Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia.

Myeloproliferative neoplasms (MPNs) feature a malignant clone containing the JAK2 V617F mutation, or another mutation causing dysregulated JAK2 kinase activity. The multiple disease phenotypes of MPNs, and their tendency to transform phenotypically, suggest pathophysiologic heterogeneities beyond a common phenomenon of JAK2 hyperactivation. JAK2 has the potential to activate multiple other signaling molecules, either directly through downstream effectors, or indirectly through induction of target gene expression. We have interrogated myeloproliferative signaling in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) patient samples using mass cytometry, which allows the quantitative measurement of multiple signaling molecules simultaneously at the single-cell level, in cell populations representing a nearly complete spectrum of hematopoiesis. MF and sAML malignant cells demonstrated a high prevalence of hyperactivation of the JAK-STAT, MAP kinase, PI3 kinase and NFκB signaling pathways. Constitutive NFκB signaling was evident across MF and sAML patients. A supporting gene set enrichment analysis (GSEA) of MF showed many NFκB target genes to be expressed above normal levels in MF patient CD34+ cells. NFκB inhibition suppressed colony formation from MF CD34+ cells. This study indicates that NFκB signaling contributes to human myeloproliferative disease and is abnormally activated in MF and sAML.

Facial changes in extraction and nonextraction patients.

The purpose of this study was to determine if there are any differences in the posttreatment faces of patients treated nonextraction and those treated with premolar extraction in properly diagnosed and treated cases. The study was conducted in two parts. In Part 1, perceptions of 192 experienced general dentists and orthodontists were tested. Facial photos of 25 consecutively treated nonextraction patients and 25 consecutively treated four-premolar-extraction patients were shown to the study participants. They were asked if the patient was treated with the extraction of four premolars or without extractions. The mean score of the respondents was 54%, only slightly better than pure chance. In Part 2, profiles were evaluated based on cephalometric tracings. There was no significant difference between pretreatment and posttreatment profiles of the groups. The mean H-line values for both groups were within the desired esthetic range. It was concluded that experienced orthodontists and general dentists could not determine whether treatment was nonextraction or extraction by looking at the face alone. Also, there was no significant difference between the faces produced by the two types of treatments. Therefore, the avoidance of extracting premolars based on a fear of a significant detrimental effect on the face is unjustified when the case has been properly diagnosed and treated.