SummaryAging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age‐related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging‐related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age‐related cognitive deficits.

BUB-related 1 (BubR1) encoded by Budding Uninhibited by Benzimidazole 1B (BUB1B) is a crucial mitotic checkpoint protein ensuring proper segregation of chromosomes during mitosis. Mutations of BUB1B are responsible for mosaic variegated aneuploidy (MVA), a human congenital disorder characterized by extensive abnormalities in chromosome number. Although microcephaly is a prominent feature of MVA carrying the BUB1B mutation, how BubR1 deficiency disturbs neural progenitor proliferation and neuronal output and leads to microcephaly is unknown. Here we show that conditional loss of BubR1 in mouse cerebral cortex recapitulates microcephaly. BubR1-deficient cortex includes a strikingly reduced number of late-born, but not of early-born, neurons, although BubR1 expression is substantially reduced from an early stage. Importantly, absence of BubR1 decreases the proportion of neural progenitors in mitosis, specifically in metaphase, suggesting shortened mitosis owing to premature chromosome segregation. In the BubR1 mutant, massive apoptotic cell death, which is likely due to the compromised genomic integrity that results from aberrant mitosis, depletes progenitors and neurons during neurogenesis. There is no apparent alteration in centrosome number, spindle formation or primary cilia, suggesting that the major effect of BubR1 deficiency on neural progenitors is to impair the mitotic checkpoint. This finding highlights the importance of the mitotic checkpoint in the pathogenesis of microcephaly. Furthermore, the ependymal cell layer does not form in the conditional knockout, revealing an unrecognized role of BubR1 in assuring the integrity of the ventricular system, which may account for the presence of hydrocephalus in some patients.

Purpose/Objectives: Accelerated partial breast irradiation (APBI) has been shown to have both acceptable oncologic and cosmetic outcomes for early stage breast cancer following breast-conserving surgery (BCS). Given the demonstrated financial toxicity (FT) of conventional radiation treatments on breast cancer patients, we wanted to quantitatively assess the FT on patients treated with APBI in our phase I five fraction stereotactic APBI (S-PBI) trial, which could be generalized across APBI treatment regimens. Methods: A phase I dose escalation trial of S-PBI for early stage breast cancer following BCS was conducted. Women age > 18 years with in-situ or stage I-II (AJCC 7) invasive breast cancer < 3 cm following BCS with > 2 mm margins were treated with S-PBI in 5 fractions to a total dose of 30 to 40 Gy over 2.5 Gy increments (Clinical trials.gov ID NCT01162200). One month following completion of treatment, patients were asked to complete our novel “Patient Perspective Cost and Convenience of Care Questionnaire” developed at our institution. Results: Of 75 patients enrolled and treated, questionnaire data was available for 66 patients. Our trial encompassed a wide spectrum of annual household incomes, with 25.5% of patients (n=14/55) reporting income of less than $30k and 45.5% (n=25/55) reporting incomes of more than $80k. Educational status was also well represented with 53.1% completing at least some college (n= 34/64), 25% holding post graduate or professional degrees (n=16/64), and 21.9% patients reporting a high school equivalent or less (n=14/64). Overall 48.4% of patients (n=30/62) said that oncologic treatment did not present a financial burden; however, 29.0% (n=20/62) patients reported a somewhat to significant financial burden. Neither household income nor patient education status predicted perceived FT. Of the 6 patients (9.7%) who reported significant FT, 5 reported travelling at least 25 miles one way for treatment with 2 of these patient travelling over 175 miles. Half of the patients reported having private insurance for medication (49.2%, n=32/65), 33.8% had governmental coverage (n=22/65), 6.1% had both private and government coverage, 7.7% had no coverage (n=5/65), and 3.0% were unsure of their coverage (n=2/65). Only 1 of the 6 patients with significant FT had no coverage. Over half of the patients (54.2%, n=34/62) reported a co-pay during their treatment with a median out of pocket cost of $300 for treatment (range $10-10000, n=16). Over half of the patients were working full or part time during treatment (54.2%, n=32/59). All 26 patients that were working full time had to take time off work for treatment (median of 5 days, range 0.25 days – 10 days). Over a third of these patients (34.6%, n=9) had to use vacation time or unpaid time off. There was an additional patient who reported months off without pay. Additionally, 24.2% of patients (n=15/62) reported they had family or friends take time off work due to the patient’s treatment. Finally, patients were surveyed on the treatment related disruption to their daily activities and enjoyment of life rated on a scale 0-10, with 0 being no disruption, median values were 3 and 1, respectively. Patients also reported a median score of 10 (scale 0-10, 10 being most satisfied) on satisfaction with treatment time. Conclusions: In this cohort of patients, interestingly FT was significant primarily in the 10% of patients who traveled a significant distance for these treatments. However, despite this, and the fact that patients were undergoing cytotoxic cancer therapy, impressively, all patients were uniformly satisfied with treatment time (median score of 10), and most did not express significant disruption to their life. We plan to explore the impact of further reducing treatment fractions (with our single fraction S-PBI studies) on FT and quality of life in future studies. Citation Format: Ambrosia Simmons, David Sher, Dong W. Nathan Kim, Marilyn Leitch, Rachel Wooldridge, Sally Goudreau, Stephen Seiler, Sarah Neufeld, Maggie Stein, Kevin Albuquerque, Ann Spangler, John Heinzerling, Dan Gardwoood, Stella Stevenson, Chul Ahn, Chuxiong Ding, Robert Timmerman, Asal Rahimi. Financial Toxicity Outcomes on a Phase I 5-fraction Partial Breast Irradiation Protocol for Early Stage Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-55.