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-β (TGF-β), 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-β 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.
Our results provide novel insights into the therapeutic value of targeting TGF-β 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-β blockade and antiandrogens to optimize therapeutic response in CRPC.
This article juxtaposes two case studies that integrated drama therapy, therapeutic theatre and experiential family therapy. Both authors engaged in arts-based research projects creating theatre with their respective families as therapy. Theoretical justifications, methodologies, limitations and future implications for how drama therapists can impact clinical work with families are presented in this account.
Introduction: Methenamine hippurate (MH) is a urinary antiseptic, indicated for prophylaxis of recurrent urinary tract infections (UTIs) but with only few and limited studies regarding its efficacy. To help address this knowledge gap we reviewed our experience with MH for UTI prophylaxis, focusing on women with recurrent uncomplicated UTIs.Methods: The University of Kentucky electronic health record was queried to identify adults who were prescribed MH from the urology clinic between January 2013 and January 2019. Charts were reviewed to assess patient-reported UTI frequency, demographics and relevant health factors. Treatment success was defined as 0e1 UTI in 6 months or 0e2 UTIs in 1 year.Results: Of 670 patients prescribed MH, 508 did not meet inclusion criteria. The most common reasons for exclusion were complicated UTI, no return visit, treatment nonadherence and insufficient followup time. The primary study population was 162 women with recurrent uncomplicated UTIs: 41 premenopausal and 121 postmenopausal. Success rates with MH were 83% and 77%, respectively. Success rates were not significantly associated with age, diabetes, immune suppression, high-tone pelvic floor dysfunction or (if postmenopausal) vaginal estrogen use. Exploratory study of patients using intermittent catheterization showed success in 20 of 30 patients (67%).Conclusions: MH had high success rates for premenopausal and postmenopausal women with recurrent uncomplicated UTIs. Patients using catheters had lower success rates. Prospective trials would strengthen the evidence to guide decisions for treatment and insurance coverage.
BackgroundThe Affordable Care Act (ACA) enacted on March 23, 2010 may have subsequently affected referral patterns for persons living with HIV (PLWH). The ACA permits states to provide Medicaid for individuals at or below 138% of the federal poverty line with federal funding for 3 years after enactment. Following the Kentucky Medicaid expansion in September 2013, the uninsured rate fell from 14.3% (~616,000) in 2013 to 6% (~261,000) in 2015 (USDC, 2016). As of June 2016 the total number of diagnosed PLWH in Kentucky was 9,928 (CHFS, 2016).This study evaluated the impact of the ACA on referrals to care for PLWH. The University of Kentucky Bluegrass Care Clinic (UK BCC) is a federally funded Ryan White HIV/AIDS clinic that serves 63 counties in central and eastern Kentucky.MethodsThis study examined 1,022 newly enrolled patients between March 24, 2010 and June 8, 2017 to observe changes in referral patterns at the UK BCC. Referral type was categorized into one of nine groups (referral by self, outpatient clinic, hospital, OB/GYN, community organization, UK BCC, transfer, health department, and unknown). Unknown observations were removed from the data analysis.ResultsOf the 1,022 intake records, 127 had an unknown referral source (12.4%). Between the period 2010–2013 (Pre-ACA) there was an 18% decrease in referrals from Health Departments between pre- and post-ACA (29.8% vs. 12.0%). In addition, there was a 13.0% increase in transfer care to the UK BCC (16.1% vs. 29.3%). There was an overall significant difference in referral care patterns between the two time periods (P < 0.0001) when considering all referral groups.ConclusionThe decrease in referral of patient from Health Departments may indicate that PLWH have more access to screening and referrals to clinic care through primary care providers with Medicaid expansion. Further, the increase in patients who transfer from pre-existing care to the Ryan White clinic suggest that the expansion of PLWH using Medicare and Medicaid may have resulted in loss of eligibility from other HIV care providers. These results have implications to engage more PLWH into care, particularly in states that have increased access to primary care through healthcare expansions.Figure 1.Proportion of Patients by Referral Source for the Years 2010–2013 and 2014–2017.Disclosures All authors: No reported disclosures.
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.
Downbeat nystagmus is a type of jerk nystagmus that may be seen in patients with lesions affecting the vestibulocerebellum. This is a case of a 7-year-old girl presenting with a history of fever, headache, and episodic vertigo with downbeat nystagmus. The diagnosis of Epstein-Barr virus meningitis with acute cerebellitis was made by contrast magnetic resonance imaging, cerebrospinal fluid analysis, and serum Epstein-Barr virus titers. Contrast magnetic resonance imaging demonstrated enhancement of the meninges and inferior cerebellar folia, correlating with the neuroophthalmological symptom of downbeat nystagmus.
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