Multidisciplinary management of sexual and gender minorities with bladder cancer.

Bladder cancer, a common urologic malignancy, has poor morbidity and mortality in sexual and gender minority (SGM) individuals, stemming from higher risk, poor access to care and lack of quality cancer care. To begin addressing this disparity, this review offers key considerations for evaluation, diagnosis and treatment of SGM individuals with bladder cancer. In addition to thorough medical and surgical history, initial evaluation should include discussion of patient goals for sexual function and organ preservation, as well as an evaluation of sexual function. Prior gender affirming surgery and patient specific sexual function goals will impact diagnosis and treatment approaches, including surgical and radiation therapy. Throughout care for SGM individuals with bladder cancer, it is critical to acknowledge the systemic discrimination that may be experienced by these individuals and approach conversations with sensitivity and humility and incorporate mental and social support as appropriate.

Novel Antireflux "RELIEF" Stent to Prevent Vesicoureteral Reflux.

OBJECTIVE: To assess efficacy, comfort, and symptoms of a novel ureteral stent (RELIEF) substituting the distal semirigid coil of a traditional double-J for a floating, monofilament tether allowing coaptation of the ureteral orifice. Ureteral instrumentation notoriously cause discomfort, urgency, frequency, dysuria, and hematuria; prolonged morbidity is likely related to stent-associated vesicoureteral reflux (VUR). We hypothesized this design would eliminate VUR, be safe and provide comfort following intervention. METHODS: Twenty-eight patients within a single institution were enrolled. Passive cystography was performed pre- and post-stent placement assessing VUR. Patients completed Ureteric Stent Symptoms Questionnaires (USSQ) before placement (baseline), postop day 1, and day of removal. RESULTS: Twenty RELIEF stents were placed (11 female and 9 male). 95% demonstrated no VUR following placement. No unexpected adverse complications occurred; 1 patient opted for early stent removal for significant discomfort. Average total USSQ scores demonstrated statistically significant improvement between first and third surveys (P < .001). Statistically significant improvement in body pain, general health, and work performance scores were noted as well (P < .05). CONCLUSION: The RELIEF stent eliminates VUR with similar stent-related morbidity and overall well-tolerance. RELIEF-associated USSQ scores were below published mean symptom scores for standard double-J stents and appear safe in this preliminary clinical trial.

The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (tripartite motif family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2's interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity.

Characterization of Small-Molecule-Induced Changes in Parkinson's-Related Trafficking via the Nedd4 Ubiquitin Signaling Cascade.

The benzdiimidazole NAB2 rescues α-synuclein-associated trafficking defects associated with early onset Parkinson's disease in a Nedd4-dependent manner. Despite identification of E3 ubiquitin ligase Nedd4 as a putative target of NAB2, its molecular mechanism of action has not been elucidated. As such, the effect of NAB2 on Nedd4 activity and specificity was interrogated through biochemical, biophysical, and proteomic analyses. NAB2 was found to bind Nedd4 (KDapp = 42 nM), but this binding is side chain mediated and does not alter its conformation or ubiquitination kinetics in vitro. Nedd4 co-localizes with trafficking organelles, and NAB2 exposure did not alter its co-localization. Ubiquitin enrichment coupled proteomics revealed that NAB2 stimulates ubiquitination of trafficking-associated proteins, most likely through modulating the substrate specificity of Nedd4, providing a putative protein network involved in the NAB2 mechanism and revealing trafficking scaffold protein TFG as a Nedd4 substrate.

Progesterone induces progesterone receptor gene (PGR) expression via rapid activation of protein kinase pathways required for cooperative estrogen receptor alpha (ER) and progesterone receptor (PR) genomic action at ER/PR target genes.

Progesterone Receptors (PRs) are critical effectors of estrogen receptor (ER) signaling required for mammary gland development and reproductive proficiency. In breast and reproductive tract malignancies, PR expression is a clinical prognostic marker of ER action. While estrogens primarily regulate PR expression, other factors likely contribute to a dynamic range of receptor expression across diverse tissues. In this study, we identified estrogen-independent but progestin (R5020)-dependent regulation of ER target genes including PGR in ER+/PR+ cancer cell lines. R5020 (10nM-10µM range) induced dose-dependent PR mRNA and protein expression in the absence of estrogen but required both PR and ERα. Antagonists of either PR (RU486, onapristone) or ERα (ICI 182,780) attenuated R5020 induction of TFF1, CTSD, and PGR. Chromatin immunoprecipitation (ChIP) assays performed on ER+/PR+ cells demonstrated that both ERα and PR were recruited to the same ERE/Sp1 site-containing region of the PGR proximal promoter in response to high dose progestin (10µM). Recruitment of ERα and PR to chromatin and subsequent PR mRNA induction were dependent upon rapid activation of MAPK/ERK and AKT; inhibition of these kinase pathways via U0126 or LY294002 blocked these events. Overall, we have identified a novel mechanism of ERα activation initiated by rapid PR-dependent kinase pathway activation and associated with phosphorylation of ERα Ser118 for estrogen-independent but progestin-dependent ER/PR cross talk. These studies may provide insight into mechanisms of persistent ER-target gene expression during periods of hormone (i.e. estrogen) ablation and suggest caution following prolonged treatment with aromatase or CYP17 inhibitors (i.e. contexts when progesterone levels may be abnormally elevated).