Background: Phenylketonuria (PKU) is one of the most common inherited metabolic disorders and the first for which newborn screening became available. Even when treated, it can impact quality of life (QoL) due to strict dietary management and potential for neuropsychiatric symptoms including anxiety, depression, and impaired executive functioning and attention. This study aimed to learn about the impact the newest treatment for PKU – pegvaliase, an enzyme substitution therapy – has on QoL and to assess the residual support and resource needs of patients using it. In clinical trials, pegvaliase was shown to improve certain neuropsychiatric symptoms. To our knowledge, no research is currently published on the impact of pegvaliase on overall QoL or residual support and resource needs.Methods: Adults who have PKU were were recruited from the National PKU Alliance patient registry and the PKU Clinic at UPMC Children’s Hospital of Pittsburgh, including adults who are and are not taking pegvaliase, and surveyed. Survey questions assessed current management, overall QoL, PKU-related QoL, currently utilized resources and supports, and remaining needs. Standardized questions assessing depression and cognition were also included. Responses were compared by whether the respondent was taking pegvaliase and whether their phenylalanine (phe) levels were above or below a set threshold.Results: Significant differences were found in satisfaction with management, impact of PKU, general satisfaction with life, and cognition when comparing by phe level. When comparing by pegvaliase status, a significant difference was only found in satisfaction with management. Residual resource and support needs predominantly involved social, financial, and adult-specific needs, although many respondents reported utilizing supports or resources in these domains.Conclusions: Phe level seemed to have the most notable impact on QoL, although pegvaliase use was shown to improve QoL to a degree, likely related to its ability to lower phe levels. PKU-related worries appeared to have a similar impact on QoL regardless of management, and should be a focus for future care. Ensuring that adult patients are aware of available supports and resources is also important in meeting residual needs reported in this study.

Abstract Steroid hormone receptors such as estrogen and progesterone receptors are well studied in breast cancer pathology; they are also used as drug targets for breast cancer therapy in the clinic. In contrast, glucocorticoid (GC) as a ubiquitous stress activated steroid hormone is less investigated in breast cancer. However, GC is frequently used as a co-treatment for breast cancer chemotherapy that generates some controversial effects to even promote cancer progression or recurrence in certain subtypes of breast cancer. To address this clinical issue, we focused on investigating the specificity of GC signaling on breast cancer cell behaviors in this study. When breast cancer cells were treated by dexamethasone (Dex), they were more responsive to cell migration (measured by electric cell-substrate impedance sensing, ECIS) than the effects on cell proliferation and apoptosis, wherein MDA-231 (triple negative breast cancer) cell was more sensitive to Dex than MCF7 cell (luminal A subtype). Further gene expression analysis by qRT-PCR microarray revealed that the glucocorticoid receptor (GR) responsive gene patterns are different between these two subtypes of breast cancer cells. One of remarked changes was that Snai2 (a zinc finger transcriptional factor) was highly activated in both cell lines. Western blotting analysis confirmed that MDA-231 cells have much higher basal level of Snai2 but with less fold increase upon Dex treatment than MCF-7. GR response elements (GREs) were also identified in the promoter region of Snai2, thus confirming Snai2 as a new target gene of GR in breast cancer. When Snai2 was knocked out by CRISPR, it was found that the basal migration rate was decreased in both cell lines. More importantly, their response rates to Dex treatment were also decreased as compared to the wild type cells. These decreases in cell migration are similar to those treated by GR antagonist RU486, thus confirming that Snai2 is a mediator to regulate the effects of GC/GR signaling on breast cancer cell migration. In summary, this study identified Snai2 as a new target gene of GR to regulate cell migration and potentially metastasis in response to GC signaling. The differential regulation of different subtypes of breast cancer cells by GC signaling was also confirmed. (+ equal contribution; * Corresponding author). Citation Format: Jun Ling, Adit Singhal, Zenaida P. Lopez-Dee, Brittany Porreca, Trinity Sprague. Snai2 is a new target to mediate glucocorticoid signaling on breast cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 45.