Nasim Ahmadiyeh

The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer

An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that the region harboring this variant is a transcriptional enhancer, that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2) and that the risk region physically interacts with the MYC proto-oncogene. These data provide strong support for a biological mechanism underlying this non-protein-coding risk variant.

8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC

The 8q24 gene desert contains risk loci for multiple epithelial cancers, including colon, breast, and prostate. Recent evidence suggests these risk loci contain enhancers. In this study, data are presented showing that each risk locus bears epigenetic marks consistent with enhancer elements and forms a long-range chromatin loop with the MYC proto-oncogene located several hundred kilobases telomeric and that these interactions are tissue-specific. We therefore propose that the 8q24 risk loci operate through a common mechanism—as tissue-specific enhancers of MYC.

Sex- and lineage-specific inheritance of depression-like behavior in the rat

The Wistar–Kyoto (WKY) rat exhibits physiological and behavioral similarities to endophenotypes of human depression. In the forced swim test (FST), a well-characterized antidepressant-reversible test for behavioral despair in rodents, WKYs express characteristics of behavioral despair; increased immobility, and decreased climbing. To map genetic loci linked to behavior in the FST, we conducted a quantitative trait loci (QTL) analysis of the segregating F2 generation of a WKY × Fisher 344 (F344) reciprocal intercross. Using linear-model-based genome scans to include covariate (sex or lineage)-by-QTL interaction effects, four significant QTL influencing climbing behavior were identified. In addition, we identified three, seven, and two suggestive QTL for climbing, immobility, and swimming, respectively. One of these loci was pleiotropic, affecting both immobility and climbing. As found in human linkage studies, several of these QTL showed sex- and/or lineage-dependent effects. A simultaneous search strategy identified three epistatic locus pairs for climbing. Multiple regression analysis was employed to characterize the joint contributions of these QTL and to clarify the sex- and lineage-dependent effects. As expected for complex traits, FST behavior is influenced by multiple QTL of small effect, each contributing 5%–10%, accounting for a total 10%–30% of the phenotypic variance. A number of loci mapped in this study share overlapping candidate regions with previously identified emotionality QTL in mice as well as with susceptibility loci recognized by linkage or genome scan analyses for major depression or bipolar disorder in humans. The presence of these loci across species suggests that these QTL may represent universal genetic factors contributing to mood disorders.

Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5′ of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P=9 × 10−18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

Career Satisfaction of Women in Surgery: Perceptions, Factors, and Strategies

BACKGROUND With the current and projected shortages of general surgeons, more attention is being paid to the increasing pool of women physicians. This study seeks to understand the variables leading to career satisfaction for women surgeons to better recruit, retain, and support them. STUDY DESIGN Eighteen semi-structured interviews of 12 female and 6 male surgeons 2 to 12 years into practice were qualitatively analyzed and converted to coded, categorized data. Significance was derived by Fishers exact test. Participants were recruited by snowball sampling. RESULTS Our sample represents a highly satisfied group of female and male surgeons. Although both women and men describe with equal frequency having made career tradeoffs for personal and family time, and vice versa, women far more frequently than men cite reasons related to their personal time, predictable time, and family relationships as why they are currently satisfied with their career (34.1% versus 8.7%; p < 0.05). Both cite being satisfied by career content equally. When describing strategies used in developing a successful surgical career, women most frequently cite social networks as a key to success (88% versus 12% by men; p < 0.05), and men more frequently cite reasons related to training (29% versus 0% by women; p < 0.05) and compensation (24% versus 0% by women; p < 0.05). CONCLUSIONS Although both men and women make tradeoffs of career for family and family for career, womens perception of satisfaction comes from viewing their surgical career within the broader context of their lives. Women might be attracted to a career that acknowledges and values the whole person beyond the surgeon, and could benefit from work infrastructures that enhance networking.

Context and strain-dependent behavioral response to stress

BackgroundThis study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized.MethodsWe studied male Fisher 344 (F344) and Wistar Kyoto (WKY) rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM) and the open field (OFT), both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests.ResultsPrior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs.ConclusionData suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.

Depressive-like behavior and stress reactivity are independent traits in a Wistar Kyoto x fisher 344 cross

Depression is a heritable disorder that is often precipitated by stress. Abnormalities of the stress-reactive hypothalamic–pituitary–adrenal (HPA) axis are also common in depressed patients. In animal models, the forced swim test (FST) is the most frequently used test of depressive-like behavior. We have used a proposed animal model of depression, the Wistar Kyoto (WKY) rat, to investigate the relationship as well as the mode of inheritance of FST behaviors and HPA measures. Through reciprocal breeding of WKY and F344 parent strains and brother–sister breeding of the F1 generation, we obtained 486 F2 animals. Parent, F1 and F2 animals were tested in the FST. Blood samples were collected for determination of basal and stress (10-min restraint) plasma corticosterone (CORT) levels, and adrenal weights were measured. We found that all measures were heritable to some extent and that this heritability was highly sex dependent. Both correlation and factor analyses of the F2 generation data demonstrate that FST behavior and HPA axis measures are not directly related. Thus, the underlying genetic components of depressive-like behavior and HPA axis abnormalities are likely to be disparate in the segregating F2 generation of a WKY × F344 cross.

X-linked and lineage-dependent inheritance of coping responses to stress

Coping—or how one routinely deals with stress—is a complex behavioral trait with bearing on chronic disease and susceptibility to psychiatric disorders. This complexity is a result of not only underlying multigenic factors, but also important non-genetic ones. The defensive burying (DB) test, although originally developed as a test of anxiety, can accurately measure differences in coping strategies by assaying an animal’s behavioral response to an immediate threat with ethological validity. Using offspring derived from reciprocal crosses of two inbred rat strains differing in DB behaviors, we provide convergent phenotypic and genotypic evidence that coping styles are inherited in an X-linked fashion. We find that first-generation (F1) males, but not females, show maternally derived coping styles, and second-generation (F2) females, but not males, show significant differences in coping styles when separated by grandmaternal lineage. By using a linear modeling approach to account for covariate effects (sex and lineage) in QTL analysis, we map three quantitative trait loci (QTL) on the X Chromosome (Chr) (Coping-1, Approach-1, and Approach-2) associated with coping behaviors in the DB paradigm. Distinct loci were associated with different aspects of coping, and their effects were modulated by both the sex and lineage of the animals, demonstrating the power of the general linear modeling approach and the important interplay of allelic and non-allelic factors in the inheritance of coping behaviors.

Test-and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality

Inbred Wistar-Kyoto rats consistently display hypoactivity in tests of emotional behavior. We used them to test the hypothesis that the genetic factors underlying the behavioral decision-making process will vary in different environmental contexts. The contexts used were the open-field test (OFT), a novel environment with no explicit threats present, and the defensive-burying test (DB), a habituated environment into which a threat has been introduced. Rearing, a voluntary behavior was measured in both tests, and our study was the first to look for genetic loci affecting grooming, a relatively automatic, stress-responsive stereotyped behavior. Quantitative trait locus analysis was performed on a population of 486 F2 animals bred from reciprocal inter-crosses. The genetic architectures of DB and OFT rearing, and of DB and OFT grooming, were compared. There were no common loci affecting grooming behavior in both tests. These different contexts produced the stereotyped behavior via different pathways, and genetic factors seem to influence the decision-making pathways and not the expression of the behavior. Three loci were found that affected rearing behavior in both tests. However, in both contexts, other loci had greater effects on the behavior. Our results imply that environmental contexts effects on decision-making vary depending on the category of behavior.

Maternal behavior modulates x-linked inheritance of behavioral coping in the defensive burying test

BACKGROUND Complex behavioral traits such as coping strategies in response to stress are usually formed by genetic and environmental influences. METHODS By exploiting the phenotypic and genotypic differences between the Wistar Kyoto (WKY) and Fischer 344 (F344) inbred rat strains, we recently identified three X chromosome-linked quantitative trait loci contributing to differences in coping strategies in the defensive burying (DB) paradigm. In this article we study the influence of postnatal maternal environment in these behaviors by characterizing the maternal behavior of these strains and the effect of cross-fostering on DB behavior of male offspring from reciprocal crossing (F1). RESULTS Maternal behavior of WKY rats can be quantitatively characterized by less contact and more periods of neglect of their F1 pups. In contrast, F344 mothers engaged in more active behaviors such as licking/grooming and arched-back nursing. Cross-fostering male F1 pups at birth did not influence the latency to bury measure in DB; however, duration of burying and prod approaches were influenced by both genotype and maternal environment in an additive manner. CONCLUSIONS These results demonstrate that different measures of behavioral coping in the DB paradigm are influenced by maternal environment to differing degrees and in addition by genetic factors.