No abstract

The nervous system of the bowel regulates the inflammatory phenotype of tissue resident muscularis macrophages (MM), and in adult mice, enteric neurons are the main local source of colony stimulating factor 1 (CSF1), a protein required for MM survival. Surprisingly, we find that during development MM colonize the bowel before enteric neurons. This calls into question the requirement for neuron-derived CSF1 for MM colonization of the bowel. To determine if intestinal innervation is required for MM development, we analyzed MM of neonatal ( KO) mice that have no enteric nervous system in small bowel or colon. We found normal numbers of well-patterned MM in KO bowel. Similarly, the abundance and distribution of MM in aganglionic human colon obtained from Hirschsprung disease patients was normal. We also identify endothelial cells and interstitial cells of Cajal as the main sources of in the developing bowel. Additionally, MM from neonatal KOs do not differ from controls in baseline activation status or cytokine-production in response to lipopolysaccharide. Unexpectedly, these data demonstrate that the enteric nervous system is dispensable for MM colonization and patterning in the bowel, and suggest that modulatory interactions between MM and the bowel nervous system are established postnatally.

Transcription factors that coordinate migration, differentiation or proliferation of enteric nervous system (ENS) precursors are not well defined. To identify novel transcriptional regulators of ENS development, we performed microarray analysis at embryonic day (E) 17.5 and identified many genes that were enriched in the ENS compared to other bowel cells. We decided to investigate the T-box transcription factor Tbx3, which is prominently expressed in developing and mature ENS. Haploinsufficiency for TBX3 causes ulnar-mammary syndrome (UMS) in humans, a multi-organ system disorder. TBX3 also regulates several genes known to be important for ENS development. To test the hypothesis that Tbx3 is important for ENS development or function, we inactivated Tbx3 in all neural crest derivatives, including ENS progenitors using Wnt1-Cre and a floxed Tbx3 allele. Tbx3 fl/fl; Wnt1-Cre conditional mutant mice die shortly after birth with cleft palate and difficulty feeding. The ENS of mutants was well-organized with a normal density of enteric neurons and nerve fiber bundles, but small bowel glial cell density was reduced. Despite this, bowel motility appeared normal. Furthermore, although Tbx3 is expressed cardiac neural crest, Tbx3 fl/fl; Wnt1-Cre mice had structurally normal hearts. Thus, loss of Tbx3 within neural crest has selective effects on Tbx3-expressing neural crest derivatives.

<b><i>Introduction:</i></b> Fine-needle aspiration (FNA) is a well-established method for sampling breast lesions with high accuracy and positive predictive value. Despite its decline in recent years relative to the use of core needle biopsies, there are several advantages to FNA which include cost-effectiveness, low complication rate, and the ability to perform rapid on-site evaluation (ROSE). The aim of this study was to evaluate breast FNAs with ROSE to identify diagnostic challenges during ROSE. <b><i>Materials and Methods:</i></b> We identified all breast FNAs with ROSE performed at Massachusetts General Hospital from January 2014 to December 2019. From the electronic medical record, clinical, radiological, and follow-up pathology results were recorded. Comparison between the rapid and final cytological diagnosis was made. All discrepancies were documented with major discrepancy defined as a malignant rapid interpretation not confirmed on final diagnosis or a negative rapid interpretation upgraded to suspicious or positive on final diagnosis. <b><i>Results:</i></b> The study cohort consisted of 483 breast FNAs with ROSE. The rapid and final cytological interpretations showed good correlation, with only 6 (1.2%) major discrepancies. Problematic areas included low-grade, lobular, and fibroepithelial lesions with low cellularity being a contributory factor to misclassification. <b><i>Conclusions:</i></b> FNA remains a highly accurate method for the evaluation of breast lesions with ROSE.