Multisite gynecologic endometrioid adenocarcinomas: Can mutation profiling be used to distinguish synchronous primary cancers from metastases?

It is well recognized that some patients with endometrioid gynecological cancers have tumors arising in multiple sites (ovary, endometrium, and endometriosis) at the time of diagnosis. Molecular analysis has helped discern whether these multisite cancers represent synchronous primary tumors or alternatively metastatic disease. We present a complex case of a patient with endometrioid carcinomas arising in multiple sites. We discuss the use of mutation profiling to discern clonality and highlight how this information may inform the clinical management of such cases

Character Displacement in the Midst of Substantial Background Evolution in Anolis Lizard Island Populations

Negative interactions between species can generate divergent selection that causes character displacement. However, other processes cause similar divergence. We use spatial and temporal replication across island populations of Anolis lizards to assess the importance of negative interactions in driving trait shifts. Previous work showed that the establishment of Anolis sagrei on islands drove resident Anolis carolinensis to perch higher and evolve larger toepads. To further test the interaction\u27s causality and predictability, we resurveyed a subset of islands nine years later. Anolis sagrei had established on one island between surveys. We found that A. carolinensis on this island now perch higher and have larger toepads. However, toepad morphology change on this island was not distinct from shifts on six other islands whose Anolis community composition had not changed. Thus, the presence of A. sagrei only partly explains A. carolinensis trait variation across space and time. We also found that A. carolinensis on islands with previously established A. sagrei now perch higher than a decade ago, and that current A. carolinensis perch height is correlated with A. sagrei density. Our results suggest that character displacement likely interacts with other evolutionary processes in this system, and that temporal data are key to detecting such interactions

Arrest History and Intimate Partner Violence Perpetration in a Sample of Men and Women Arrested for Domestic Violence

Intimate partner violence (IPV) is a serious and prevalent problem throughout the United States. Currently, individuals arrested for domestic violence are often court mandated to batterer intervention programs (BIPs). However, little is known about the arrest histories of these individuals, especially women. The current study examined the arrest histories of men (n = 303) and women (n = 82) arrested for domestic violence and court-referred to BIPs. Results demonstrated that over 30% of the entire sample had been previously arrested for a non-violent offense, and over 25% of the participants had been previously arrested for a violent offense other than domestic violence. Moreover, men were arrested significantly more frequently for violence-related and non-violent offenses than their female counterparts. In addition, men were more likely than women to have consumed binge-levels of alcohol prior to the offense that led to their most recent arrest and court-referral to a BIP. Lastly, arrest history was positively associated with physical and psychological aggression perpetration against an intimate partner for men only, such that more previous arrests were associated with more frequent aggression. These results provide evidence that many men and women arrested for domestic violence have engaged in a number of diverse criminal acts during their lifetimes, suggesting that BIPs may need to address general criminal behavior

DNA copy number, including telomeres and mitochondria, assayed using next-generation sequencing

<p>Abstract</p> <p>Background</p> <p>DNA copy number variations occur within populations and aberrations can cause disease. We sought to develop an improved lab-automatable, cost-efficient, accurate platform to profile DNA copy number.</p> <p>Results</p> <p>We developed a sequencing-based assay of nuclear, mitochondrial, and telomeric DNA copy number that draws on the unbiased nature of next-generation sequencing and incorporates techniques developed for RNA expression profiling. To demonstrate this platform, we assayed UMC-11 cells using 5 million 33 nt reads and found tremendous copy number variation, including regions of single and homogeneous deletions and amplifications to 29 copies; 5 times more mitochondria and 4 times less telomeric sequence than a pool of non-diseased, blood-derived DNA; and that UMC-11 was derived from a male individual.</p> <p>Conclusion</p> <p>The described assay outputs absolute copy number, outputs an error estimate (p-value), and is more accurate than array-based platforms at high copy number. The platform enables profiling of mitochondrial levels and telomeric length. The assay is lab-automatable and has a genomic resolution and cost that are tunable based on the number of sequence reads.</p

Comparison of Molecular Phenotypes of Ductal Carcinoma In Situ and Invasive Breast Cancer

Introduction: At least four major categories of invasive breast cancer that are associated with different clinical outcomes have been identified by gene expression profiling: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) and basal-like. However, the prevalence of these phenotypes among cases of ductal carcinoma in situ (DCIS) has not been previously evaluated in detail. The purpose of this study was to compare the prevalence of these distinct molecular subtypes among cases of DCIS and invasive breast cancer. Methods: We constructed tissue microarrays (TMAs) from breast cancers that developed in 2897 women enrolled in the Nurses' Health Study (1976 to 1996). TMA slides were immunostained for oestrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR). Using these immunostain results, cases were grouped into molecularly defined subtypes. Results: The prevalence of the distinct molecular phenotypes differed significantly between DCIS (n = 272) and invasive breast cancers (n = 2249). The luminal A phenotype was significantly more frequent among invasive cancers (73.4%) than among DCIS lesions (62.5%) (p = 0.0002). In contrast, luminal B and HER2 molecular phenotypes were both more frequent among DCIS (13.2% and 13.6%, respectively) as compared with invasive tumours (5.2% and 5.7%, respectively) (p < 0.0001). The basal-like phenotype was more frequent among the invasive cancers (10.9%) than DCIS (7.7%), although this difference was not statistically significant (p = 0.15). High-grade DCIS and invasive tumours were more likely to be HER2 type and basal-like than low- or intermediate-grade lesions. Among invasive tumours, basal-like and HER2 type tumours were more likely to be more than 2 cm in size, high-grade and have nodal involvement compared with luminal A tumours. Conclusion: The major molecular phenotypes previously identified among invasive breast cancers were also identified among cases of DCIS. However, the prevalence of the luminal A, luminal B and HER2 phenotypes differed significantly between DCIS and invasive breast cancers

Ascent Aerodynamic Force and Moment Database Development for the Space Launch System

The Space Launch System Aerodynamics Task Team is responsible for delivering aerodynamic force and moment databases from liftoff through ascent until the rocket leaves the Earths atmosphere. The process for developing the ascent portion of this database is described in the current paper. The data used to develop the database were generated using a combination of wind tunnel testing and CFD simulations. The details of the wind tunnel testing performed at the NASA Ames Unitary Plan Wind Tunnel and CFD simulations performed using FUN3D at wind tunnel and flight conditions are discussed, and comparisons of these data sets are provided. The methods used for converting the source data into the final database response surfaces with corresponding uncertainty are also detailed

Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants

OBJECTIVE:To investigate the association of macronutrient intake with all cause mortality and cardiovascular disease (CVD), and the implications for dietary advice. DESIGN:Prospective population based study. SETTING:UK Biobank. PARTICIPANTS:195 658 of the 502 536 participants in UK Biobank completed at least one dietary questionnaire and were included in the analyses. Diet was assessed using Oxford WebQ, a web based 24 hour recall questionnaire, and nutrient intakes were estimated using standard methodology. Cox proportional models with penalised cubic splines were used to study non-linear associations. MAIN OUTCOME MEASURES:All cause mortality and incidence of CVD. RESULTS:4780 (2.4%) participants died over a mean 10.6 (range 9.4-13.9) years of follow-up, and 948 (0.5%) and 9776 (5.0%) experienced fatal and non-fatal CVD events, respectively, over a mean 9.7 (range 8.5-13.0) years of follow-up. Non-linear associations were found for many macronutrients. Carbohydrate intake showed a non-linear association with mortality; no association at 20-50% of total energy intake but a positive association at 50-70% of energy intake (3.14 v 2.75 per 1000 person years, average hazard ratio 1.14, 95% confidence interval 1.03 to 1.28 (60-70% v 50% of energy)). A similar pattern was observed for sugar but not for starch or fibre. A higher intake of monounsaturated fat (2.94 v 3.50 per 1000 person years, average hazard ratio 0.58, 0.51 to 0.66 (20-25% v 5% of energy)) and lower intake of polyunsaturated fat (2.66 v 3.04 per 1000 person years, 0.78, 0.75 to 0.81 (5-7% v 12% of energy)) and saturated fat (2.66 v 3.59 per 1000 person years, 0.67, 0.62 to 0.73 (5-10% v 20% of energy)) were associated with a lower risk of mortality. A dietary risk matrix was developed to illustrate how dietary advice can be given based on current intake. CONCLUSION:Many associations between macronutrient intake and health outcomes are non-linear. Thus dietary advice could be tailored to current intake. Dietary guidelines on macronutrients (eg, carbohydrate) should also take account of differential associations of its components (eg, sugar and starch)

Dealing with missing data in a multi-question depression scale: a comparison of imputation methods

BACKGROUND: Missing data present a challenge to many research projects. The problem is often pronounced in studies utilizing self-report scales, and literature addressing different strategies for dealing with missing data in such circumstances is scarce. The objective of this study was to compare six different imputation techniques for dealing with missing data in the Zung Self-reported Depression scale (SDS). METHODS: 1580 participants from a surgical outcomes study completed the SDS. The SDS is a 20 question scale that respondents complete by circling a value of 1 to 4 for each question. The sum of the responses is calculated and respondents are classified as exhibiting depressive symptoms when their total score is over 40. Missing values were simulated by randomly selecting questions whose values were then deleted (a missing completely at random simulation). Additionally, a missing at random and missing not at random simulation were completed. Six imputation methods were then considered; 1) multiple imputation, 2) single regression, 3) individual mean, 4) overall mean, 5) participant's preceding response, and 6) random selection of a value from 1 to 4. For each method, the imputed mean SDS score and standard deviation were compared to the population statistics. The Spearman correlation coefficient, percent misclassified and the Kappa statistic were also calculated. RESULTS: When 10% of values are missing, all the imputation methods except random selection produce Kappa statistics greater than 0.80 indicating 'near perfect' agreement. MI produces the most valid imputed values with a high Kappa statistic (0.89), although both single regression and individual mean imputation also produced favorable results. As the percent of missing information increased to 30%, or when unbalanced missing data were introduced, MI maintained a high Kappa statistic. The individual mean and single regression method produced Kappas in the 'substantial agreement' range (0.76 and 0.74 respectively). CONCLUSION: Multiple imputation is the most accurate method for dealing with missing data in most of the missind data scenarios we assessed for the SDS. Imputing the individual's mean is also an appropriate and simple method for dealing with missing data that may be more interpretable to the majority of medical readers. Researchers should consider conducting methodological assessments such as this one when confronted with missing data. The optimal method should balance validity, ease of interpretability for readers, and analysis expertise of the research team

Exploring the Nexus of Alzheimer’s Disease and Related Dementias with Cancer and Cancer Therapies

Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer’s disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation convened a one day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations and partnerships for future action