Ariel - Volume 10 Number 1

Executive Editors Madalyn Schaefgen David Reich Business Manager David Reich News Editors Medical College Edward Zurad CAHS John Guardiani World Mark Zwanger Features Editors Meg Trexler Jim O\u27Brien Editorials Editor Jeffrey Banyas Photography and Sports Editor Stuart Singer Commons Editor Brenda Peterso

Interim heterogeneity changes measured using entropy texture features on T2- weighted MRI at 3.0 T predict pathological response to neoadjuvant chemotherapy in primary breast cancer

Objectives: This study investigated whether interim changes in hetereogeneity (measured using entropy features) on magnetic resonance images (MRI) were associated with pathological residual cancer burden (RCB) at final surgery in patients receiving neoadjuvant chemotherapy (NAC) for primary breast cancer.Methods: Institutional review board approval was waived for this retrospective study of 88 consenting women (age:30-79). Scanning was performed on a 3.0T MRI scanner prior to NAC (baseline) and after 2-3 cycles of treatment (interim). Entropy was derived from the grey-level co-occurrence matrix, on slice-matched baseline/interim T2- weighted images. Response, assessed using RCB score on surgically resected specimens, was compared statistically with entropy/heterogeneity changes and ROC analysis performed. Prediction of pCR within each tumour immunophenotype was evaluated.Results: Mean entropy percent differences between examinations, by response category, were: pCR:32.8%, RCB-I:10.5%, RCB-II:9.7% and RCB-III:3.0%. Prediction of ultimate pCR from coarse entropy changes between baseline/interim MRI across all lesions yielded 85.2% accuracy (area under ROC curve:0.845). Excellent sensitivity/specificity was obtained for pCR prediction within each immunophenotype: ER+: 100%/100%; HER2+: 83.3%/95.7%, TNBC: 87.5%/80.0%.Conclusions: Lesion T2 heterogeneity changes are associated with response to NAC using RCB scores, particularly for pCR, and can be useful in prediction across all immunophenotypes with good diagnostic accuracy

Abstract 424: Hyper-Inflammatory Macrophages in Coronary Artery Disease and Rheumatoid Arthritis; A Signature of CCL18, Krüppel-like Factor 2 and 4 and Oxidative Stress Response Genes

Background: Autoimmune disease is an independent risk factor for accelerated coronary artery disease (CAD). Patients with rheumatoid arthritis (RA) have a 2-fold increased risk for CAD, comparable to the impact of diabetes mellitus. Abnormalities in the immune system contribute to both RA and CAD pathogenesis and defining these might elucidate disease mechanisms. We studied inflammatory macrophages in RA and CAD to identify shared and disease-specific molecular pathways. Methods: Patients with CAD and a history of myocardial infarction, patients with RA who satisfied the 2010 RA Classification Criteria and age-matched controls were enrolled. Monocytes isolated from peripheral blood were differentiated into macrophages and further polarized into M1 or M2 with IFNγ and lipopolysaccharide or IL-4 and IL-13, respectively. The expression of 55 genes was measured by quantitative PCR. Intracellular reactive oxygen species (ROS) were quantified using CellROX and the oxidant superoxide was scavenged using the SOD mimetic Tempol. Results: Both CAD and RA macrophages exhibited a gene expression signature of excess inflammatory activity when compared to controls. Besides the upregulation of cytokine genes, the hyper-inflammatory signature included the loss of the inflammatory suppressors Krüppel-like factor (KLF)-2 and KLF-4, and the gain of the chemokine CCL18 and the oxidative stress response gene, NAD(P)H:quinone oxidoreductase 1 (NQO1). Quantification of intracellular ROS confirmed increased oxidative stress in the patient-derived macrophages. To examine whether superoxide affects production of CCL18, cells were treated with Tempol. ROS depletion normalized the excess production of CCL18. Conclusion: Pro-inflammatory macrophages in RA and CAD share molecular abnormalities characterized by excessive cytokines and chemokine production, the loss of negative regulators and the gain of oxidative stress responses. Unbalanced ROS production is upstream of abnormal chemokine production and correcting redox balance in macrophages may be helpful in suppressing the hyper-inflammatory phenotype of these cells in CAD and in the CAD-prone autoimmune disease RA. </jats:p

Serotonin and psilocybin activate 5-HT1B receptors to suppress cortical signaling through the claustrum

Abstract Through its widespread reciprocal connections with the cerebral cortex, the claustrum is implicated in sleep and waking cortical network states. Yet, basic knowledge of neuromodulation in this structure is lacking. The claustrum is richly innervated by serotonergic fibers, expresses serotonin receptors, and is suggested to play a role in the ability of psilocybin, which is metabolized to the non-specific serotonin receptor agonist psilocin, to disrupt cortex-wide network states. We therefore addressed the possible role of serotonin, and the classic psychedelic psilocybin, in modulating cortical signaling through the claustrum. We show that serotonin activates 5-HT1B receptors on anterior cingulate cortex inputs – a primary driver of claustrum activity – to suppress signaling to parietal association cortex-projecting claustrum neurons. Additionally, we demonstrate that psilocybin injection also activates anterior cingulate cortex presynaptic 5-HT1B receptors to suppress cortical signaling through the claustrum. Thus, serotonin, via 5-HT1B, may provide gain-control of cortical input to the claustrum, a mechanism that may be directly targeted by psilocybin to modulate downstream cortical network states