The future of myeloma precision medicine: integrating the compendium of known drug resistance mechanisms with emerging tumor profiling technologies.

Multiple myeloma (MM) is a hematologic malignancy that is considered mostly incurable in large part due to the inability of standard of care therapies to overcome refractory disease and inevitable drug-resistant relapse. The post-genomic era has been a productive period of discovery where modern sequencing methods have been applied to large MM patient cohorts to modernize our current perception of myeloma pathobiology and establish an appreciation for the vast heterogeneity that exists between and within MM patients. Numerous pre-clinical studies conducted in the last two decades have unveiled a compendium of mechanisms by which malignant plasma cells can escape standard therapies, many of which have potentially quantifiable biomarkers. Exhaustive pre-clinical efforts have evaluated countless putative anti-MM therapeutic agents and many of these have begun to enter clinical trial evaluation. While the palette of available anti-MM therapies is continuing to expand it is also clear that malignant plasma cells still have mechanistic avenues by which they can evade even the most promising new therapies. It is therefore becoming increasingly clear that there is an outstanding need to develop and employ precision medicine strategies in MM management that harness emerging tumor profiling technologies to identify biomarkers that predict efficacy or resistance within an individual's sub-clonally heterogeneous tumor. In this review we present an updated overview of broad classes of therapeutic resistance mechanisms and describe selected examples of putative biomarkers. We also outline several emerging tumor profiling technologies that have the potential to accurately quantify biomarkers for therapeutic sensitivity and resistance at genomic, transcriptomic and proteomic levels. Finally, we comment on the future of implementation for precision medicine strategies in MM and the clear need for a paradigm shift in clinical trial design and disease management.

Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy.

BACKGROUND: Autism spectrum disorder is commonly co-diagnosed intellectual disability, language disorder, anxiety, and epilepsy, however, symptom management is difficult due to the complex genetic nature of ASD. METHODS: We present a next-generation sequencing-based case study with both de novo and inherited genetic variants and highlight the impact of structural variants on post-translational regulation of protein expression. Since management of symptoms has classically been through pharmaceutical therapies, a pharmacogenomics screen was also utilized to determine possible drug/gene interactions. RESULTS: A de novo variant was identified within the FOXP1 3' untranslated regulatory region using exome sequencing. Additionally, inherited variants that likely contribute to the current and potential future traits were identified within the COMT, SLC6A4, CYP2C19, and CYP2D6 genes. CONCLUSION: This study aims to elucidate how a collection of variant genotypes could potentially impact neural development resulting in a unique phenotype including ASD and epilepsy. Each gene's contribution to neural development is assessed, and the interplay of these genotypes is discussed. The results highlight the utility of exome sequencing in conjunction with pharmacogenomics screening when evaluating possible causes of and therapeutic treatments for ASD-related symptoms.

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes.

Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation. Pre-treatment with EZH2 inhibitors greatly enhanced the sensitivity of HMCLs to the pan-HDAC inhibitor panobinostat in nearly all cases regardless of single agent EZH2 inhibitor sensitivity. Transcriptomic profiling revealed large-scale transcriptomic alteration by EZH2 inhibition highly enriched for cancer-related pathways. Combination treatment greatly increased the scale of gene expression change with a large portion of differentially expressed genes being unique to the combination. Transcriptomic analysis demonstrated that combination treatment further perturbed oncogenic pathways and signaling nodes consistent with an antiproliferative/pro-apoptotic state. We conclude that combined inhibition of HDAC and EZH2 inhibitors is a promising therapeutic strategy to broadly target the epigenetic landscape of aggressive MM.

Development and psychometric validation of a Domestic Violence Coping Self-efficacy Measure (DV-CSE).

Psychometric properties of a Domestic Violence Coping Self-Efficacy Measure were examined. Two-hundred eighty three women assaulted within the past 6 months were recruited. Internal reliability of the measure was very good (alpha = .97). Principle components factor analysis indicated one primary factor accounting for 56% of the variance. The measure was positively associated with optimism, adaptive coping, and healthy psychological functioning, and negatively associated with trauma-related distress, negative mood, and maladaptive coping. A small positive association with social desirability was found. This measure may have significant clinical utility in helping survivors by indicating areas where individuals feel especially vulnerable or empowered.