Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Degeneration of the central autonomic network with relative sparing of peripheral autonomic neurons underlies neurogenic orthostatic hypotension in patients with multiple system atrophy (MSA). Ampreloxetine, a novel, selective, norepinephrine (NE) reuptake inhibitor, allows once-daily dosing to precisely target residual peripheral autonomic neurons. Based on the hypothesis that patients with MSA would be most responsive and the substantial unmet need for symptomatic therapy in this population, an MSA subgroup analysis was prespecified. METHODS:We conducted a run-in 4-week, parallel-group, randomized controlled trial (SEQUOIA), followed by a pivotal enriched randomized withdrawal (RW) trial with 16-week open-label treatment and 6 weeks of 1:1 RW (REDWOOD). Inclusion criteria for the MSA subgroup included (1) probable or possible MSA, (2) 3-minute orthostatic blood pressure (BP) fall >20/10 mm Hg, and (3) dizziness or lightheadedness score >4 points. Outcome measures included self-reported symptom burden captured on the 10-item OH Questionnaire (OHQ). Differences were analyzed using logistic regression and mixed-model repeated measures analysis. RESULTS:= 0.015). Standing BP remained unchanged from open-label in the ampreloxetine group (systolic: 5.6 ± 4.1; diastolic: 3.7 ± 2.9 [SE] mm Hg) but fell after placebo withdrawal (systolic: -10.0 ± 4.5; diastolic: -6.0 ± 3.1 mm Hg). The catecholamine profile was consistent with NE transporter inhibition. There were no observed increases in supine BP. DISCUSSION/CONCLUSIONS:In a prespecified subgroup analysis of MSA participants in the REDWOOD trial, patients randomized to placebo worsened, whereas those who were randomized to treatment maintained their open-label level of function. TRIAL REGISTRATION INFORMATION/UNASSIGNED:REDWOOD trial, NCT03829657; first submitted to registry January 10, 2019; first participant enrolled February 22, 2019. SEQUOIA trial, NCT03750552; first submitted to registry November 20, 2018; first participant enrolled January 24, 2019. See ClinicalTrials.gov for full-protocol and statistical analysis plan. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that in patients with MSA who had symptomatic benefit on orthostatic hypotension with ampreloxetine, there was no difference in the odds of treatment failures between those maintained on ampreloxetine and those withdrawn to placebo.

Alston's singing mouse has emerged as an intriguing model for the comparative study of vocal control. New work on the species sets the stage to understand the proximate mechanisms and evolutionary roots of novel acoustic communication traits.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Circumferential minimally invasive surgery (cMIS) techniques in adult spinal deformity (ASD) surgery may reduce physiological burden compared with open technique, but their utility in octogenarians has not been previously assessed. METHODS:Operative ASD patients aged 80 years or older with complete baseline (BL) and 2-year postoperative radiographic and health-related quality of life data were assessed and compared by surgical technique: open vs cMIS. Propensity score matching aligned groups by BL Charlson Comorbidity Index (CCI), C7-S1 sagittal vertical axis, pelvic incidence minus lumbar lordosis mismatch, and C7 plumb line. BL and peri/postoperative factors were assessed using analysis of variance and Bonferroni-adjusted analysis of covariance while controlling for BL CCI and posterior fusion length. RESULTS:Thirty-four octogenarian ASD patients met inclusion criteria, of whom 29.4% underwent cMIS and 70.6% underwent open correction. cMIS patients were less likely to require surgical intensive care unit (10% vs 75%, P < .001) and had shorter hospital stays (4.6 vs 10.1 days, P = .013). Open patients reported higher Scoliosis Research Society-22 Appearance and Mental domain scores (both P < .005) and more frequently reached minimal clinically important difference in both domains by 2 years (P = .025, .024). cMIS patients more often required reoperation for radiographic sagittal imbalance by 2 years when controlling for CCI and levels fused (20.0% vs 8.3%, P < .001). No deaths occurred in either group by 2 years. CONCLUSION/CONCLUSIONS:In octogenarians undergoing ASD surgery, cMIS reduced physiological burden but had higher reoperation rates, whereas open surgery showed greater durability.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency - loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor Stk11 (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5'-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to Il36g mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5'UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.

Following their engagement toward differentiation, tissue stem cells often transit through a precursor state that is difficult to define because of its transient nature; similarly, the precise role of lineage precursors in the implementation of tissue architecture and function is unknown. In the present work, we used two mouse models of deficient feedback regulation to characterize precursors of the pituitary corticotrope lineage that regulates the stress response. Both the POMC knockout and adrenalectomized mouse models develop glucocorticoid deficiency and compensatory accumulation of corticotrope precursors that have so far eluded characterization. We found that pre-corticotrope differentiation depends on the lineage-specific factor Tpit and is repressed by glucocorticoids. We identified brain-derived neurotrophic factor (BDNF) as the signal that engages pituitary stem cells toward differentiation in these models as well as in normal pituitary development. A glucocorticoid-sensitive BDNF autocrine loop active in pre-corticotropes turns these cells into signaling hubs for maintenance of pituitary-adrenal homeostasis.

Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.

PURPOSE/UNASSIGNED:To compare a strategy utilizing testing to guide treatment, also known as selective therapy, to a strategy of initiating interventions without testing, termed empiric therapy, on urinary supersaturation of calcium oxalate and calcium phosphate. MATERIALS AND METHODS/UNASSIGNED:In this single-center trial, adult individuals with recurrent idiopathic calcium stone disease were randomized to either an empiric or selective strategy. Participants received 24-hour urine testing at baseline, 4 weeks, and 8 weeks. Treatment in the empiric arm was comprised of dietary and fluid counseling and pharmacologic treatment with indapamide and potassium citrate irrespective of 24-hour urine results. For the selective arm, diet and pharmacologic treatments, which included indapamide, potassium citrate, and/or allopurinol, were tailored based on urine testing at baseline and 4 weeks. The primary outcome was urinary supersaturation of calcium oxalate and calcium phosphate at 8 weeks. RESULTS/UNASSIGNED:= 0.58). Similarly, there were no significant differences at 8 weeks in urine volume and pH, or in excretion of calcium, oxalate, citrate, uric acid, and sodium. CONCLUSIONS/UNASSIGNED:In this short-term trial among individuals at high-risk for stone recurrence, there was no statistically significant difference in the urinary stone risk comparing an empiric versus selective strategy for kidney stone prevention.