directly interferes with the PH domain binding to PIP3 and facilitates Akt ubiquitination. A known PH domain-dependent allosteric inhibitor, which stabilizes Akt, prevents the SC66-induced Akt ubiquitination. A cancer-relevant Akt1 (e17k) mutant is unstable, making it intrinsically sensitive to functional inhibition by SC66 in cellular contexts in which the PI3K inhibition has little inhibitory effect. As a result of its dual inhibitory activity, SC66 manifests a more effective growth suppression of transformed cells that contain a high level of Akt signaling, compared with other inhibitors of PIP3/Akt pathway. Finally, we show the anticancer activity of SC66 by using a soft agar assay as well as a mouse xenograft tumor model. In conclusion, in this study, we not only identify a dualfunction Akt inhibitor, but also demonstrate that Akt ubiquitination could be chemically exploited to effectively facilitate its deactivation, thus identifying an avenue for pharmacological intervention in Akt signaling.chemical screening | cell death

We evaluated the spontaneous and immunotherapy‐induced histological changes in the tumor microenvironment of a mouse melanoma regression model consisting of immunocompetent C57BL/6J mice implanted with syngeneic YUMMER1.7 melanoma cells. We focused on tumor regression phenotypes and spatial relationships of melanoma cells with B cells and neutrophils since this was not previously described. We found common themes to the host response to cancer irrespective of the mode of tumor regression. In nonregression tumors, melanoma cells were epithelioid shaped and tightly packed. In regression tumors, melanoma cells were spindle shaped and discohesive. B cells including plasmablasts and plasma cells were numerous and were increased with immunotherapy. Neutrophils were in direct contact with dead or dying melanoma cells. Immunotherapy increased neutrophil counts and induced neutrophil extracellular traps (NETs)‐like formations and geographic necrosis. Beyond tumor regression, the increase in the B cell and neutrophil response could play a role in immunotherapy‐induced adverse reactions.

Due to the increasing number of patients with end-stage renal disease, there is a growing demand for transplants for recipients and donors aged 60 years and older. Using data from the Scientific Registry of Transplant Recipients, we performed survival analyses and multivariate logistic regression to help guide transplant professional decisions regarding the selection of graft type (living vs deceased) and donor age (60-69 vs 70+ years) for recipients aged 60 years and older.

vaporization with CO2 laser may have similarities with the results in our case.Compared with corticosteroid infiltrations, CO2 laser treatment needs the use of local anesthesia and an experienced clinician to correctly manage the laser parameters. On the contrary, from our single case experience, it seems to have a lower risk of recurrence, and it may be a definitive treatment by causing a certain degree of fibrosis that could prevent the reappearance of the granulomatous reaction. Nevertheless, further studies should evaluate the pathogenesis and mechanism behind this treatment for OFG.This treatment has also a high level of security because the vaporization is progressive and superficial. The presence of abundant hair follicles in the face allows this area to easily re-epithelialize. The risk of adverse effects, such as scarring, can occur in the case of using inappropriate parameters or excessive vaporization beyond prominent tissue.In short, the therapeutic approach of OFG is still under debate, because there are only small case series published. The management of OFG is also difficult because of frequent relapses. To the best of our knowledge, this is the first patient with OFG treated successfully with CO2 laser. This therapy is a well-tolerated option, with a low risk of side effects. Hence, we propose the use of ablative CO2 laser to treat patients with OFG who have not responded to other therapeutic approaches.