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Raloxifene agonism of estrogen receptor (ER) in post-menopausal endometrium is not negligible. Based on a rational drug design workflow, we synthesized 14 analogues of raloxifene bearing a polar group in the aromatic ring of the basic side chain (BSC) and/or changes in the bulkiness of the BSC amino group. Analogues with a polar BSC aromatic ring and amino group substituents of increasing volume displayed increasing ER antagonism in Ishikawa cells. Analogues with cyclohexylaminoethoxy (13a) or adamantylaminoethoxy BSC (13b) lacking a polar aromatic ring displayed high ER-binding affinity and ER antagonism in Ishikawa cells higher than raloxifene and similar to fulvestrant (ICI182,780). The endometrial surface epithelium of immature female CD1 mice injected with 13b was comparable to that of vehicle-treated mice, while that of mice treated with estradiol, raloxifene or 13b in combination with estradiol was hyperplastic. These findings indicate that raloxifene analogues with a bulky BSC amino group could provide for higher endometrial safety treatment of the menopausal syndrome. © 2020 Elsevier Inc.

Preclinical evidence has been accumulating on the impact of the DNA repair status on the sensitivity/resistance to anticancer agents in different tumor types, including lung cancer. The possibility to predict the response to therapy, and specifically to platinum agents, based on tumor specific DNA repair functionality would enable to tailor its use only in those patients with maximum chances to respond, avoiding the burden of toxicity in those ones with lesser chances. We here reviewed the clinical evidence on the prognostic role of DNA repair markers and/or functional assays in predicting the response to a platinum-based chemotherapy in lung cancer patients. Consequently, we focused on those proteins involved in pathways repairing platinum induced DNA inter-strand and intra-strand crosslinks. Most promising clinical trials targeting the nucleotide repair protein ERCC1 in non-small cell lung cancer later on suffered from serious drawbacks. Nevertheless, these results spurred a variety of preclinical studies on a multitude of alternative DNA repair markers. However so far, no one of the analyzed DNA repair markers can be considered a reliable and mature biomarker for selecting patients. We discuss the reasons for such failure which discloses novel strategies for the future. © 2016 Elsevier Ltd.

This article discusses the possible uses of a digital library by people with various kinds of disability, such as visual or motor disabilities. The subject has not yet been sufficiently explored, especially using a situated action model that takes account of the specific circumstances of each person. We have approached the subject through a series of case studies. The cases are related using a short story format, without avoiding complications, and cross-referenced with fragments of accounts taken from numerous examples. This analysis allows the gradual extraction of phenomena of a more general nature which provide insights for the design of digital books, helping both to identify obstacles in the incorporation of external resources and to pinpoint internal resources developed by the persons. One idea that emerges is the importance of developing open technical systems capable of accommodating various situations and disabilities so that a more user-friendly approach to design can be taken. The conclusion, made from a more theoretical viewpoint, looks at the concept of “empowerment” (pouvoir d’agir) and the resources employed by readers in an attempt to regain it.