RESUMO
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.
Assuntos
Proteínas de Ciclo Celular/genética , Microcefalia/genética , Mitose/genética , Neurogênese/genética , Proteínas Serina-Treonina Quinases/genética , Alelos , Animais , Apoptose/genética , Proteínas de Ciclo Celular/deficiência , Proliferação de Células/genética , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Segregação de Cromossomos/genética , Modelos Animais de Doenças , Humanos , Camundongos , Microcefalia/metabolismo , Microcefalia/fisiopatologia , Mosaicismo , Mutação/genética , Neurônios/metabolismo , Neurônios/patologia , Proteínas Serina-Treonina Quinases/deficiência , Fuso Acromático/genética , Fuso Acromático/patologiaRESUMO
PURPOSE: We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. METHODS AND MATERIALS: Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size <3 cm treated with lumpectomy were enrolled in this phase 1 single-fraction S-PBI dose-escalation trial. Women received either 22.5, 26.5, or 30 Gy in a single fraction using a robotic stereotactic radiation system. The primary outcome was to reach tumoricidal dose of 30 Gy in a single fraction to the lumpectomy cavity without exceeding the maximum tolerated dose. Secondary outcomes were to determine dose-limiting toxicity and cosmesis. Tertiary goals were ipsilateral breast recurrence rate, distant disease-free interval, recurrence-free survival, and overall survival. RESULTS: From June 2016 to January 2021, 11, 8, and 10 patients were treated to doses of 22.5, 26.5, or 30 Gy in a single fraction, respectively, with median follow-up being 47.9, 25.1, and 16.2 months. No patients experienced acute (<90 days) grade 3 or higher treatment-related toxicity, and maximum tolerated dose was not reached. There were 2 delayed grade 3 toxicities. Four patients (13.8%) developed fat necrosis across all 3 cohorts, which compares favorably with results from other PBI trials. No dose cohort had a statistically significant cosmetic detriment from baseline to 12 months or 24 months follow-up by patient- or physician-reported global cosmetic scores. There were no reports of disease recurrence. CONCLUSIONS: This phase 1 trial demonstrates that S-PBI can be used to safely escalate dose to 30 Gy in a single fraction with low toxicity and without detriment in cosmesis relative to baseline.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia , Mastectomia Segmentar , Recidiva Local de Neoplasia/cirurgia , Estudos ProspectivosRESUMO
Aging 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.