Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit?

The link between estrogen and the development and proliferation of breast cancer is well documented. Estrogen stimulates growth and inhibits apoptosis through estrogen receptor-mediated mechanisms in many cell types. Interestingly, there is strong evidence that estrogen induces apoptosis in breast cancer and other cell types. Forty years ago, before the development of tamoxifen, high-dose estrogen was used to induce tumor regression of hormone-dependent breast cancer in post-menopausal women. While the mechanisms by which estrogen induces apoptosis were not completely known, recent evidence from our laboratory and others demonstrates the involvement of the extrinsic (Fas/FasL) and the intrinsic (mitochondria) pathways in this process. We discuss the different apoptotic signaling pathways involved in E2 (17β-estradiol)-induced apoptosis, including the intrinsic and extrinsic apoptosis pathways, the NF-κB (nuclear factor-kappa-B)-mediated survival pathway as well as the PI3K (phosphoinositide 3-kinase)/Akt signaling pathway. Breast cancer cells can also be sensitized to estrogen-induced apoptosis through suppression of glutathione by BSO (L-buthionine sulfoximine). This finding has implications for the control of breast cancer with low-dose estrogen and other targeted therapeutic drugs

Awareness and perceived risk of cardiovascular disease among individuals living with rheumatoid arthritis is low: results of a systematic literature review

Abstract Background Individuals with rheumatoid arthritis (RA) are at risk of developing cardiovascular disease (CVD), but patient perceptions of CVD are not routinely assessed. We performed a systematic literature review to evaluate awareness of the association between RA and CVD, and perceived risk of CVD among individuals with RA. Methods Three electronic databases (MEDLINE, EMBASE, and PubMed) were searched for English language articles between the years of 1990–2018. Search terms pertained to RA, CVD, knowledge, awareness, or perceptions of CVD risk. Abstracts were screened for inclusion/exclusion by two independent reviewers. Results A total of 33 abstracts were screened and 6 underwent full review. The overall sample size was 478 subjects and included patients with established RA who were predominantly female with a mean age range of 53 to 64 years. RA disease characteristics relevant to CVD were not uniformly reported, including the use of DMARDs, corticosteroids, or NSAIDs. A high proportion of subjects (range 73 to 97%) were unaware of an increased risk of developing CVD in relation to their RA, and this frequently occurred in those with a greater number of traditional CVD risk factors. Misperceptions about CVD were common, and the majority of subjects misestimated their actual CVD risk. Conclusion Individuals with RA at highest risk for CVD report low awareness and perceived risk of this comorbidity. This represents a knowledge gap in need of intervention but must be tailored to patients’ needs. An understanding of the system- and individual-level barriers preventing CVD awareness is needed. Only then will approaches to improve CVD screening and management in RA be successful

The spontaneous location recognition task for assessing spatial pattern separation and memory across a delay in rats and mice

Keeping similar memories distinct from one another is a critical cognitive process without which we would have difficulty functioning in everyday life. Memories are thought to be kept distinct through the computational mechanism of pattern separation, which reduces overlap between similar input patterns to amplify differences among stored representations. At the behavioral level, impaired pattern separation has been shown to contribute to memory deficits seen in neuropsychiatric and neurodegenerative diseases, including Alzheimer’s disease, and in normal aging. This protocol describes the use of the spontaneous location recognition (SLR) task in mice and rats to behaviorally assess spatial pattern separation ability. This two-phase spontaneous memory task assesses the extent to which animals can discriminate and remember object locations presented during the encoding phase. Using three configurations of the task, the similarity of the to-be-remembered locations can be parametrically manipulated by altering the spatial positions of objects—dissimilar, similar or extra similar—to vary the load on pattern separation. Unlike other pattern separation tasks, SLR varies the load on pattern separation during encoding, when pattern separation is thought to occur. Furthermore, SLR can be used in standard rodent behavioral facilities with basic expertise in rodent handling. The entire protocol takes ~20 d from habituation to testing of the animals on all three task configurations. By incorporating breaks between testing, and varying the objects used as landmarks, animals can be tested repeatedly, increasing experimental power by allowing for within-subjects manipulations