Wedelolactone inhibits human cytomegalovirus replication by targeting distinct steps of the viral replication cycle.

Wedelolactone (WDL) is a coumestan present in the plants Eclipta prostrata and Wedelia calendulacea which are used for treatment of a multitude of health problems in traditional medicine. It has previously been shown that WDL exerts antiviral activity against human immunodeficiency virus and hepatitis C virus. In this study, we investigated the effect of WDL on lytic human cytomegalovirus (HCMV) infection. We demonstrate a strong interference with HCMV replication as analyzed in multi-round replication settings. A more detailed analysis of the underlying mechanisms revealed that WDL acts at two distinct steps of the viral replication cycle. During immediate early (IE) times, we observe an inhibition of IE1/IE2 expression. Although WDL was reported to interfere with NF-κB signaling our results suggest the existence of additional mechanisms that impede viral IE expression. During later time points of infection, WDL induced a disruption of the interaction between EZH2 and EED, components of the virus-supportive polycomb repressive complex 2 (PRC2). Thereby, the stability of the PRC2 complex as well as the related complex PRC1 was disturbed leading to diminished viral DNA synthesis. Taken together, we identify WDL as a potent agent against HCMV which interferes at two distinct steps of viral replication.

Clinical implications of growth pattern and extension of tumor-associated intraductal carcinoma of the breast.

UNLABELLED: Tumor specimens from 410 patients with primary invasive breast cancer were investigated to identify the clinically relevant features of tumor-associated intraductal component (IDC) surrounding invasive breast cancer. A tumor-associated IDC associated with invasive tumor was mostly localized between the tumor and nipple. Thus, segmental resection of breast tissue is suggested. INTRODUCTION: The goal of the present study was to identify the clinically relevant features of tumor-associated intraductal component (IDC) surrounding invasive breast cancer. PATIENTS AND METHODS: The tumor specimens from 410 patients with primary invasive breast cancer were investigated. The distance between the surgical margins and tumor edge (invasive and intraductal areas) was measured prospectively. RESULTS: Of the 410 investigated patients, 395 were eligible for analysis. An IDC was observed in 241 specimens (61.0%) and was associated with a younger age at diagnosis, postmenopausal status, and positive estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2) expression status. Most cases with tumor-associated ductal carcinoma in situ (DCIS) were found in the upper-outer quadrants of the breasts. An extended intraductal component (EIC) tended to be present in the outer and lower quadrants of the breasts. In the study cohort of 187 patients with tumor-associated DCIS, 1496 surgical margins were investigated. IDC was associated with invasive tumor growth predominantly in the nipple direction. The nipple-associated growth of DCIS correlated with patient age > 40 years, tumor size ≤ 2 cm, poor histologic differentiation of the noninvasive and invasive components, and positive estrogen and progesterone receptor status and negative HER2 status. CONCLUSIONS: Our data provide evidence that in patients with primary breast cancer, the EIC areas will be mostly segmentally localized between the invasive tumor and the nipple. Therefore, if EIC is present or assumed, surgery should consist of segmental resection of the breast tissue, at least in patients with breast cancer who are > 40 years old, with a tumor size of < 2 cm, and with hormone receptor-positive and HER2-negative, poorly differentiated tumors.