A new generation of sequencing technologies, from Illumina/Solexa, ABI/SOLiD, 454/Roche, and Helicos, has provided unprecedented opportunities for high-throughput functional genomic research. To ...date, these technologies have been applied in a variety of contexts, including whole-genome sequencing, targeted resequencing, discovery of transcription factor binding sites, and noncoding RNA expression profiling. This review discusses applications of next-generation sequencing technologies in functional genomics research and highlights the transforming potential these technologies offer.
Next-generation sequencing has allowed identification of millions of somatic mutations and epigenetic changes in cancer cells. A key challenge in interpreting cancer genomes and epigenomes is ...distinguishing which genetic and epigenetic changes are drivers of cancer development. Frequency-based and function-based approaches have been developed to identify candidate drivers; we discuss the advantages and drawbacks of these methods as well as their latest refinements. We focus particularly on identification of the types of drivers most likely to be missed, such as genes affected by copy number alterations, mutations in noncoding regions, dysregulation of microRNA, epigenetic changes, and mutations in chromatin modifiers.
Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological ...transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.
Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.
Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
The interaction between galloping and Kármán-vortex resonance for long rectangular cylinders is a crucial issue in flow-induced vibration, since this type of instability can cause catastrophic ...oscillations of structures or structural elements exposed to wind. Nevertheless, the models for galloping and vortex-induced vibrations fail to predict the onset of the excitation and its evolution with the flow speed. The main goal of this work is to clarify the most relevant features of the VIV–galloping instability for structures with rectangular cross section and to outline the parameters that control the phenomenon. First, this is pursued through an extensive literature review concerning two- and three-dimensional rectangular prisms with a side ratio in the range 1–2, which shows the complexity of the issue and the need for further investigations. Then, the results of new wind tunnel tests in smooth flow on a two-dimensional rectangular 3:2 cylinder were provided. This cross section was found very prone to instability and large-amplitude vibrations were observed also for high values of the Scruton number (product of non-dimensional mass times damping) and relatively low wind speeds. Also, for low Scruton numbers, the paper underscores the possibility to observe non-negligible excitation at low wind speed due to secondary vortex-resonance. Finally, the non-conservativeness of the values provided by Eurocode 1 for the galloping stability parameter and the Strouhal number is discussed.
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•Extensive literature review on the VIV–galloping instability of rectangular cylinders.•Large database for the galloping stability parameter of rectangular sections.•Experiments show the proclivity to VIV–galloping interaction of a rectangular 3:2 cylinder.•This interaction may foster a galloping-type instability at low reduced wind speed.•Eurocode 1 provides non-conservative data about galloping of rectangular sections.
Bronchial thermoplasty (BT) is a recently developed treatment for patients with moderate-to-severe asthma. A few studies have suggested the clinical efficacy of this intervention. However, no study ...has evaluated the cost-effectiveness of BT compared to other alternative treatments for moderate-to-severe allergic asthma, which currently include omalizumab and standard therapy.
To evaluate the cost-effectiveness of standard therapy, BT, and omalizumab for moderate-to-severe allergic asthma in the USA.
A probabilistic Markov model with weekly cycles was developed to reflect the course of asthma progression over a 5-year time horizon. The study population was adults with moderate-to-severe allergic asthma whose asthma remained uncontrolled despite using high-dose inhaled corticosteroids (ICS, with or without long-acting beta-agonists LABA). A perspective of the health-care system was adopted with asthma-related costs as well as quality-adjusted life years (QALYs) and exacerbations as the outcomes.
For standard therapy, BT, and omalizumab, the discounted 5-year costs and QALYs were $15,400 and 3.08, $28,100 and 3.24, and $117,000 and 3.26, respectively. The incremental cost-effectiveness ratio (ICER) of BT versus standard therapy and omalizumab versus BT was $78,700/QALY and $3.86 million/QALY, respectively. At the willingness-to-pay (WTP) of $50,000/QALY and $100,000/QALY, the probability of BT being cost-effective was 9%, and 67%, respectively. The corresponding expected value of perfect information (EVPI) was $155 and $1,530 per individual at these thresholds. In sensitivity analyses, increasing the costs of BT from $14,900 to $30,000 increased its ICER relative to standard therapy to $178,000/QALY, and decreased the ICER of omalizumab relative to BT to $3.06 million/QALY. Reducing the costs of omalizumab by 25% decreased its ICER relative to BT by 29%.
Based on the available evidence, our study suggests that there is more than 60% chance that BT becomes cost-effective relative to omalizumab and standard therapy at the WTP of $100,000/QALY in patients with moderate-to-severe allergic asthma. However, there is a substantial uncertainty in the underlying evidence, indicating the need for future research towards reducing such uncertainty.
Transcriptome analysis has been a key area of biological inquiry for decades. Over the years, research in the field has progressed from candidate gene-based detection of RNAs using Northern blotting ...to high-throughput expression profiling driven by the advent of microarrays. Next-generation sequencing technologies have revolutionized transcriptomics by providing opportunities for multidimensional examinations of cellular transcriptomes in which high-throughput expression data are obtained at a single-base resolution.
Gate-model quantum computers promise to solve currently intractable computational problems if they can be operated at scale with long coherence times and high-fidelity logic. Neutral-atom hyperfine ...qubits provide inherent scalability owing to their identical characteristics, long coherence times and ability to be trapped in dense, multidimensional arrays
. Combined with the strong entangling interactions provided by Rydberg states
, all the necessary characteristics for quantum computation are available. Here we demonstrate several quantum algorithms on a programmable gate-model neutral-atom quantum computer in an architecture based on individual addressing of single atoms with tightly focused optical beams scanned across a two-dimensional array of qubits. Preparation of entangled Greenberger-Horne-Zeilinger (GHZ) states
with up to six qubits, quantum phase estimation for a chemistry problem
and the quantum approximate optimization algorithm (QAOA)
for the maximum cut (MaxCut) graph problem are demonstrated. These results highlight the emergent capability of neutral-atom qubit arrays for universal, programmable quantum computation, as well as preparation of non-classical states of use for quantum-enhanced sensing.
Tuberculosis remains a major public health problem worldwide. In recent years, increasing efforts have been dedicated to assessing the health-related quality of life experienced by people infected ...with tuberculosis. The objectives of this study were to better understand the impact of tuberculosis and its treatment on people's quality of life, and to review quality of life instruments used in current tuberculosis research.
A systematic literature search from 1981 to 2008 was performed through a number of electronic databases as well as a manual search. Eligible studies assessed multi-dimensional quality of life in people with tuberculosis disease or infection using standardized instruments. Results of the included studies were summarized qualitatively.
Twelve original studies met our criteria for inclusion. A wide range of quality of life instruments were involved, and the Short-Form 36 was most commonly used. A validated tuberculosis-specific quality of life instrument was not located. The findings showed that tuberculosis had a substantial and encompassing impact on patients' quality of life. Overall, the anti-tuberculosis treatment had a positive effect of improving patients' quality of life; their physical health tended to recover more quickly than the mental well-being. However, after the patients successfully completed treatment and were microbiologically 'cured', their quality of life remained significantly worse than the general population.
Tuberculosis has substantially adverse impacts on patients' quality of life, which persist after microbiological 'cure'. A variety of instruments were used to assess quality of life in tuberculosis and there has been no well-established tuberculosis-specific instrument, making it difficult to fully understand the impact of the illness.
Summary Our objective was to determine international estimates of the economic burden of falls in older people living in the community. Our systematic review emphasized the need for a consensus on ...methodology for cost of falls studies to enable more accurate comparisons and subgroup-specific estimates among different countries. Introduction The purpose of this study was to determine international estimates of the economic burden of falls in older people living in the community. Methods This is a systematic review of peer-reviewed journal articles reporting estimates for the cost of falls in people aged ≥60 years living in the community. We searched for papers published between 1945 and December 2008 in MEDLINE, PUBMED, EMBASE, CINAHL, Cochrane Collaboration, and NHS EED databases that identified cost of falls in older adults. We extracted the cost of falls in the reported currency and converted them to US dollars at 2008 prices, cost items measured, perspective, time horizon, and sensitivity analysis. We assessed the quality of the studies using a selection of questions from Drummond's checklist. Results Seventeen studies met our inclusion criteria. Studies varied with respect to viewpoint of the analysis, definition of falls, identification of important and relevant cost items, and time horizon. Only two studies reported a sensitivity analysis and only four studies identified the viewpoint of their economic analysis. In the USA, non-fatal and fatal falls cost US $23.3 billion (2008 prices) annually and US $1.6 billion in the UK. Conclusions The economic cost of falls is likely greater than policy makers appreciate. The mean cost of falls was dependent on the denominator used and ranged from US $3,476 per faller to US $10,749 per injurious fall and US $26,483 per fall requiring hospitalization. A consensus on methodology for cost of falls studies would enable more accurate comparisons and subgroup-specific estimates among different countries.
We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer ...Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.
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