Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine biosynthesis; it uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to DOPA. Its amino terminal 150 amino acids comprise a domain whose structure is involved in regulating the enzyme's activity. Modes of regulation include phosphorylation by multiple kinases at 4 different serine residues, and dephosphorylation by 2 phosphatases. The enzyme is inhibited in feedback fashion by the catecholamine neurotransmitters. Dopamine binds to TyrH competitively with tetrahydrobiopterin, and interacts with the R domain. TyrH activity is modulated by protein-protein interactions with enzymes in the same pathway or the tetrahydrobiopterin pathway, structural proteins considered to be chaperones that mediate the neuron's oxidative state, and the protein that transfers dopamine into secretory vesicles. TyrH is modified in the presence of NO, resulting in nitration of tyrosine residues and the glutathionylation of cysteine residues. KeywordsTyrosine hydroxylase; dopamine biosynthesis; protein kinases; protein nitration; protein glutathionylation; protein-protein interactions; 14-3-3 protein; α-synuclein Tyrosine hydroxylase (TyrH) is the rate-limiting enzyme of catecholamine synthesis. It catalyzes the hydroxylation of tyrosine to L-DOPA (1). The catecholamines dopamine, epinephrine and norepinephrine are the products of the pathway, important as hormones and neurotransmitters in both the central and peripheral nervous systems. In the latter, they are synthesized in the adrenal medulla (1,2). The biosynthetic pathway is illustrated in Figure 1. These catechol monoamines play roles in many brain functions, such as attention (3), memory (4), cognition (5), and emotion (6,7). As the hormone of the fight-or-flight response, epinephrine produced in the adrenal gland affects many tissues throughout the body (8). Therefore deficits and surfeits in the levels of the catecholamines have many repercussions, perhaps including high blood pressure, bipolar disorder, addiction, and dystonias (9-11). Because of this, the activity of TyrH as the slowest enzyme in the pathway is of great interest in many fields of biomedical research.Given the importance of the activity of TyrH, the complexity of its regulation is not surprising. Control of its expression by transcriptional mechanisms is a very active field of research, as is the relatively new field of its degradation in the proteosome after † To whom inquiries should be addressed: Dept of Biological Sciences, St Mary's University, One Camino Santa Maria, San Antonio TX 78228, sdaubner@stmarytx.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could a...

Background Genomic classifiers (GC) have been shown to improve risk stratification post prostatectomy. However, their clinical benefit has not been prospectively demonstrated. We sought to determine the impact of GC testing on postoperative management in men with prostate cancer post prostatectomy. Methods Two prospective registries of prostate cancer patients treated between 2014 and 2019 were included. All men underwent Decipher tumor testing for adverse features post prostatectomy (Decipher Biosciences, San Diego, CA). The clinical utility cohort, which measured the change in treatment decision-making, captured pre-and postgenomic treatment recommendations from urologists across diverse practice settings (n = 3455). The clinical benefit cohort, which examined the difference in outcome, was from a single academic institution whose tumor board predefined "best practices" based on GC results (n = 135). Results In the clinical utility cohort, providers' recommendations pregenomic testing were primarily observation (69%). GC testing changed recommendations for 39% of patients, translating to a number needed to test of 3 to change one treatment decision. In the clinical benefit cohort, 61% of patients had genomic high-risk tumors; those who received the recommended adjuvant radiation therapy (ART) had 2-year PSA recurrence of 3 vs. 25% for those who did not (HR 0.1 [95% CI 0.0-0.6], p = 0.013). For the genomic low/intermediate-risk patients, 93% followed recommendations for observation, with similar 2year PSA recurrence rates compared with those who received ART (p = 0.93). Conclusions The use of GC substantially altered treatment decision-making, with a number needed to test of only 3. Implementing best practices to routinely recommend ART for genomic-high patients led to larger than expected improvements in early biochemical endpoints, without jeopardizing outcomes for genomic-low/intermediate-risk patients.

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Introduction: Lutetium-177 (177Lu)-DOTATATE received FDA approval in 2018 to treat somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors (NETs). Little data are available on response and outcomes for well differentiated (WD) high grade (HG) NETs treated with 177Lu-DOTATATE. Materials and Methods: Patients with WD HG NETs treated with 177Lu-DOTATATE at MSK from 2018-2020 were identified. Demographics, response (RECIST 1.1), progression-free survival (PFS) were determined. Next-generation sequencing (NGS) was performed in archival tumor. Results: Nineteen patients, all with progressive, heavily-treated disease, were identified. Site of tumor origin: pancreas (74%), small bowel (11%), rectal (11%), lung (5%); median Ki-67 32% (range 22-56). Thirteen patients (68%) completed all four 177Lu-DOTATATE cycles. Best response (N=18 evaluable): 5/18 (28%) partial response, 8/18 (44%) stable disease, 5/18 (28%) disease progression. Median PFS 13.1 months (95% CI 8.7-20.9). Most common treatment-related toxicities: thrombocytopenia (9 patients, 47%; G3/4, 1 patient, 5%), anemia (7 patients, 37%; G3/4, 2 patients, 11%), leukopenia (6 patients, 32%; G3/4, 0 patients), liver function test elevation (4 patients, 21%; G3/4, 0 patients). NGS results were available from 13/19 tumors (68%). The most observed alterations were in MEN1 (6/13, 46%), DAXX (4/13, 31%). No RB1 alterations identified. Conclusion: We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with 177Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone-marrow related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations.