Citations

Objective. To evaluate longitudinal cognitive/behavioral change over 12 months in participants enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS). Methods. We analyzed data from 294 ALS participants, 134 of whom were studied serially. Change over time was evaluated controlling for age, sex, symptom duration, education, race, and ethnicity. Using multiple regression, we evaluated associations among decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and cognitive/behavioral changes. Change in cognitive/behavioral subgroups was assessed using one-way analyses of covariance. Results. Participants with follow-up data had fewer baseline behavior problems compared to patients without follow-up data. We found significant worsening of behavior (ALS Cognitive Behavioral Screen (ALS CBS) behavioral scale, p<0.001; Frontal Behavioral Inventory-ALS (FBI-ALS) disinhibition subscale, p=0.044). Item analysis suggested change in frustration tolerance, insight, mental rigidity, and interests (p<0.05). Changes in ALSFRS-R correlated with the ALS CBS. Worsening disinhibition (FBI-ALS) did not correlate with ALSFRS-R, FVC, or disease duration. Conclusion. We did not detect cognitive change. Behavioral change was detected, and increased disinhibition was found among patients with abnormal baseline behavioral scores. Disinhibition changes did not correlate with disease duration or progression. Baseline behavioral problems were associated with advanced, rapidly progressive disease and study attrition.

Purpose The majority of patients with cancer receive treatments that are minimally informed by omics data. We propose a precision medicine computational framework, PANOPLY (Precision Cancer Genomic Report: Single Sample Inventory), to identify and prioritize drug targets and cancer therapy regimens. Materials and Methods The PANOPLY approach integrates clinical data with germline and somatic features obtained from multiomics platforms and applies machine learning and network analysis approaches in the context of the individual patient and matched controls. The PANOPLY workflow uses the following four steps: selection of matched controls to the patient of interest; identification of patient-specific genomic events; identification of suitable drugs using the driver-gene network and random forest analyses; and provision of an integrated multiomics case report of the patient with prioritization of anticancer drugs. Results The PANOPLY workflow can be executed on a stand-alone virtual machine and is also available for download as an R package. We applied the method to an institutional breast cancer neoadjuvant chemotherapy study that collected clinical and genomic data as well as patient-derived xenografts to investigate the prioritization offered by PANOPLY. In a chemotherapy-resistant patient-derived xenograft model, we found that that the prioritized drug, olaparib, was more effective than placebo in treating the tumor ( P < .05). We also applied PANOPLY to in-house and publicly accessible multiomics tumor data sets with therapeutic response or survival data available. Conclusion PANOPLY shows promise as a means to prioritize drugs on the basis of clinical and multiomics data for an individual patient with cancer. Additional studies are needed to confirm this approach.

Significance Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and patients exhibit high rates of recurrence and mortality in part due to lack of treatment options beyond standard-of-care chemotherapy regimens. In the subset of TNBCs that express estrogen receptor beta (ERβ), ligand-mediated activation of ERβ elicits potent anticancer effects. We report here the elucidation of the ERβ cistrome and transcriptome in TNBC and identify a mechanism whereby ERβ induces cystatin gene expression resulting in inhibition of canonical TGFβ signaling and a blockade of metastatic phenotypes. These findings suggest that ERβ-targeted therapies represent a treatment option for the subset of women with ERβ-expressing TNBC.