Conducting Molecular Epidemiological Research in the Age of HIPAA: A Multi-Institutional Case-Control Study of Breast Cancer in African-American and European-American Women

Breast cancer in African-American (AA) women occurs at an earlier age than in European-American (EA) women and is more likely to have aggressive features associated with poorer prognosis, such as high-grade and negative estrogen receptor (ER) status. The mechanisms underlying these differences are unknown. To address this, we conducted a case-control study to evaluate risk factors for high-grade ER- disease in both AA and EA women. With the onset of the Health Insurance Portability and Accountability Act of 1996, creative measures were needed to adapt case ascertainment and contact procedures to this new environment of patient privacy. In this paper, we report on our approach to establishing a multicenter study of breast cancer in New York and New Jersey, provide preliminary distributions of demographic and pathologic characteristics among case and control participants by race, and contrast participation rates by approaches to case ascertainment, with discussion of strengths and weaknesses

Low diversity Cryptococcus neoformans variety grubii multilocus sequence types from Thailand are consistent with an ancestral African origin.

Published versio

RBE Wiki for Independent Learning

This project, which performed research on web based academic resources, revolved around the focus question "how does one utilize web-based communication media in order to facilitate the self-perpetuating exchange of knowledge in the academic engineering community?". It examined the social implications of self-sustaining web-based resources, and found that any new web resource needs to fill a previously vacant niche in order to gather the user-base required to be self-sustaining

Predicting transcription factor activity using prior biological information

Summary: Dysregulation of normal transcription factor activity is a common driver of disease. Therefore, the detection of aberrant transcription factor activity is important to understand disease pathogenesis. We have developed Priori, a method to predict transcription factor activity from RNA sequencing data. Priori has two key advantages over existing methods. First, Priori utilizes literature-supported regulatory information to identify transcription factor-target gene relationships. It then applies linear models to determine the impact of transcription factor regulation on the expression of its target genes. Second, results from a third-party benchmarking pipeline reveals that Priori detects aberrant activity from 124 single-gene perturbation experiments with higher sensitivity and specificity than 11 other methods. We applied Priori and other top-performing methods to predict transcription factor activity from two large primary patient datasets. Our work demonstrates that Priori uniquely discovered significant determinants of survival in breast cancer and identified mediators of drug response in leukemia

Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia.

Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood super-enhancer, suppressing super-enhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD AML. Implications: This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific super-enhancer complex

Antisense transcription of the myotonic dystrophy locus yields low-abundant RNAs with and without (CAG)n repeat

<p>The unstable (CTG·CAG)n trinucleotide repeat in the myotonic dystrophy type 1 (DM1) locus is bidirectionally transcribed from genes with terminal overlap. By transcription in the sense direction, the <i>DMPK</i> gene produces various alternatively spliced mRNAs with a (CUG)n repeat in their 3′ UTR. Expression in opposite orientation reportedly yields (CAG)n-repeat containing RNA, but both structure and biologic significance of this antisense gene (<i>DM1-AS</i>) are largely unknown. Via a combinatorial approach of computational and experimental analyses of RNA from unaffected individuals and DM1 patients we discovered that <i>DM1-AS</i> spans >6 kb, contains alternative transcription start sites and uses alternative polyadenylation sites up- and downstream of the (CAG)n repeat. Moreover, its primary transcripts undergo alternative splicing, whereby the (CAG)n segment is removed as part of an intron. Thus, in patients a mixture of <i>DM1-AS</i> RNAs with and without expanded (CAG)n repeat are produced. <i>DM1-AS</i> expression appears upregulated in patients, but transcript abundance remains very low in all tissues analyzed. Our data suggest that <i>DM1-AS</i> transcripts belong to the class of long non-coding RNAs. These and other biologically relevant implications for how (CAG)n-expanded transcripts may contribute to DM1 pathology can now be explored experimentally.</p