Portfolio theory, utility theory and mate selection

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HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGEþ) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGEþexpression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+ did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+ and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+ residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC

A Freeze Frame View of Vesicular Stomatitis Virus Transcription Defines a Minimal Length of RNA for 5′ Processing

The RNA synthesis machinery of vesicular stomatitis virus (VSV) comprises the genomic RNA encapsidated by the viral nucleocapsid protein (N) and associated with the RNA dependent RNA polymerase, the viral components of which are a large protein (L) and an accessory phosphoprotein (P). The 241 kDa L protein contains all the enzymatic activities necessary for synthesis of the viral mRNAs, including capping, cap methylation and polyadenylation. Those RNA processing reactions are intimately coordinated with nucleotide polymerization such that failure to cap results in termination of transcription and failure to methylate can result in hyper polyadenylation. The mRNA processing reactions thus serve as a critical check point in viral RNA synthesis which may control the synthesis of incorrectly modified RNAs. Here, we report the length at which viral transcripts first gain access to the capping machinery during synthesis. By reconstitution of transcription in vitro with highly purified recombinant polymerase and engineered templates in which we omitted sites for incorporation of UTP, we found that transcripts that were 30-nucleotides in length were uncapped, whereas those that were 31-nucleotides in length contained a cap structure. The minimal RNA length required for mRNA cap addition was also sufficient for methylation since the 31-nucleotide long transcripts were methylated at both ribose-2′-O and guanine-N-7 positions. This work provides insights into the spatial relationship between the active sites for the RNA dependent RNA polymerase and polyribonucleotidyltransferase responsible for capping of the viral RNA. We combine the present findings with our recently described electron microscopic structure of the VSV polymerase and propose a model of how the spatial arrangement of the capping activities of L may influence nucleotide polymerization

Emergence of scale-free leadership structure in social recommender systems

The study of the organization of social networks is important for understanding of opinion formation, rumor spreading, and the emergence of trends and fashion. This paper reports empirical analysis of networks extracted from four leading sites with social functionality (Delicious, Flickr, Twitter and YouTube) and shows that they all display a scale-free leadership structure. To reproduce this feature, we propose an adaptive network model driven by social recommending. Artificial agent-based simulations of this model highlight a "good get richer" mechanism where users with broad interests and good judgments are likely to become popular leaders for the others. Simulations also indicate that the studied social recommendation mechanism can gradually improve the user experience by adapting to tastes of its users. Finally we outline implications for real online resource-sharing systems

The influence of growth factors on the proliferative potential of normal and primary breast cancer-derived human breast epithelial cells

In previous studies, we developed serum-free, bovine pituitary extract (BPE)-free culture conditions for the growth of normal and neoplastic rat mammary epithelial cells. The present studies were aimed at determining if these culture methods could be used to study the influence of specific growth factors on the proliferative potential of normal human mammary epithelial (HME) cells and cells derived from human breast cancer (HBC) specimens. Our results indicate that normal HME cells in primary culture express stringent requirements for insulin (IN), epidermal growth factor (EGF), and cholera toxin (CT). Of these factors, EGF is most important, with essentially no proliferation taking place in the absence of this factor. By contrast, when cells are grown in serum-free primary culture in the presence of a full complement of growth factors and then subcultured, growth in secondary culture is not influenced by the removal of individual growth factors. Growth in secondary culture in the absence of EGF is mediated by autocrine factors secreted by the cells. However, there is no evidence for autocrine activity that mediates growth in the absence of IN in secondary cultures. Primary culture of HBC cells in serum-free, BPE-free medium revealed two patterns of growth factor requirements. One set of HBC cells expressed identical requirements for IN and EGF in primary culture as normal cells. Likewise, these cells grew in secondary culture in the absence of either factor. The second set of tumors expressed independence of IN for growth in primary culture. These cells grew to confluence in primary culture in the absence of IN and could be subcultured in this medium. All tumor cells examined expressed a requirement for EGF for primary culture growth, whereas none of the HBC cells examined expressed a significant CT requirement. In many cases, growth in the absence of CT exceeded that observed in its presence. Thus, our culture system allows analysis of the growth factor requirements of HME and HBC cells in primary culture. Our results indicate significant differences between HME and HBC cells in this regard. However, the results of secondary culture experiments indicate that the growth factor milieu from which cells are taken can have a profound effect on the requirements for growth factors in culture.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44196/1/10549_2005_Article_BF01806371.pd

Sharing Data for Public Health Research by Members of an International Online Diabetes Social Network

Background: Surveillance and response to diabetes may be accelerated through engaging online diabetes social networks (SNs) in consented research. We tested the willingness of an online diabetes community to share data for public health research by providing members with a privacy-preserving social networking software application for rapid temporal-geographic surveillance of glycemic control. Methods and Findings: SN-mediated collection of cross-sectional, member-reported data from an international online diabetes SN entered into a software applicaction we made available in a “Facebook-like” environment to enable reporting, charting and optional sharing of recent hemoglobin A1c values through a geographic display. Self-enrollment by 17% (n = 1,136) of n = 6,500 active members representing 32 countries and 50 US states. Data were current with 83.1% of most recent A1c values reported obtained within the past 90 days. Sharing was high with 81.4% of users permitting data donation to the community display. 34.1% of users also displayed their A1cs on their SN profile page. Users selecting the most permissive sharing options had a lower average A1c (6.8%) than users not sharing with the community (7.1%, p = .038). 95% of users permitted re-contact. Unadjusted aggregate A1c reported by US users closely resembled aggregate 2007–2008 NHANES estimates (respectively, 6.9% and 6.9%, p = 0.85). Conclusions: Success within an early adopter community demonstrates that online SNs may comprise efficient platforms for bidirectional communication with and data acquisition from disease populations. Advancing this model for cohort and translational science and for use as a complementary surveillance approach will require understanding of inherent selection and publication (sharing) biases in the data and a technology model that supports autonomy, anonymity and privacy.Centers for Disease Control and Prevention (U.S.) (P01HK000088-01)Centers for Disease Control and Prevention (U.S.) (P01HK000016 )National Institute of Alcohol Abuse and Alcoholism (U.S.) (R21 AA016638-01A1)National Center for Research Resources (U.S.) (1U54RR025224-01)Children's Hospital (Boston, Mass.) (Program for Patient Safety and Quality

Adult-Onset Obesity Reveals Prenatal Programming of Glucose-Insulin Sensitivity in Male Sheep Nutrient Restricted during Late Gestation

BACKGROUND: Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese. METHODS/PRINCIPAL FINDINGS: Pregnant sheep received adequate (1.0M; CE, n = 6) or energy restricted (0.7M) diet during early (1-65 days; LEE, n = 6) or late (65-128 days; LEL, n = 7) gestation (term approximately 147 days). Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT) and body composition determination by dual energy x-ray absorptiometry (DXA). All animals were then exposed to an obesogenic environment for 6-7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were 'lean' (1.5 years). Obesity revealed generalised metabolic 'inflexibility' and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulin(AUC) (from 133 to 341 [s.e.d. 26] ng.ml(-1).120 mins) during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml(-1)) and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml(-1); LEL male vs. CE male, respectively). Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism. CONCLUSIONS: This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and 'reveals' programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young prenatally 'programmed' animals so long as weight is adequately controlled. Nutritional excess in adulthood exacerbates any programmed phenotype, indicating greater vigilance over weight control is required for those individuals exposed to nutritional thrift during gestation

Optimising care for patients with cognitive impairment and dementia following hip fracture

The global shift in demographics towards aging populations is leading to a commensurate increase in age-related disease and frailty. It is essential to optimise health services to meet current needs and prepare for anticipated future demands. This paper explores issues impacting on people living with cognitive impairment and/or dementia who experience a hip fracture and are cared for in acute settings. This is important given the high mortality and morbidity associated with this population. Given the current insufficiency of clear evidence on optimum rehabilitation of this patient group, this paper explored three key themes namely: recognition of cognitive impairment, response by way of training and education of staff to optimise care for this patient group and review of the importance of outcomes measures. Whilst there is currently insufficient evidence to draw conclusions about the optimal ways of caring for patients living with dementia following hip fracture, this paper concludes that future research should improve understanding of healthcare staff education to improve the outcomes for this important group of patients

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.