Breast cancer: Current and future endocrine therapies

Endocrine therapy forms a central modality in the treatment of estrogen receptor positive breast cancer. The routine use of 5 years of adjuvant tamoxifen has improved survival rates for early breast cancer, and more recently has evolved in the postmenopausal setting to include aromatase inhibitors. The optimal duration of adjuvant endocrine therapy remains an active area of clinical study with recent data supporting 10 years rather than 5 years of adjuvant tamoxifen. However, endocrine therapy is limited by the development of resistance, this can occur by a number of possible mechanisms and numerous studies have been performed which combine endocrine therapy with agents that modulate these mechanisms with the aim of preventing or delaying the emergence of resistance. Recent trial data regarding the combination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus with endocrine therapy have resulted in a redefinition of the clinical treatment pathway in the metastatic setting. This review details the current endocrine therapy utilized in both early and advanced disease, as well as exploring potential new targets which modulate pathways of resistance, as well as agents which aim to modulate adrenal derived steroidogenic hormones.     

Beta cyclodextrins bind,stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

Accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there are no approved treatments for these diseases; hence, agents that efficiently remove LBs from RPE would be valuable therapeutic candidates. Here, we show that beta cyclodextrins (β-CDs) bind LBs and protect them against oxidation. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of LBs within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from Abca4-Rdh8 double knock-out (DKO) mice, respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of DKO animals. Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs.The retinal pigment epithelium (RPE), strategically situated between the neural retina and the choroid blood vessels, is essential for photoreceptor (PR) function. It recycles vitamin A, which is required for the visual cycle and clears debris generated by the circadian shedding of PR outer segments (1, 2). Each RPE cell phagocytoses and digests the material produced by 30–50 overlying PRs, which shed 10% of their mass daily. The intense and continual phagocytic activity of RPE cells results in the progressive accumulation of indigestible products or “lipofuscin” in their lysosomal compartment (3, 4). Unlike lipofuscins found in other body tissues, which are composed mainly of protein, RPE lipofuscin consists predominantly of lipid-bisretinoids and only 2% protein (5). Lipofuscin bisretinoids (LBs) are vitamin A-derived side products of the visual cycle. Light converts 11-cis-retinal (11CR), the visual pigment chromophore, into all-trans-retinal (ATR), which is immediately flipped by the ATP-binding cassette transporter 4 (Abca4) transporter from the lumen of the outer segment discs to the cytoplasm, where it is reduced to inert all-trans-retinol by retinol dehydrogenase 8 (Rdh8), in mice (6, 7). Small fractions of 11CR and ATR are converted into N-retinylidine-N-ethanolamine (A2E) and other less abundant bisretinoids, which once accumulated in the lysosomes of RPE cells are refractory to all known lysosomal hydrolases (8, 9). The concept that LB accumulation causes retinal degeneration is supported by in vitro and in vivo data that show that excessive LBs are toxic for cultured RPE cells (10, 11), that photoreceptors overlying A2E-laden RPE are more prone to degeneration (12) and that excessive accumulation of LBs in Stargardt’s disease precedes macular degeneration (13). Mice carrying null mutations in Abca4 and Rdh8 develop blindness, basal laminar deposits, and focal accumulations of extracellular debris between the RPE and the Bruch membrane (drusen) (6).Here we report that a family of modified cyclic oligosaccharides, beta cyclodextrins (β-CDs), formed by seven d-glucose units, can encapsulate the hydrophobic arms of A2E within their nonpolar cavity, protect A2E from oxidation, and remove A2E from RPE cells. Our data demonstrate a direct correlation between the ability of β-CDs to perform these protective functions and their affinity for A2E.     

Motive attribution asymmetry for love vs. hate drives intractable conflict

Five studies across cultures involving 661 American Democrats and Republicans, 995 Israelis, and 1,266 Palestinians provide previously unidentified evidence of a fundamental bias, what we term the “motive attribution asymmetry,” driving seemingly intractable human conflict. These studies show that in political and ethnoreligious intergroup conflict, adversaries tend to attribute their own group’s aggression to ingroup love more than outgroup hate and to attribute their outgroup’s aggression to outgroup hate more than ingroup love. Study 1 demonstrates that American Democrats and Republicans attribute their own party’s involvement in conflict to ingroup love more than outgroup hate but attribute the opposing party’s involvement to outgroup hate more than ingroup love. Studies 2 and 3 demonstrate this biased attributional pattern for Israelis and Palestinians evaluating their own group and the opposing group’s involvement in the current regional conflict. Study 4 demonstrates in an Israeli population that this bias increases beliefs and intentions associated with conflict intractability toward Palestinians. Finally, study 5 demonstrates, in the context of American political conflict, that offering Democrats and Republicans financial incentives for accuracy in evaluating the opposing party can mitigate this bias and its consequences. Although people find it difficult to explain their adversaries’ actions in terms of love and affiliation, we suggest that recognizing this attributional bias and how to reduce it can contribute to reducing human conflict on a global scale.Many human conflicts appear extraordinarily difficult to resolve even when outsiders can see the contours of a rational resolution. Ideological opponents risk the health of their economies and their planet because they are unable to make political compromises. Ethnic and religious groups across the world engage in mass acts of violence, rejecting solutions of mutual benefit that involve sharing power, land, or religious sites. Why are so many conflicts so intractable when people on both sides could gain from a compromise?Approaches to this question typically center on the complexity and profundity of the issues involved and each side’s construal of the conflict (1, 2). An additional, deeper barrier to conflict resolution may be simple pessimism toward compromise. If adversaries believe inflexibility on the other side renders mutual compromise impossible, they will be unlikely to adopt seemingly rational strategies for conciliation (3). In other words, the perception of conflict intractability may be an independent cause of a stalemate. Here, we identify a fundamental cognitive bias that contributes to the belief in conflict intractability, and may therefore contribute to conflict spirals (4–6).We predict and observe that people often attribute their outgroup’s actions during conflict to hatred. This attribution occurs despite evidence that intergroup aggression stems at least as much, if not more, from ingroup love (7–13). We hypothesized that whereas people can clearly identify ingroup love as the source of their own group’s engagement in conflict (14), when attempting to explain their outgroup’s actions, people focus on dislike (15) and “why they hate us” (16). Expanding on prior research, we propose a previously untested hypothesis: People will attribute ingroup engagement in conflict to love more than hate, but they will attribute outgroup engagement in conflict to hate more than love. We term this pattern the “motive attribution asymmetry” and document this bias across five studies among American Democrats and Republicans as well as Palestinians and Israelis, demonstrating consequences of this bias that further fuel intergroup conflict. We use the term “bias” to mean response tendency (rather than error); in this case, a tendency to attribute love vs. hate to one’s ingroup to a greater degree than to one’s outgroup and to attribute hate vs. love to one’s outgroup to a greater degree than to one’s ingroup.These studies provide a number of contributions:

• i)This research offers an account of why people fail to recognize or implement the solutions that research on conflict resolution has established to be effective.
• ii)This research examines specific attributions of love vs. hate rather than dispositional vs. situational attributions more broadly.
• iii)This research compares these attributions toward one’s outgroup with the outgroup’s attributions toward itself.
• iv)The studies themselves contain numerous previously unexamined features, investigating this phenomenon in diverse linguistic and political contexts, examining different types of real intergroup conflicts (one intensely ideological yet predominantly nonviolent and the other ethnoreligious and chronically violent), characterizing previously unexamined consequences of this attributional bias, and establishing a manipulation aimed at mitigating this bias and its effects.
• v)This research reveals the disconnect between the motives pertaining to love and hate that actually appear to drive intergroup conflict (7–13) and people’s own intuitive assessment of these motives.