Personalized cancer medicine is based on increased knowledge of the cancer mutation repertoire and availability of agents that target altered genes or pathways. Given advances in cancer genetics, ...technology, and therapeutics development, the timing is right to develop a clinical trial and research framework to move future clinical decisions from heuristic to evidence-based decisions. Although the challenges of integrating genomic testing into cancer treatment decision making are wide-ranging and complex, there is a scientific and ethical imperative to realize the benefits of personalized cancer medicine, given the overwhelming burden of cancer and the unprecedented opportunities for advancements in outcomes for patients.
We propose an extension to quantile normalization that removes unwanted technical variation using control probes. We adapt our algorithm, functional normalization, to the Illumina 450k methylation ...array and address the open problem of normalizing methylation data with global epigenetic changes, such as human cancers. Using data sets from The Cancer Genome Atlas and a large case-control study, we show that our algorithm outperforms all existing normalization methods with respect to replication of results between experiments, and yields robust results even in the presence of batch effects. Functional normalization can be applied to any microarray platform, provided suitable control probes are available.
Companies are increasingly allocating more of their marketing spending to social media programs. Yet there is little research about how social media use is associated with consumer–brand ...relationships. We conducted three studies to explore how individual and national differences influence the relationship between social media use and customer brand relationships. The first study surveyed customers in France, the U.K. and U.S. and compared those who engage with their favorite brands via social media with those who do not. The findings indicated that social media use was positively related with brand relationship quality and the effect was more pronounced with high anthropomorphism perceptions (the extent to which consumers' associate human characteristics with brands). Two subsequent experiments further validated these findings and confirmed that cultural differences, specifically uncertainty avoidance, moderated these results. We obtained robust and convergent results from survey and experimental data using both student and adult consumer samples and testing across three product categories (athletic shoes, notebook computers, and automobiles). The results offer cross-national support for the proposition that engaging customers via social media is associated with higher consumer–brand relationships and word of mouth communications when consumers anthropomorphize the brand and they avoid uncertainty.
•We conducted studies to explore how individual and national differences influence the relationship between social media and brand relationships.•The first study surveyed customers in France, the U.K. and U.S. and compared those who engage with brands via social media with those who do not.•The findings indicated that social media use was positively related with brand relationship quality.•The effect was more pronounced with high anthropomorphism perceptions.•Two subsequent experiments further validated these findings and confirmed that cultural differences moderated these results.•The results offer support for the proposition that engaging customers via social media is associated with higher consumer-brand relationships.
The accurate detection of biological materials has remained at the forefront of scientific research for decades. This includes the detection of molecules, proteins, and bacteria. Biomimetic sensors ...look to replicate the sensitive and selective mechanisms that are found in biological systems and incorporate these properties into functional sensing platforms. Molecularly imprinted polymers (MIPs) are synthetic receptors that can form high affinity binding sites complementary to the specific analyte of interest. They utilise the shape, size, and functionality to produce sensitive and selective recognition of target analytes. One route of synthesizing MIPs is through electropolymerization, utilising predominantly constant potential methods or cyclic voltammetry. This methodology allows for the formation of a polymer directly onto the surface of a transducer. The thickness, morphology, and topography of the films can be manipulated specifically for each template. Recently, numerous reviews have been published in the production and sensing applications of MIPs; however, there are few reports on the use of electrosynthesized MIPs (eMIPs). The number of publications and citations utilising eMIPs is increasing each year, with a review produced on the topic in 2012. This review will primarily focus on advancements from 2012 in the use of eMIPs in sensing platforms for the detection of biologically relevant materials, including the development of increased polymer layer dimensions for whole bacteria detection and the use of mixed monomer compositions to increase selectivity toward analytes.
DNA methylation, an important type of epigenetic modification in humans, participates in crucial cellular processes, such as embryonic development, X-inactivation, genomic imprinting and chromosome ...stability. Several platforms have been developed to study genome-wide DNA methylation. Many investigators in the field have chosen the Illumina Infinium HumanMethylation microarray for its ability to reliably assess DNA methylation following sodium bisulfite conversion. Here, we analyzed methylation profiles of 489 adult males and 357 adult females generated by the Infinium HumanMethylation450 microarray. Among the autosomal CpG sites that displayed significant methylation differences between the two sexes, we observed a significant enrichment of cross-reactive probes co-hybridizing to the sex chromosomes with more than 94% sequence identity. This could lead investigators to mistakenly infer the existence of significant autosomal sex-associated methylation. Using sequence identity cutoffs derived from the sex methylation analysis, we concluded that 6% of the array probes can potentially generate spurious signals because of co-hybridization to alternate genomic sequences highly homologous to the intended targets. Additionally, we discovered probes targeting polymorphic CpGs that overlapped SNPs. The methylation levels detected by these probes are simply the reflection of underlying genetic polymorphisms but could be misinterpreted as true signals. The existence of probes that are cross-reactive or of target polymorphic CpGs in the Illumina HumanMethylation microarrays can confound data obtained from such microarrays. Therefore, investigators should exercise caution when significant biological associations are found using these array platforms. A list of all cross-reactive probes and polymorphic CpGs identified by us are annotated in this paper.
Macrophages are required for tissue homeostasis through their role in regulation of the immune response and the resolution of injury. Here we show, using the kidney as a model, that the Wnt pathway ...ligand Wnt7b is produced by macrophages to stimulate repair and regeneration. When macrophages are inducibly ablated from the injured kidney, the canonical Wnt pathway response in kidney epithelial cells is reduced. Furthermore, when Wnt7b is somatically deleted in macrophages, repair of injury is greatly diminished. Finally, injection of the Wnt pathway regulator Dkk2 enhances the repair process and suggests a therapeutic option. Because Wnt7b is known to stimulate epithelial responses during kidney development, these findings suggest that macrophages are able to rapidly invade an injured tissue and reestablish a developmental program that is beneficial for repair and regeneration.
Polydimethylsiloxane (PDMS) elastomer is used in a wide range of biomaterial applications including microfluidics, cell culture substrates, flexible electronics, and medical devices. However, it has ...proved challenging to 3D print PDMS in complex structures due to its low elastic modulus and need for support during the printing process. Here we demonstrate the 3D printing of hydrophobic PDMS prepolymer resins within a hydrophilic Carbopol gel support via freeform reversible embedding (FRE). In the FRE printing process, the Carbopol support acts as a Bingham plastic that yields and fluidizes when the syringe tip of the 3D printer moves through it, but acts as a solid for the PDMS extruded within it. This, in combination with the immiscibility of hydrophobic PDMS in the hydrophilic Carbopol, confines the PDMS prepolymer within the support for curing times up to 72 h while maintaining dimensional stability. After printing and curing, the Carbopol support gel releases the embedded PDMS prints by using phosphate buffered saline solution to reduce the Carbopol yield stress. As proof-of-concept, we used Sylgard 184 PDMS to 3D print linear and helical filaments via continuous extrusion and cylindrical and helical tubes via layer-by-layer fabrication. Importantly, we show that the 3D printed tubes were manifold and perfusable. The results demonstrate that hydrophobic polymers with low viscosity and long cure times can be 3D printed using a hydrophilic support, expanding the range of biomaterials that can be used in additive manufacturing. Further, by implementing the technology using low cost open-source hardware and software tools, the FRE printing technique can be rapidly implemented for research applications.
Current standard therapies for pancreatic ductal adenocarcinoma have failed to attenuate the aggressiveness of this disease or confer notable improvements in survival. Previous molecular research ...into pancreatic cancers, along with advances in sequencing technologies, have identified many altered genes in patients with pancreatic cancer and revealed the marked genetic heterogeneity of individual tumors. Thus, the lack of success of conventional empiric therapy can be partly attributed to the underlying heterogeneity of pancreatic tumors. The genetic alterations that have been detected in pancreatic cancer range from simple mutations at the level of base pairs to complex chromosomal structural changes and rearrangements. The identification of molecular changes that are unique to an individual patient's tumors, and the subsequent development of strategies to target the tumors in a personalized approach to therapeutics, is a necessary advance to improve therapy for patients with this disease.
In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce ...drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.
Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet ...identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations--with a meta-analysis false discovery rate less than 10(-4)--between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.
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