The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer

Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off >= 10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95% CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95% CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95% CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95% CI: 1.1-6.7), and cyclin A (HR=2.7, 95% CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found

Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice[S]

To investigate the effects of abolished cholic acid (CA) synthesis in the ApoE knockout model [apolipoprotein E (apoE) KO],a double-knockout (DKO) mouse model was created by crossbreeding Cyp8b1 knockout mice (Cyp8b1 KO), unable to synthesize the primary bile acid CA, with apoE KO mice. After 5 months of cholesterol feeding, the development of atherosclerotic plaques in the proximal aorta was 50% less in the DKO mice compared with the apoE KO mice. This effect was associated with reduced intestinal cholesterol absorption, decreased levels of apoB-containing lipoproteins in the plasma, enhanced bile acid synthesis, reduced hepatic cholesteryl esters, and decreased hepatic activity of ACAT2. The upregulation of Cyp7a1 in DKO mice seemed primarily caused by reduced expression of the intestinal peptide FGF15. Treatment of DKO mice with the farnesoid X receptor (FXR) agonist GW4064 did not alter the intestinal cholesterol absorption, suggesting that the action of CA in this process is confined mainly to formation of intraluminal micelles and less to its ability to activate the nuclear receptor FXR. Inhibition of CA synthesis may offer a therapeutic strategy for the treatment of hyperlipidemic conditions that lead to atherosclerosis

A novel neurodevelopmental syndrome caused by loss-of-function of the Zinc Finger Homeobox 3 gene (ZFHX3)

Intellectual disability (ID) is a very heterogeneous disorder, and hitherto, over 1000 genes have been described to be involved in the etiology of ID. Here, we report on 28 patients with ID and congenital anomalies, and a deletion or protein truncating variant in the ZFHX3 gene. Through a large international collaboration, phenotypical details of all patients were gathered, and the most consistent phenotype of ZFHX3 aberrations has herein been determined by ID, postnatal growth retardation, feeding difficulties and recognizable facial characteristics. ZFHX3 belongs to the family of zinc-finger homeodomain transcription factors and encodes the ATBF1 protein playing a role in multiple biological processes including tumorigenesis and cell differentiation. It has been previously linked to neural differentiation and shows high expression in the developing human brain, but hitherto has never been linked to intellectual disability. Publicly available and our own data confirm increased expression of ZFHX3 during neural differentiation. Using IP-MS, we identified ZFHX3 interactors belonging to the chromatin remodeling mSWI/SNF complex (BAF complex) and the cleavage and polyadenylation complex (CPC). Further research aims to determine the localization of ZFHX3 in the cell during neural differentiation and to identify the precise role and targets of ZFHX3 in chromatin remodeling and gene transcription. In conclusion our study identified ZFHX3 as a novel gene underlying syndromal ID and revealed novel targets in neuronal differentiation and functioning