No abstract

Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. Since the clinical evolution from surgical orchiectomy, we have typically used ADT and orchiectomy to be synonymous terms for castration. The goal of this study is to determine if, in contemporary medical practice, surgical and chemical castration provide for similar levels of diminishment of total and free testosterone. Further, what approaches should be used to most accurately measure testosterone levels in men with advanced prostate cancer and what cutoff values, for example for total testosterone 50 ng dl −1 or 20 ng dl −1 , should be utilized. Studies available in the literature have been analyzed and compiled to address these questions. Finally, evidence is provided that free testosterone, the biologically active component, should be utilized to provide clinically relevant state of castration.

Angiotensin 1-7 (Ang 1-7) is a product of the renin-angiotensin system (RAS) that can reduce blood pressure and fibrosis. For more than a decade Mas has been viewed as the receptor for Ang 1-7, however, there are lingering doubts regarding the nature of the interaction between the heptapeptide and Mas. To date, no one has pharmacologically characterized Ang 1-7 binding in tissue membrane preparations. In this study we show that 125 I-Ang 1-7 binds to a site for which Ang 1-7 has low (μmolar) affinity, suggesting that the addition of an iodine molecule to the tyrosine in position 4 of Ang 1-7 drastically changes the characteristics of this peptide making it unsuitable for characterization of Ang 1-7 receptors. 125 I-Ang 1-7 binds with moderately high affinity (10-20 nM) and saturability to a binding site in rat liver membranes that is displaceable by 127 I-Ang 1-7 (iodoAng 1-7) at nanomolar concentrations. This binding is also displaceable by inhibitors of metalloproteases. To test the hypothesis that 125 I-Ang 1-7 binds to a peptidase, a series of peptidase inhibitors were evaluated for their ability to inhibit 125 I-Ang 1-7 binding. The non-selective matrix metalloprotease (MMP) and A Disintegrin And Metalloprotease (ADAM) inhibitors marimastat, batimastat, and GM-6001, which inhibit MMP1,2,3,7,8,13,14 and ADAM 9,17, partially inhibited 125 I-Ang 1-7 binding with nanomolar affinities, similar to their IC 50 values for MMPs, suggesting that 125 I-Ang 1-7 binds to MMPs and/or ADAMs as well as other tissue elements. Further testing with the specific MMP-2 (ARP100), MMP-9 and ADAM-17 inhibitors indicate that 125 I-Ang 1-7 is not binding to these peptidases. Continuing studies are underway to establish conditions under which the 125 I-Ang 1-7 ligand is not metabolized by peptidases, while retaining the ability to bind to peptidases is underway to enable the identification of the specific peptidase(s) or other binding moieties to which 125 I-Ang 1-7 binds to determine their potential therapeutic importance as a druggable targets.

Angiotensin 1–7 (Ang 1‐7) is a product of the renin‐angiotensin system (RAS) that exhibits central actions to reduce blood pressure and improve baroreflex sensitivity. For more than a decade Mas has been considered the receptor for Ang 1‐7, however, to date, no published studies have characterized Mas receptor radioligand binding in tissue membrane preparations. Our laboratory has demonstrated high affinity (low nanomolar KD) binding of a preparation of 125/127I‐Ang 1‐7 in liver membranes, however, this binding is not pharmacologically specific in that the IC50 of Ang 1‐7 is in the micromolar range and all angiotensin peptides compete for 125/127I‐Ang 1‐7 binding equivalently. 125/127I‐Ang 1‐7 binding to liver, kidney, brain and testes membrane preparations from both rats and mice has also failed to demonstrate a high affinity, pharmacologically specific binding site for 125/127I‐Ang 1‐7. Considering that rapid degradation of Ang 1‐7 could be adversely affecting the binding assay, we tested different peptidase inhibitors (JMV‐390, O‐phenanthroline and a proprietary combination of peptidase inhibitors Biotools®) to prevent degradation of the radioligand. Although we were able to reduce Ang 1‐7 degradation with these inhibitors (~80% preservation), we also reduced the total and specific binding of 125I‐Ang 1‐7. Indeed, competition binding assays for 125I‐Ang‐(1–7) with JMV‐390, O‐phenanthroline and Biotools® showed that 125I‐Ang‐(1–7) and all the inhibitors compete for the same binding site with JMV‐390 having a nanomolar IC50. It is important to note that the radioligand used for receptor binding studies contains an iodine125 on the tyrosine in position four of Ang 1‐7, and may have different characteristics for enzymatic metabolism. To assess this possibility, we determined the metabolism of 127I‐Ang 1‐7 (non‐radioactive iodine isotope) and indeed, the metabolism of Ang 1‐7 and 127I‐Ang 1‐7 in liver appear to differ, with 127I‐Ang 1‐7 being more resistant to metabolism. In addition, competition binding assays showed that 127I‐Ang 1‐7 is ~1000‐fold more potent than Ang 1‐7 in competing for 125I‐Ang 1‐7 binding. In conclusion, our results suggest that 125I‐Ang‐(1–7) may be binding to a peptidase rather than a receptor and the addition of the iodine molecule to the tyrosine in position four attenuates its degradation. Studies are underway to identify this peptidase and determine its potential therapeutic importance as a druggable target.Support or Funding InformationCardiovascular Neuroscience Research Fund 337667 Speth (PI) 03/31/15‐12/31/18 ‐ Nova Southeastern Univ.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

With the evolving nature of the business world, it has become a modern necessity to have a diverse workforce. As such, human resources professionals and managers must be prepared for the redesign of their organizations to be more inclusive throughout their formal hierarchies. Although the overall attitudes have become generally more feminist, the unfortunate reality is that women continue to face internal and external barriers which act as a ceiling to their career development and advancement. Rather than viewing the paucity of women in management positions as a problem because of public disdain towards gender disparities within the workplace, this paper emphasizes that organizations should view this as an opportunity to gain a competitive advantage, given that having more women in leadership positions is correlated to improved organizational performance. The main argument of this research is that gender diversity can lead to better outcomes for an organization; in addition to this, research demonstrates that the inclusion of more women within management positions may also encourage a transformational leadership style, which could potentially lead to sustainable growth for a company. Throughout this paper, using the methodology of reviewing recently published literature, this paper demonstrates the fact that the glass ceiling is detrimental to the economic development of both women and the companies as institutional barriers seem to persistently block them from equitable advancement opportunities. Using published data and expert analysis, we provide suggestions and recommendations for the creation of an inclusive work environment where all employees can have fair and transparent progress based on their goals and qualifications. The “glass ceiling” literature has empirically demonstrated that managers can reduce the negative gender-based stereotypes by empowering more qualified women to take on leadership responsibilities. At the meantime, professionals can serve as advocates in their local governments to create and change laws that are unfair and unjust. All local leaders, managers and employees must promote the benefits of diversity to build and encourage inclusion in the workplace. Furthermore, all organizations can improve their inclusion training so their employees can keep an open mind regarding diversity. With the application of the recommended skills and suggestions, coupled along with public awareness and advocacy for equity in hiring and promotion decisions, the “glass ceiling” can certainly be eliminated in all organizational settings. Keywords: glass ceiling, discrimination, wage gap, inclusion, gender equality, mentoring, and career development.