Toward Practical Integration of Omic and Imaging Data in Co-Clinical Trials.

Co-clinical trials are the concurrent or sequential evaluation of therapeutics in both patients clinically and patient-derived xenografts (PDX) pre-clinically, in a manner designed to match the pharmacokinetics and pharmacodynamics of the agent(s) used. The primary goal is to determine the degree to which PDX cohort responses recapitulate patient cohort responses at the phenotypic and molecular levels, such that pre-clinical and clinical trials can inform one another. A major issue is how to manage, integrate, and analyze the abundance of data generated across both spatial and temporal scales, as well as across species. To address this issue, we are developing MIRACCL (molecular and imaging response analysis of co-clinical trials), a web-based analytical tool. For prototyping, we simulated data for a co-clinical trial in "triple-negative" breast cancer (TNBC) by pairing pre- (T0) and on-treatment (T1) magnetic resonance imaging (MRI) from the I-SPY2 trial, as well as PDX-based T0 and T1 MRI. Baseline (T0) and on-treatment (T1) RNA expression data were also simulated for TNBC and PDX. Image features derived from both datasets were cross-referenced to omic data to evaluate MIRACCL functionality for correlating and displaying MRI-based changes in tumor size, vascularity, and cellularity with changes in mRNA expression as a function of treatment.

Performance of Screening Breast MRI After Negative Full-Field Digital Mammography Versus After Negative Digital Breast Tomosynthesis in Women at Higher Than Average Risk for Breast Cancer.

OBJECTIVE: The objective of our study was to compare the supplemental cancer yield and performance of breast MRI in women at higher-than-average risk for breast cancer after negative 2D full-field digital mammography (FFDM) or negative digital breast tomosynthesis (DBT). MATERIALS AND METHODS: Retrospective review identified 4418 screening breast MRI examinations: 2291 were performed from January 2010 through January 2012 of patients with a negative FFDM examination in the 12 months before MRI (FFDM group), and 2127 were performed from January 2013 through January 2015 of patients with a negative DBT examination in the 12 months before MRI (DBT group). Screening indications included genetic predisposition, personal history of breast cancer or high-risk lesion, prior chest irradiation, family history, or other risk factors conferring a lifetime risk of greater than 20%. Supplemental cancer detection rate (CDR), abnormal interpretation rate (AIR), and positive predictive values (PPVs) were estimated with 95% exact CIs. Logistic regression analysis, adjusting for differences in patient demographics, was used to compare metrics. RESULTS: There was no significant difference in the CDR of MRI in the FFDM group versus the DBT group (11 vs 16 cancers per 1000 examinations, respectively; odds ratio, 1.4; 95% CI, 0.4-1.2; p = 0.23). The AIR, PPV1, PPV2, and PPV3 were 7.4%, 15%, 23%, and 28% for the FFDM group and 7.3%, 22%, 33%, and 35% for the DBT group, with no statistical differences. Of the cancers detected in both groups, the majority were invasive, less than 1 cm, and node-negative. CONCLUSION: In women at higher-than-average risk of breast cancer screened with DBT, the supplemental CDR of MRI is similar to that of MRI after FFDM screening, with most cancers being invasive, subcentimeter, and node-negative.

Impact of Simulation-Based Training on Radiology Trainee Education in Ultrasound-Guided Breast Biopsies.

PURPOSE: The aim of this study is to determine the impact of a simulation-based ultrasound-guided (USG) breast biopsy training session on radiology trainee procedural knowledge, comfort levels, and overall procedural confidence and anxiety. METHODS: Twenty-one diagnostic radiology residents from a single academic institution were recruited to participate in an USG breast biopsy training session. The residents filled out a questionnaire before and after the training session. Ten multiple-choice questions tested general knowledge in diagnostic breast ultrasound and USG breast biopsy concepts. Subjective comfort levels with ultrasound machine and biopsy device functionality, patient positioning, proper biopsy technique, image documentation, needle safety and overall procedural confidence and anxiety levels were reported on a 5-point Likert scale before and after training. RESULTS: Participants demonstrated significant improvement in number of correctly answered general knowledge questions after training (P < .0001). Significant improvement was seen in resident comfort level in ultrasound machine functionality, patient positioning, biopsy device functionality, biopsy technique, image documentation, as well as overall confidence level (all P < .05). Participants indicated a slight but not significant reduction in anxiety levels (P = .27). CONCLUSIONS: A simulation-based USG breast biopsy training session may improve radiology trainee procedural knowledge, comfort levels, and overall procedural confidence.

Modification of papillomavirus E2 proteins by the small ubiquitin-like modifier family members (SUMOs).

Papillomavirus E2 proteins are critical regulatory proteins that function in replication, genome segregation, and viral transcription, including control of expression of the viral oncogenes, E6 and E7. Sumoylation is a post-translational modification that has been shown to target and modulate the function of many transcription factors, and we now demonstrate that E2 proteins are sumoylated. Both bovine and human papillomavirus E2 proteins bind to the SUMO conjugation enzyme, Ubc9, and using in vitro and E. coli sumoylation systems, these E2 proteins were readily modified by SUMO proteins. In vivo experiments further confirmed that E2 can be sumoylated by SUMO1, SUMO2, or SUMO3. Mapping studies identified lysine 292 as the principal residue for covalent conjugation of SUMO to HPV16 E2, and a lysine 292 to arginine mutant showed defects for both transcriptional activation and repression. The expression levels, intracellular localization, and the DNA-binding activity of HPV16 E2 were unchanged by this K292R mutation, suggesting that the transcriptional defect reflects a functional contribution by sumoylation at this residue. This study provides evidence that sumoylation has a role in the regulation of papillomavirus E2, and identifies a new mechanism for the modulation of E2 function at the post-translational level.