Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Book Review: Faserwerkstatt by Doris Fischer

As the title implies, Faser Werkstatt: Traditionelle Textiltechnik mit natürlichen Materialien is a direct and practical book on the historical creation and use of fibers. It is aimed at a casual reader with little to no knowledge or experience with the fiber arts, with detailed instructions on creating and using threads and ropes made from natural fibers

Harvard Sexual Harassment Survey, 1983

This survey was conducted to determine the extent to which sexual harassment is a widespread problem at Harvard University. Due to the nature of sexual harassment, an anonymous survey was used to determine the prevalence of harassment at Harvard instead of analyzing reported cases. Questionnaires were completed by 322 male and 349 female graduate students, 720 female and 710 male undergraduates, and 432 male (75%) and 72 female (98%) members of the Faculty of Arts and Sciences. The students' names were selected randomly from registrar's lists. The questionnaires addressed attitudes toward and definitions of sexual harassment, general experiences of sexual harassment, experiences of harassment involving authority figures, experiences involving peers, experiences as the accused in a sexual harassment situation, and potential remedies. Both open-ended and precoded questions were included. The measure is similar to the one used in the Federal Sexual Harassment Survey by the U.S. Merit Systems Protection Board (00661), also archived at the Murray Research Archive. The Murray Research Archive holds numeric file data, and transcribed copies of the written responses to the open-ended questions

Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas

Oncogenic Notch1 mutations are found in most T-lineage acute lymphoblastic leukemias in humans and T-cell lymphomas in mice. However, the mechanism by which Notch1 promotes transformation or maintains malignant cell survival has not been determined fully. Here, we report that expression of the transcription factor lymphoid enhancer factor 1 (Lef1) is Notch dependent in murine T-cell lymphomas in vitro and in vivo, and that the intracellular domain of Notch1 (ICN1) is present at the Lef1 promoter. Lef1 expression is not Notch dependent in primary T-cell progenitors, but Lef1 mRNA is increased by ectopic expression of ICN1 in these cells. We show that Lef1 is required for survival of T-cell lymphoma lines, and that ectopic expression of Lef1 delays lymphoma cell death in the absence of Notch signaling, indicating that Lef1 is an important Notch target in these cells. Therefore, Notch1 co-opts Lef1 during the process of transformation to maintain survival of T-cell lymphomas

Notch1 promotes survival of E2A-deficient T cell lymphomas through pre–T cell receptor–dependent and –independent mechanisms

Loss of E2A transcription factor activity or activation of the intracellular form of Notch1 (ICN) leads to the development of leukemia or lymphoma in humans or mice, respectively. Current models propose that ICN functions by suppressing E2A through a pre–T cell receptor (TCR)–dependent mechanism. Here we show that lymphomas arising in E2A–/– mice require the activation of Notch1 for their survival and have accumulated mutations in, or near, the Notch1 PEST domain, resulting in increased stability and signaling. In contrast, lymphomas arising in p53–/– mice show the activation of Notch1, but no mutations were identified in ICN. The requirement for Notch1 signaling in E2A–/– lymphomas cannot be overcome by ectopic expression of pTα; however, pTα is required for optimal survival and expansion of these cells. Our findings indicate that the activation of Notch1 is an important “second hit” for the transformation of E2A–/– T cell lymphomas and that Notch1 promotes survival through pre–TCR-dependent and -independent mechanisms