Session 10

Active genetic elements are transmitted during reproduction at greater than expected Mendelian frequencies. Such "super-Mendelian" inheritance can be used for a variety of applications including: gene-drive systems for disseminating beneficial traits throughout populations (e.g., spreading immunizing factors that prevent mosquitoes from transmitting malarial parasites), reversing insecticide resistance, devising elements that can eliminate or inactivate gene drives, creating active genetic modifications that facilitate breeding by bypassing constraints imposed by independent assortment and linkage, and development of self-amplifying systems in bacteria to scrub antibiotic resistance factors from the environment or potentially from patients with chronic bacterial infections, and engineering next-generation genetic circuits for synthetic biology.

Survival depends on selecting and executing behaviors that are adaptive for the current environment. For example, a mouse should run from a rapidly looming hawk but should freeze if the hawk is coasting across the sky. Although serotonin has been implicated in adaptive, context-dependent behavior, environmental regulation of its functional role remains poorly understood. In mice, we found that brief stimulation of dorsal raphe serotonin neurons suppressed movement in low- and moderate-threat environments but induced escape behavior in high-threat environments, and that movement-related dorsal raphe serotonin neural dynamics inverted in high-threat environments. Although serotonin neurons appear to switch their functional role in different environments, we suggest an integrative framework in which phasic activity in serotonin neurons provokes a fast, environmentally appropriate emotional reaction – freeze at moderate threat, escape at high threat. This hypothesis cleanly explains our data, and has the potential to encompass a wide range of other environment- and internal state-dependent functions ascribed to this neuromodulatory system. We will discuss how this framework may have relevance for understanding the anti-anxiety effects of chronically administered selective serotonin reuptake inhibitors.

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Skin cancer is the most common type of cancer. Although ultraviolet radiation is its preventable risk factor, the incidence of skin cancer, including squamous cell carcinoma (SCC), has doubled over the last decade in the United States. Besides morbidity and mortality associated with skin cancer, skin cancer treatments represent a rising public health challenge with increasing complications and rising costs. Therefore, skin cancer prevention is urgently needed. To accomplish this goal, we developed topical calcipotriol plus 5-fluorouracil (5-FU) immunotherapy that effectively eliminated SCC precursors called actinic keratosis in a randomized double-blind clinical trial. Since, we performed a blinded prospective cohort study on its participants in order to determine the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention. Calcipotriol plus 5-FU combination induced tissue-resident memory T (TRM) cell formation in face and scalp skin, which was associated with significantly higher erythema scores compared to control groups (Vaseline plus 5-FU, p < 0.01). Importantly, more participants in the test cohort remained SCC-free over the > 1500-day follow-up period, and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 [7%] versus 11 of 40 [28%] in control group, hazard ratio 0.215 [95% CI: 0.048-0.972], p=0.032). Interestingly, we found more epidermal TRM cells persisting in the calcipotriol plus 5-FU-treated face and scalp skin compared with control months to years post treatment (p=0.0028). Our findings demonstrate that a short course of a topical immunotherapy that induces T cell immunity and effectively eliminates actinic keratosis can significantly lower the long-term risk of SCC. Our research substantiates a previously unrecognized concept that immunotherapy against premalignant lesions can be used to prevent cancer development and recurrence in high-risk patients.