Early-life Origins of Breast Development and the Implications for Breast Cancer Risk

Breast cancer incidence, particularly late-stage disease, is increasing in U.S. women under 40 years of age, pointing to the importance of exposures acting early in the life course to increase breast cancer risk. Earlier onset of breast development has recently been identified as an independent risk factor for breast cancer. Thus, identifying modifiable factors that can delay the onset of breast development may provide an opportunity for breast cancer primary prevention starting early in life. This dissertation examined the influence of the early-life environment on the age at onset of breast development through: 1) a systematic review of the literature relating maternal pre-pregnancy body size, gestational weight gain (GWG), birth size, and infant growth to the timing of breast development and menarche; 2) analyses assessing the associations between these factors and the onset of breast development in a pubertal cohort enriched for breast cancer family history (BCFH); and 3) a pilot study assessing whether these factors are associated with serum levels of insulin-like growth factor(IGF)-1 and insulin-like growth factor binding protein(IGFBP)-3 during puberty. Our systematic review identified 96 studies, the majority of which examined the association between birthweight and age at menarche. Although low birthweight is often cited as a risk factor for early menarche, the majority of studies (40/73 total) that examined this association did not observe a statistically significant association. Differences in exposure assessment, inadequate control for confounders, and differences in postnatal growth across studies may drive inconsistencies in the birthweight literature. In contrast, higher maternal body mass index (BMI) prior to pregnancy, GWG in excess of recommended guidelines and faster rates of weight gain between birth and 2 years of age were consistently associated with earlier age at breast development and menarche. We used data from the LEGACY Girls Study, a prospective cohort of girls primarily ages 6-13 years at baseline in which approximately 50% of girls had a family history of breast cancer, to examine the relations between maternal factors, birth size and infant growth and the onset of breast development, defined as a maternal report of breast Tanner stage 2 or greater. Daughters of women with a pre-pregnancy BMI of 25 or greater and who gained 30lbs or more during pregnancy experienced breast development at an earlier age than daughters of women with a pre-pregnancy BMI less than 25 and who gained less than 30lbs. This association was similar in girls with and without a BCFH. Birthweight and birthlength were not associated with the timing of breast development. In a subset of LEGACY girls with height and weight data during infancy available from medical records, we examined the associations between changes in weight-for-age and length-for-age Z-scores from birth to 1 year of age and the onset of breast development. We observed a modest association between faster rates of weight gain from 0-12 months and earlier age at breast development. When we examined smaller age intervals within infancy, faster weight gain from 2-4 months and 6-9 months were each associated with an earlier age at breast development. A similar pattern was observed for growth in length, and these associations did not vary by BCFH. In our pilot study including 109 girls with available serum samples between 6-17 years of age at the LEGACY New York site, rapid weight gain from 0-12 months was associated with higher mean levels of IGF-1 relative to IGFBP-3. Although not statistically significant, girls with a maternal pre-pregnancy BMI≥25 and GWG≥30lbs also had higher mean levels of the IGF-1/IGFBP-3 ratio. Since serum IGF-1 and IGFBP-3 are objective measures that are known to increase rapidly during puberty, the results of our pilot study support that the maternal BMI, GWG and rapid infant weight gain are associated with biological changes in the girls. Our findings suggest that measurement error in outcome assessment or confounding did not drive the associations that we observed between these factors and earlier onset of breast development. In conclusion, we identified higher maternal pre-pregnancy BMI, excess GWG and rapid growth during infancy as modifiable factors associated with earlier onset of breast development in girls across the spectrum of familial risk for breast cancer. While this suggests that modifying these factors may decrease breast cancer risk later in life, further research should consider additional and potentially opposing pathways, such as childhood body size, through which the early-life environment affects breast cancer risk

Training Performance Assessment for Intracranial Aneurysm Clipping Surgery Using a Patient-Specific Mixed-Reality Simulator: A Learning Curve Study.

BACKGROUND AND OBJECTIVES The value of simulation-based training in medicine and surgery has been widely demonstrated. This study investigates the introduction and use of a new mixed-reality neurosurgical simulator in aneurysm clipping surgery, focusing on the learning curve and performance improvement. METHODS Five true-scale craniotomy head models replicating patient-specific neuroanatomy, along with a mixed-reality simulator, a neurosurgical microscope, and a set of microsurgical instruments and clips, were used in the operation theater to simulate aneurysm microsurgery. Six neurosurgical residents participated in five video-recorded simulation sessions over 4 months. Complementary learning modalities were implemented between sessions. Thereafter, three blinded analysts reported on residents' use of the microscope, quality of manipulation, aneurysm occlusion, clipping techniques, and aneurysm rupture. Data were also captured regarding training time and clipping attempts. RESULTS Over the course of training, clipping time and number of clipping attempts decreased significantly (P = .018, P = .032) and the microscopic skills improved (P = .027). Quality of manipulation and aneurysm occlusion scoring improved initially although the trend was interrupted because the spacing between sessions increased. Significant differences in clipping time and attempts were observed between the most and least challenging patient models (P = .005, P = .0125). The least challenging models presented higher rates of occlusion based on indocyanine green angiography evaluation from the simulator. CONCLUSION The intracranial aneurysm clipping learning curve can be improved by implementing a new mixed-reality simulator in dedicated training programs. The simulator and the models enable comprehensive training under the guidance of a mentor

Socioeconomic disparities in breast cancer incidence and survival among parous women: findings from a population-based cohort, 1964–2008

Background Socioeconomic position (SEP) has been associated with breast cancer incidence and survival. We examined the associations between two socioeconomic indicators and long-term breast cancer incidence and survival in a population-based cohort of parous women. Methods Residents of Jerusalem who gave birth between 1964–1976 (n = 40,586) were linked to the Israel Cancer Registry and Israel Population Registry to determine breast cancer incidence and vital status through mid-2008. SEP was assessed by husband’s occupation and the woman’s education. We used log ranks tests to compare incidence and survival curves by SEP, and Cox proportional hazard models to adjust for demographic, reproductive and diagnostic factors and assess effect modification by ethnic origin. Results In multivariable models, women of high SEP had a greater risk of breast cancer compared to women of low SEP (Occupation: HR 1.18, 95 % CI 1.03-1.35; Education: HR 1.39, 95 % CI 1.21-1.60) and women of low SEP had a greater risk of mortality after a breast cancer diagnosis (Occupation: HR 1.33, 95 % CI 1.04-1.70; Education: HR 1.37, 95 % CI 1.06-1.76). The association between education and survival was modified by ethnic origin, with a gradient effect observed only among women of European origin. Women of Asian, North African and Israeli origin showed no such trend. Conclusions SEP was associated with long-term breast cancer incidence and survival among Israeli Jews. Education had a stronger effect on breast cancer outcomes than occupation, suggesting that a behavioral mechanism may underlie disparities. More research is needed to explain the difference in the effect of education on survival among European women compared to women of other ethnicities

Circulating growth factor concentrations and breast cancer risk: a nested case-control study of IGF-1, IGFBP-3, and breast cancer in a family-based cohort

Background Insulin-like growth factor 1 (IGF-1) and binding protein 3 (IGFBP-3) are associated with breast cancer in women at average risk of cancer. Less is known whether these biomarkers also predict risk in women with breast cancer family history. Methods We conducted a nested case-control study within the New York site of the Breast Cancer Family Registry (BCFR, n = 80 cases, 156 controls), a cohort enriched for breast cancer family history. Using conditional logistic regression, we estimated the association between IGF-1 and IGFBP-3 levels and breast cancer risk and examined whether this risk differed by predicted absolute breast cancer risk based on pedigree models. Results The overall association between IGF-1 or IGFBP-3 elevation (≥ median in controls) and breast cancer risk was elevated, but not statistically significant (IGF-1 OR = 1.37, 95% CI = 0.66–2.85; IGFBP-3 OR = 1.62, 95% CI = 0.81–3.24). Women with elevated predicted absolute 10-year risk ≥ 3.4% and elevated IGFBP-3 (≥ median) had more than a 3-fold increased risk compared to women with lower predicted absolute 10-year risk (< 3.4%) and low IGFBP-3 (OR = 3.47 95% CI = 1.04–11.6). Conclusions These data offer some support that the overall magnitude of the associations between IGF-1 and IGFBP3 seen in average risk cohorts may be similar in women enriched with a strong breast cancer family history

Control of human adenovirus type 5 gene expression by cellular Daxx/ATRX chromatin-associated complexes

Death domain–associated protein (Daxx) cooperates with X-linked α-thalassaemia retardation syndrome protein (ATRX), a putative member of the sucrose non-fermentable 2 family of ATP-dependent chromatin-remodelling proteins, acting as the core ATPase subunit in this complex, whereas Daxx is the targeting factor, leading to histone deacetylase recruitment, H3.3 deposition and transcriptional repression of cellular promoters. Despite recent findings on the fundamental importance of chromatin modification in host-cell gene regulation, it remains unclear whether adenovirus type 5 (Ad5) transcription is regulated by cellular chromatin remodelling to allow efficient virus gene expression. Here, we focus on the repressive role of the Daxx/ATRX complex during Ad5 replication, which depends on intact protein–protein interaction, as negative regulation could be relieved with a Daxx mutant that is unable to interact with ATRX. To ensure efficient viral replication, Ad5 E1B-55K protein inhibits Daxx and targets ATRX for proteasomal degradation in cooperation with early region 4 open reading frame protein 6 and cellular components of a cullin-dependent E3-ubiquitin ligase. Our studies illustrate the importance and diversity of viral factors antagonizing Daxx/ATRX-mediated repression of viral gene expression and shed new light on the modulation of cellular chromatin remodelling factors by Ad5. We show for the first time that cellular Daxx/ATRX chromatin remodelling complexes play essential roles in Ad gene expression and illustrate the importance of early viral proteins to counteract cellular chromatin remodelling

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144684/1/ajt14752_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144684/2/ajt14752.pd

Multidimensional Characterization and Differentiation of Neurons in the Anteroventral Cochlear Nucleus

Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies