LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2.

SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63-Å resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys(370) at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor types that display amplification and/or overexpression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. These findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes.

Stage-specific educational interventions for patients with end-stage renal disease: psychological and psychiatric considerations.

To optimize the success of educational interventions for adults with end-stage renal disease, we developed a psychosocial framework of illness adjustment. Currently, no stage-specific guidelines are available for understanding the psychosocial concerns of patients with end-stage renal disease nor are there specific models of coping with the disease. The content and implementation of educational programs must correspond to a patient's stage of adjustment to the illness. Psychological or psychiatric concerns may also affect participation in and response to educational interventions. Recommendations for structuring and implementing educational interventions about renal replacement that are specific to the unique psychosocial tasks associated with adjusting to each stage of end-stage renal disease are presented. Increased information about this disease and the treatment options available can be instrumental in improving patients' quality of life.

Depression and social functioning in preschool children with chronic medical conditions.

OBJECTIVE: To investigate the relations among depressive symptoms, social behavior, and chronic medical illness in preschool children. STUDY DESIGN: Caregivers of 273 preschool children (3.0-5.2 years of age) completed questionnaires about preschoolers' physical health, depressive symptoms, and social behavior. Interviewers determined ratings for preschoolers' impairment in social and behavioral functioning. Analyses examined the relationships among chronic medical conditions, depressive symptoms, peer acceptance/rejection, and social behavior. RESULTS: Chronic illness was significantly associated with early-onset depressive symptoms and impairment in several social functioning domains, even after accounting for socioeconomic status. Regression analyses demonstrated that the number of health conditions predicted higher depression scores, frequency of asocial behaviors, and impairment in daycare role cooperation and behavior toward others. Preschoolers with at least 1 medical condition experienced a greater frequency of peer rejection and bullying compared with healthy peers. Depressive symptoms mediated the relationship between illness and asocial behavior. CONCLUSIONS: There is a need for greater attention to depression and difficulties in social functioning in preschool children with chronic illness. Because of the potential impact on later developmental and mental health outcomes, primary care physicians should be attentive now to depressive symptoms in chronically ill preschoolers.

Disordered eating, trauma, and sense of community: examining women in substance abuse recovery homes.

Women with substance-related disorders are likely to suffer from disordered eating and past traumatic experience, issues that might inhibit the recovery process. The present study determined the prevalence of co-morbidity of disordered eating, trauma, and substance-related disorders among 60 women living in one of 15 mutual help substance abuse recovery homes that establish new social networks for residents. Psychological sense of community was also examined to determine whether residents were able to obtain support that may have previously been absent. Results indicated that women with co-existing disordered eating and substance-related disorders, as well as women who have experienced trauma benefit from democratic, independent-living environments. Implications for treatment and future research are discussed.