Impact of the Affordable Care Act on Referral to Care for People Living with HIV in Appalachia.

Introduction: The Affordable Care Act (ACA) enacted on March 23, 2010 significantly impacted access to healthcare for people living with HIV (PLWH). Expansion of care was accomplished in three areas: eliminating exclusions for pre-existing conditions, elimination of lifetime caps on healthcare expenditures, and expansion of Medicaid eligibility. Purpose: This study evaluated the impact of state implementation of the ACA Medicaid expansion on referral to HIV care at a Ryan White federally funded clinic in Kentucky (University of Kentucky Bluegrass Care Clinic [UK BCC]). Methods: Retrospective chart review of all newly enrolled patients at the UK BCC between March 2010 and June 2017. Data included patient demographics and referral source, and were divided into two groups to compare enrollments before and after Kentucky implemented the ACA Medicaid expansion. Data were collected from 2018-2019 and analyzed in 2020. Results: Following Medicaid expansion there were statistically significant changes in the patterns of referral to federally funded HIV care. These included a significant decrease in the proportion of referrals from state and local health departments, and an increase in both proportion of referrals from outpatient clinics and transfers from different HIV care providers. Implications: These results have implications for engaging more PLWH into HIV care, particularly in states where patients have increased access to screening and assessment of risk at primary care encounters through implementation of the ACA Medicaid expansion.

Impact of α-adrenoceptor antagonists on prostate cancer development, progression and prevention.

Two decades following the discovery that α1-adrenoceptor antagonists suppress prostate tumor growth at the molecular and cellular level, the impact of α-blockade as re-purposed treatment strategy in the medical management of prostate cancer is gradually being recognized. Prostate cancer is the second most common cause of cancer deaths among males in the United States, yet the disease maintains inconsistent recommendations for prevention and screening. The functional relationship between α-adrenergic signaling and smooth muscle cells in the stroma of the prostate gland and the bladder neck empowered the use of α-adrenoceptor antagonists for the relief of urethral obstruction and clinical symptoms associated with benign prostatic hyperplasia (BPH). Adrenoceptors are G-protein-coupled receptors (GCPRs) that are functionally bound by catecholamines: epinephrine (ER) and norepinephrine (NE). The α1A adrenoceptor subtype is primarily responsible for smooth muscle contraction in the bladder neck and prostate gland. α1-adrenoceptor antagonists are clinically indicated as first-line therapies for the relief of BPH, hypertension, and post-traumatic stress disorder (PTSD). Compelling evidence from cellular and pre-clinical models have identified additional effects of α1-adrenoceptor antagonists regarding their ability to induce apoptosis-mediated suppression of prostate tumor growth and metastasis. Additionally, early epidemiologic data suggest that they may serve as a safe treatment to reduce the risk of prostate cancer. Optimization of quinazoline based compounds (doxazosin) to exploit pharmacologic targeting of tumor growth and vascularization revealed high efficacy of the lead novel compound DZ-50 against prostate tumors. This review discusses the experimental and pre-clinical evidence on the impact of α-blockade on prostate cancer.

TGF-ß receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer.

BACKGROUND: Prostate cancer progression is navigated by the androgen receptor (AR) and transforming-growth factor-ß (TGF-ß) signaling. We previously demonstrated that aberrant TGF-ß signaling accelerates prostate tumor progression in a transgenic mouse model of prostate cancer via effects on epithelial-mesenchymal transition (EMT), driving castration-resistant prostate cancer (CRPC). METHODS: This study examined the antitumor effect of the combination of TGF-ß receptor I (TßRI) inhibitor, galunisertib, and FDA-approved antiandrogen enzalutamide, in our pre-clinical model. Age-matched genotypically characterized DNTGFßRII male mice were treated with either galunisertib and enzalutamide, in combination or as single agents in three "mini"-trials and the effects on tumor growth, phenotypic EMT, and actin cytoskeleton were evaluated. RESULTS: Galunisertib in combination with enzalutamide significantly suppressed prostate tumor growth, by increasing apoptosis and decreasing cell proliferation of tumor cell populations compared to the inhibitor as a monotherapy (P < 0.05). The combination treatment dramatically reduced cofilin levels, actin cytoskeleton regulator, compared to single agents. Treatment with galunisertib targeted nuclear Smad4 protein (intracellular TGF-ß effector), but had no effect on nuclear AR. Consequential to TGF-ß inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-ß1 ligand, in response to galunisertib, was blocked by enzalutamide. CONCLUSION: Our results provide novel insights into the therapeutic value of targeting TGF-ß signaling to overcome resistance to enzalutamide in prostate cancer by phenotypic reprogramming of EMT towards tumor re-differentiation and cytoskeleton remodeling. This translational work is significant in sequencing TGF-ß blockade and antiandrogens to optimize therapeutic response in CRPC.

Profiling Prostate Cancer Therapeutic Resistance.

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-ß (TGF-ß), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-ß signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery.