Lower breast cancer survival in mothers of children with a malignancy: a national study

As it is unclear if hereditary factors affect breast cancer survival, this was compared using fertility and cancer registry data, among all women so diagnosed during 1961–1999 in Sweden, having a child with childhood cancer (⩽20 years of age; n=254) and with that of other women (n=74 781). Those having a child with a childhood malignancy had a significantly worse survival than other women, relative risk (RR)=1.25, 95% CI 1.02–1.55, P<0.04, adjusted for age at diagnosis, year of diagnosis, parity and time since last pregnancy. Childhood sarcomas or acute myeloid leukaemia seemed to be most associated with a worse survival in the mother (RR=1.38 and 1.69, respectively). The lower survival of the mother was present for breast cancer diagnosed both before and after 50 years of age. The Li–Fraumeni syndrome and possibly other genetic disorders may lower breast cancer survival

Spatiotemporally Controlled Cardiac Conduction Block Using High-Frequency Electrical Stimulation

Background: Methods for the electrical inhibition of cardiac excitation have long been sought to control excitability and conduction, but to date remain largely impractical. High-amplitude alternating current (AC) stimulation has been known to extend cardiac action potentials (APs), and has been recently exploited to terminate reentrant arrhythmias by producing reversible conduction blocks. Yet, low-amplitude currents at similar frequencies have been shown to entrain cardiac tissues by generation of repetitive APs, leading in some cases to ventricular fibrillation and hemodynamic collapse in vivo. Therefore, an inhibition method that does not lead to entrainment – irrespective of the stimulation amplitude (bound to fluctuate in an in vivo setting) – is highly desirable. Methodology/Principal Findings: We investigated the effects of broader amplitude and frequency ranges on the inhibitory effects of extracellular AC stimulation on HL-1 cardiomyocytes cultured on microelectrode arrays, using both sinusoidal and square waveforms. Our results indicate that, at sufficiently high frequencies, cardiac tissue exhibits a binary response to stimulus amplitude with either prolonged APs or no effect, thereby effectively avoiding the risks of entrainment by repetitive firing observed at lower frequencies. We further demonstrate the ability to precisely define reversible local conduction blocks in beating cultures without influencing the propagation activity in non-blocked areas. The conduction blocks were spatiotemporally controlled by electrode geometry and stimuli duration, respectively, and sustainable for long durations (300 s). Conclusion/Significance: Inhibition of cardiac excitation induced by high-frequency AC stimulation exhibits a binary response to amplitude above a threshold frequency, enabling the generation of reversible conduction blocks without the risks of entrainment. This inhibition method could yield novel approaches for arrhythmia modeling in vitro, as well as safer and more efficacious tools for in vivo cardiac mapping and radio-frequency ablation guidance applications

Engaging Undergraduates to Solve Global Health Challenges: A New Approach Based on Bioengineering Design

Recent reports have highlighted the need for educational programs to prepare students for careers developing and disseminating new interventions that improve global public health. Because of its multi-disciplinary, design-centered nature, the field of Biomedical Engineering can play an important role in meeting this challenge. This article describes a new program at Rice University to give undergraduate students from all disciplines a broad background in bioengineering and global health and provides an initial assessment of program impact. Working in partnership with health care providers in developing countries, students in the Beyond Traditional Borders (BTB) initiative learn about health challenges of the poor and put this knowledge to work immediately, using the engineering design process as a framework to formulate solutions to complex global health challenges. Beginning with a freshman design project and continuing through a capstone senior design course, the BTB curriculum uses challenges provided by partners in the developing world to teach students to integrate perspectives from multiple disciplines, and to develop leadership, communication, and teamwork skills. Exceptional students implement their designs under the guidance of clinicians through summer international internships. Since 2006, 333 students have designed more than 40 technologies and educational programs; 28 have been implemented in sub-Saharan Africa, Latin America, the Caribbean, southeast Asia, and the United States. More than 18,000 people have benefited from these designs. 95% of alumni who completed an international internship reported that participation in the program changed or strengthened their career plans to include a focus on global health medicine, research, and/or policy. Empowering students to use bioengineering design to address real problems is an effective way to teach the new generation of leaders needed to solve global health challenges

Diagnostic classification of childhood cancer using multiscale transcriptomics

The causes of pediatric cancers’ distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types

Action Spectroscopy on Dense Samples of Photosynthetic Reaction Centers of Rhodobacter sphaeroides WT Based on Nanosecond Laser-Flash 13C Photo-CIDNP MAS NMR

Photochemically induced dynamic nuclear polarization magic-angle spinning nuclear magnetic resonance (photo-CIDNP MAS NMR) allows for the investigation of the electronic structure of the photochemical machinery of photosynthetic reaction centers (RCs) at atomic resolution. For such experiments, either continuous radiation from white xenon lamps or green laser pulses are applied to optically dense samples. In order to explore their optical properties, optically thick samples of isolated and quinone-removed RCs of the purple bacteria of Rhodobacter sphaeroides wild type are studied by nanosecond laser-flash 13C photo-CIDNP MAS NMR using excitation wavelengths between 720 and 940 nm. Action spectra of both the transient nuclear polarization as well as the nuclear hyperpolarization, remaining in the electronic ground state at the end of the photocycle, are obtained. It is shown that the signal intensity is limited by the amount of accessible RCs and that the different mechanisms of the photo-CIDNP production rely on the same photophysical origin, which is the photocycle induced by one single photon

Getting research into policy - Herpes simplex virus type-2 (HSV-2) treatment and HIV infection: international guidelines formulation and the case of Ghana

BACKGROUND: Observational epidemiological and biological data indicate clear synergies between Herpes simplex virus type 2 (HSV-2) and HIV, whereby HSV-2 enhances the potential for HIV acquisition or transmission. In 2001, the World Health Organization (WHO) launched a call for research into the possibilities of disrupting this cofactor effect through the use of antiherpetic therapy. A WHO Expert Meeting was convened in 2008 to review the research results. The results of the trials were mostly inconclusive or showed no impact. However, the WHO syndromic management treatment guidelines were modified to include acyclovir as first line therapy to treat genital ulcer disease on the basis of the high prevalence of HSV-2 in most settings, impact and cost-benefit of treatment on ulcer healing and quality of life among patients. METHODS: This paper examines the process through which the evidence related to HIV-HSV-2 interactions influenced policy at the international level and then the mechanism of international to national policy transfer, with Ghana as a case study. To better understand the context within which national policy change occurs, special attention was paid to the relationships between researchers and policy-makers as integral to the process of getting evidence into policy. Data from this study were then collected through interviews conducted with researchers, program managers and policy-makers working in sexual health/STI at the 2008 WHO Expert Meeting in Montreux, Switzerland, and in Accra, Ghana. RESULTS: The major findings of this study indicate that investigations into HSV-2 as a cofactor of HIV generated the political will necessary to reform HSV-2 treatment policy. Playing a pivotal role at both the international level and within the Ghanaian policy context were 'policy networks' formed either formally (WHO) or informally (Ghana) around an issue area. These networks of professionals serve as the primary conduit of information between researchers and policy-makers. Donor influence was cited as the single strongest impetus and impediment to policy change nationally. CONCLUSIONS: Policy networks may serve as the primary driving force of change in both international context and in the case of Ghana. Communication among researchers and policy-makers is critical for uptake of evidence and opportunities may exist to formalize policy networks and engage donors in a productive and ethical way

Juxtamembrane Shedding of Plasmodium falciparum AMA1 Is Sequence Independent and Essential, and Helps Evade Invasion-Inhibitory Antibodies

The malarial life cycle involves repeated rounds of intraerythrocytic replication interspersed by host cell rupture which releases merozoites that rapidly invade fresh erythrocytes. Apical membrane antigen-1 (AMA1) is a merozoite protein that plays a critical role in invasion. Antibodies against AMA1 prevent invasion and can protect against malaria in vivo, so AMA1 is of interest as a malaria vaccine candidate. AMA1 is efficiently shed from the invading parasite surface, predominantly through juxtamembrane cleavage by a membrane-bound protease called SUB2, but also by limited intramembrane cleavage. We have investigated the structural requirements for shedding of Plasmodium falciparum AMA1 (PfAMA1), and the consequences of its inhibition. Mutagenesis of the intramembrane cleavage site by targeted homologous recombination abolished intramembrane cleavage with no effect on parasite viability in vitro. Examination of PfSUB2-mediated shedding of episomally-expressed PfAMA1 revealed that the position of cleavage is determined primarily by its distance from the parasite membrane. Certain mutations at the PfSUB2 cleavage site block shedding, and parasites expressing these non-cleavable forms of PfAMA1 on a background of expression of the wild type gene invade and replicate normally in vitro. The non-cleavable PfAMA1 is also functional in invasion. However – in contrast to the intramembrane cleavage site - mutations that block PfSUB2-mediated shedding could not be stably introduced into the genomic pfama1 locus, indicating that some shedding of PfAMA1 by PfSUB2 is essential. Remarkably, parasites expressing shedding-resistant forms of PfAMA1 exhibit enhanced sensitivity to antibody-mediated inhibition of invasion. Drugs that inhibit PfSUB2 activity should block parasite replication and may also enhance the efficacy of vaccines based on AMA1 and other merozoite surface proteins

The Equifinality of Archaeological Networks: an Agent-Based Exploratory Lab Approach

When we find an archaeological network, how can we explore the necessary versus contingent processes at play in the formation of that archaeological network? Given a set of circumstances or processes, what other possible network shapes could have emerged? This is the problem of equifinality, where many different means could potentially arrive at the same end result: the networks that we observe. This paper outlines how agent-based modelling can be used as a laboratory for exploring different processes of archaeological network formation. We begin by describing our best guess about how the (ancient) world worked, given our target materials (here, the networks of production and patronage surrounding the Roman brick industry in the hinterland of Rome). We then develop an agent-based model of the Roman extractive economy which generates different kinds of networks under various assumptions about how that economy works. The rules of the simulation are built upon the work of Bang (2006; 2008) who describes a model of the Roman economy which he calls the ‘imperial Bazaar’. The agents are allowed to interact, and the investigators compare the kinds of networks this description generates over an entire landscape of economic possibilities. By rigorously exploring this landscape, and comparing the resultant networks with those observed in the archaeological materials, the investigators will be able to employ the principle of equifinality to work out the representativeness of the archaeological network and thus the underlying processes