Factors That Contribute to Indeterminate Results From the QuantiFERON-TB Gold In-Tube Test in Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The QuantiFERON-Tuberculosis Gold In-Tube (QFT-GIT) (QIAGEN Group, Hilden, Germany) test is widely used to screen for latent Mycobacterium tuberculosis infection in patients with inflammatory bowel diseases (IBD) before treatment with a tumor necrosis factor antagonist. The test frequently produces indeterminate results, prompting additional testing. We evaluated factors associated with indeterminate results from the QFT-GIT test among patients with IBD. METHODS: We conducted a case-control study among eligible adults with QFT-GIT test results and a concomitant diagnosis of IBD receiving care at a tertiary referral center from 2011 through 2013. We compared patients with IBD with indeterminate and determinate (positive or negative) results from the QFT-GIT test. We collected data on patient demographics, clinical features, laboratory parameters, and medication use from medical charts. We calculated odds ratios (OR) and 95% CIs using multivariate logistic regression models. RESULTS: A total of 400 patients with IBD (265 Crohn's disease and 135 ulcerative colitis) were included in the final analyses. Indeterminate results were noted in 11.5% of patients. At the time of testing, a higher proportion of patients with indeterminate results from the QFT-GIT test were on systemic corticosteroid therapy (60.9% vs 30.5% of patients with conclusive test results; P < .001), had levels of C-reactive protein above 0.8 mg (62.2% vs 39.9% of patients with clear test results; P = .005), had an erythrocyte sedimentation rate above 15 mm/h (55.6% vs 35.8% of patients with clear test results; P = .01), had serum levels of albumin below 3.5 g/dL (33.3% vs 6.3% of patients with clear test results; P < .001), and had low levels of hemoglobin (52.2% vs 28.3% of patients with clear test results; P = .001). In multivariable analysis, corticosteroid use (adjusted OR, 2.92; 95% CI, 1.44-5.88; P = .003) and serum levels of albumin below 3.5 g/dL (adjusted OR, 3.62; 95% CI, 1.36-9.60; P = .009) were independently associated with increased risk of indeterminate QFT-GIT test results. We did not identify a dose-related effect with corticosteroid therapy and the odds of indeterminate QFT-GIT test results. CONCLUSIONS: In a case-control study of patients with IBD, we associated systemic corticosteroid therapy and low levels of albumin with an increased likelihood of having indeterminate QFT-GIT test result.

Identifying Significantly Impacted Pathways and Putative Mechanisms with iPathwayGuide.

iPathwayGuide is a gene expression analysis tool that provides biological context and inferences from data generated by high-throughput sequencing. iPathwayGuide utilizes a systems biology approach to identify significantly impacted signaling pathways, Gene Ontology terms, disease processes, predicted microRNAs, and putative mechanisms based on the given differential expression signature. By using a novel analytical approach called Impact Analysis, iPathwayGuide considers the role, position, and relationships of each gene within a pathway, which results in a significant reduction in false positives, as well as a better ability to identify the truly impacted pathways and putative mechanisms that can explain all measured gene expression changes. It is a Web-based, user-friendly, interactive tool that does not require prior training in bioinformatics. The protocols in this unit describe how to use iPathwayGuide to analyze a single contrast between two phenotypes (any number of samples), and provide guidance on how to interpret the results obtained from iPathwayGuide. Even though iPathwayGuide has powerful meta-analysis capabilities, these are not covered in this unit. © 2017 by John Wiley & Sons, Inc.

Combinatorial therapeutic targeting of BMP2 and MEK-ERK pathways in NF1-associated malignant peripheral nerve sheath tumors.

The clinical management of malignant peripheral nerve sheath tumors (MPNSTs) is challenging not only due to its aggressive and invasive nature, but also limited therapeutic options. Using gene expression profiling, our lab identified BMP2-SMAD1/5/8 pathway as a potential therapeutic target for treating MPNSTs. In this study, we explored the therapeutic impact of targeting BMP2-SMAD1/5/8 pathway in conjunction with RAS-MEK-ERK signaling, which is constitutively activated in MPNSTs. Our results indicated that single agent treatment with LDN-193189, a BMP2 Type I receptor inhibitor, did not affect the growth and survival of MPNST cells at biochemically relevant inhibitory concentrations. However, addition of a MEK1/2 inhibitor, selumetinib, to LDN-193189-treated cells resulted in significant inhibition of cell growth and induction of cell death. LDN-193189 at biochemically effective concentrations significantly inhibited motility and invasiveness of MPNST cells, and these effects were enhanced by the addition of selumetinib. Overall, our results advocate for a combinatorial therapeutic approach for MPNSTs that not only targets the growth and survival via inhibition of MEK1/2, but also its malignant spread by suppressing the activation of BMP2-SMAD1/5/8 pathway. Importantly, these studies were conducted in low-passage patient-derived MPNST cells, allowing for an investigation of the effects of the proposed drug treatments in a biologically-relevant context.

Variants in the Signaling Protein TSAd are Associated with Susceptibility to Ovarian Cancer in BRCA1/2 Negative High Risk Families.

A substantial fraction of familial ovarian cancer cases cannot be attributed to specific genetic factors. The discovery of additional susceptibility genes will permit a more accurate assessment of hereditary cancer risk and allow for monitoring of predisposed women in order to intervene at the earliest possible stage. We focused on a population with elevated familial breast and ovarian cancer risk. In this study, we identified a SNP rs926103 whose minor allele is associated with predisposition to ovarian but not breast cancer in a Caucasian high-risk population without BRCA1/BRCA2 mutations. We have found that the allelic variation of rs926103, which alters amino acid 52 of the encoded protein SH2D2A/TSAd, results in differences in the activity of this protein involved in multiple signal transduction pathways, including regulation of immune response, tumor vascularization, cell growth, and differentiation. Our observation provides a novel candidate genetic biomarker of elevated ovarian cancer risk in members of high-risk families without BRCA1/2 mutations, as well as a potential therapeutic target, TSAd.