Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated.

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor-beta (ERbeta) in BPH and PCa. ERbeta agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFalpha knock-out mice fail to respond to ERbeta agonist, demonstrating the requirement for TNFalpha signaling. In human tissues, ERbeta agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133(+) enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERbeta causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERbeta agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERbeta agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

Disparities In Diabetes-Related Lower Extremity Amputations In The United States: A Systematic Review.

Disparities in rates of peripheral diabetic neuropathy and lower extremity amputation exist in the United States. To investigate the factors linked to this disparity, we performed a systematic review of the literature on the subject published during the period 2000-20. Nineteen observational studies were included. Disparities in rates of lower extremity amputation were reported according to patient race, ethnicity, sex, and age; across hospital referral regions, residential area characteristics, and income estimates; and on the basis of payer type and hospital characteristics. Several of these factors were interrelated. There was a reduction in major lower extremity amputation rates among Black, Hispanic, and White patients with diabetes over time, suggesting narrowing disparities in the odds of this procedure among Black and White patients. There is a need for a national strategy that integrates public awareness, screening, early initiated multidisciplinary care, and quality measures for peripheral artery disease management, as well as neighborhood-level public health interventions, to reduce the disproportionate burden of lower extremity amputation in underserved communities.

Primary culture and propagation of human prostate epithelial cells.

Basic and translational (or preclinical) prostate cancer research has traditionally been conducted with a limited repertoire of immortalized cell lines, which have homogeneous phenotypes and have adapted to long-term tissue culture. Primary cell culture provides a model system that allows a broader spectrum of cell types from a greater number of patients to be studied, in the absence of artificially induced genetic mutations. Nevertheless, primary prostate epithelial cell culture can be technically challenging, even for laboratories experienced in immortalized cell culture. Therefore, we provide methods to isolate and culture primary epithelial cells directly from human prostate tissue. Initially, we describe the isolation of bulk epithelial cells from benign or tumor tissues. These cells have a predominantly basal/intermediate phenotype and co-express cytokeratin 8/18 and high molecular weight cytokeratins. Since prostatic stem cells play a major role in disease progression and are considered to be a therapeutic target, we also describe a prospective approach to specifically isolate prostatic basal cells that include both stem and transit-amplifying basal populations, which can be studied independently or subsequently differentiated to supply luminal cells. This approach allows the study of stem cells for the development of new therapeutics for prostate cancer.

Estrogen receptor ß activation impairs prostatic regeneration by inducing apoptosis in murine and human stem/progenitor enriched cell populations.

Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor ß (ERß) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERß agonist (8ß-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin(-)Sca1(+)CD49f(hi)) and human (CD49f(hi)Trop2(hi)) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ERß, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ERß-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ERß activation for prostate disease and suggest that combining selective activation of ERß with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.