Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation.

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.

Precision pharmacological reversal of genotype-specific diet-induced metabolic syndrome in mice informed by transcriptional regulation.

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genomic DNA methylation analyses and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects reveals a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts genotype-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis, as well as increased inflammatory-related gene expression changes in NOD. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention, and a mouse platform for guiding this approach.

Fluoroscopic Intraoperative Breast Neoplasm and Node Detection.

BACKGROUND: Preoperative localization is necessary for nonpalpable breast lesions. A novel procedure, fluoroscopic intraoperative neoplasm and node detection (FIND), obviates the preoperative painful and potentially expensive localization by using intraoperative visualization of the standard clip placed during diagnostic biopsy. We hypothesized FIND would improve negative margin rates. STUDY DESIGN: This is an IRB-approved retrospective study (September 2016 to March 2021). Electronic chart review identified breast and axillary node procedures using wire localization (WL) or FIND. Primary outcome was margin status. Secondary outcomes included re-excision rate, specimen weight, surgery time, and axillary node localization rate. RESULTS: We identified 459 patients, of whom 116 (25.3%) underwent FIND and 343 (74.7%) WL. Of these, 68.1% of FIND and 72.0% of WL procedures were for malignant lesions. Final margin positivity was 5.1% (4 of 79) for FIND and 16.6% (41 of 247) for WL (p = 0.008). This difference lost statistical significance on multivariable logistic regression (p = 0.652). Re-excision rates were 7.6% and 14.6% for FIND and WL (p = 0.125), with an equivalent mean specimen weight (p = 0.502), and mean surgery time of 177.5 ± 81.7 and 157.1 ± 66.8 minutes, respectively (mean ± SD; p = 0.022). FIND identified all (29 of 29) targeted axillary nodes, and WL identified only 80.1% (21 of 26) (p = 0.019). CONCLUSIONS: FIND has lower positive margin rates and a trend towards lower re-excision rates compared with WL, proving its value in localizing nonpalpable breast lesions. It also offers accurate localization of axillary nodes, valuable in the era of targeted axillary dissection. It is a method of visual localization, using a skill and equipment surgeons already have, and saves patients and medical systems an additional schedule-disruptive, painful procedure, especially valuable when using novel localization devices is cost-prohibitive.

Genotypic and phenotypic variability of 22q11.2 microdeletions - an institutional experience.

Patients with chromosome 22q11.2 deletion syndromes classically present with variable cardiac defects, parathyroid and thyroid gland hypoplasia, immunodeficiency and velopharyngeal insufficiency, developmental delay, intellectual disability, cognitive impairment, and psychiatric disorders. New technologies including chromosome microarray have identified smaller deletions in the 22q11.2 region. An increasing number of studies have reported patients presenting with various features harboring smaller 22q11.2 deletions, suggesting a need to better elucidate 22q11.2 deletions and their phenotypic contributions so that clinicians may better guide prognosis for families. We identified 16 pediatric patients at our institution harboring various 22q11.2 deletions detected by chromosomal microarray and report their clinical presentations. Findings include various neurodevelopmental delays with the most common one being attention deficit hyperactivity disorder (ADHD), one reported case of infant lethality, four cases of preterm birth, one case with dual diagnoses of 22q11.2 microdeletion and Down syndrome. We examined potential genotypic contributions of the deleted regions.