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In JoVE (1)
Other Publications (14)
- Pharmacogenomics and Personalized Medicine
- Qualitative Health Research
- Physical Review Letters
- Physical Review Letters
- Physical Review Letters
- Health Technology Assessment (Winchester, England)
- Journal of the American Academy of Audiology
- Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies
- Journal of the American College of Cardiology
- Cell
- Clinical and Molecular Allergy : CMA
- Systematic Biology
- PloS One
- PloS One
Articles by Jonathan D. Cook in JoVE
JoVE General
A Convenient and General Expression Platform for the Production of Secreted Proteins from Human Cells
Department of Laboratory Medicine and Pathobiology, University of Toronto
In the post-human genomics era, the availability of recombinant proteins in native conformations is crucial to structural, functional and therapeutic research and development. Here, we describe a test- and large-scale protein expression system in human embryonic kidney 293T cells that can be used to produce a variety of recombinant proteins.
Other articles by Jonathan D. Cook on PubMed
Sulfation of Fulvestrant by Human Liver Cytosols and Recombinant SULT1A1 and SULT1E1
Fulvestrant (Faslodex™) is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Previous studies have demonstrated that fulvestrant metabolism in humans involves cytochromes P450 and UDP-glucuronosyltransferases (UGTs). To date, fulvestrant sulfation has not been characterized. This study examined fulvestrant sulfation with nine recombinant sulfotransferases and found that only SULT1A1 and SULT1E1 displayed catalytic activity toward this substrate, with K(m) of 4.2 ± 0.99 and 0.2 ± 0.16 μM, respectively. In vitro assays of 104 human liver cytosols revealed marked individual variability that was highly correlated with β-naphthol sulfation (SULT1A1 diagnostic substrate; r = 0.98, P < 0.0001), but not with 17β-estradiol sulfation (SULT1E1 diagnostic substrate; r = 0.16, P = 0.10). Fulvestrant sulfation was correlated with both SULT1A1*1/2 genotype (P value = 0.023) and copy number (P < 0.0001). These studies suggest that factors influencing SULT1A1/1E1 tissue expression and/or enzymatic activity could influence the efficacy of fulvestrant therapy.
Patterns of Dating Violence Across Adolescence
Adolescent dating violence (ADV) is a prevalent social and health problem associated with a number of adolescent risk behaviors and negative outcomes. The purpose of this study was to identify patterns of dating violence across adolescence. We used cross-case analysis to analyze interviews with 88 young adults (men and women aged 18 to 21) who were involved in violent dating relationships as teens. We identified four patterns of dating violence throughout adolescence. We also identified two patterns for adolescents who had only one violent relationship based on the length of the relationship-contained ADV and prolonged ADV-and two patterns for those who had multiple violent relationships based on the level of violence severity-repetitive ADV and escalating ADV. Knowledge of these four patterns can be used to guide therapeutic interactions with teens and to develop pattern-specific prevention and intervention strategies.
First Observation of the Decays B(0) †’ D(+)K(-)Ï€(+)Ï€(-) and B(-) †’ D(0)K(-)Ï€(+)Ï€(-)
First observations of the Cabibbo-suppressed decays B(0) → D(+)K(-)π(+)π(-) and B(-) → D(0)K(-)π(+)π(-) are reported using 35 pb(-1) of data collected with the LHCb detector. Their branching fractions are measured with respect to the corresponding Cabibbo-favored decays, from which we obtain B(B(0) → D(+)K(-)π(+)π(-))/B(B(0) → D(+)π(-)π(+)π(-))=(5.9±1.1±0.5)×10(-2) and B(B(-) → D(0)K(-)π(+)π(-))/B(B(-) → D(0)π(-)π(+)π(-))=(9.4±1.3±0.9)×10(-2), where the uncertainties are statistical and systematic, respectively. The B(-) → D(0)K(-)π(+)π(-) decay is particularly interesting, as it can be used in a similar way to B(-) → D(0)K(-) to measure the Cabibbo-Kobayashi-Maskawa phase γ.
Search for Scalar Bottom Quark Pair Production with the ATLAS Detector in Pp Collisions at Sqrt[s]=7  TeV
The results of a search for pair production of the scalar partners of bottom quarks in 2.05  fb(-1) of pp collisions at sqrt[s]=7  TeV using the ATLAS experiment are reported. Scalar bottom quarks are searched for in events with large missing transverse momentum and two jets in the final state, where both jets are identified as originating from a bottom quark. In an R-parity conserving minimal supersymmetric scenario, assuming that the scalar bottom quark decays exclusively into a bottom quark and a neutralino, 95% confidence-level upper limits are obtained in the b(1) - χ(1)(0) mass plane such that for neutralino masses below 60 GeV scalar bottom masses up to 390 GeV are excluded.
Differential Branching Fraction and Angular Analysis of the Decay B0 †’ K*0 μ+ μ-
The angular distributions and the partial branching fraction of the decay B0 → K*0 μ+ μ- are studied by using an integrated luminosity of 0.37  fb(-1) of data collected with the LHCb detector. The forward-backward asymmetry of the muons, A(FB), the fraction of longitudinal polarization, F(L), and the partial branching fraction dB/dq2 are determined as a function of the dimuon invariant mass. The measurements are in good agreement with the standard model predictions and are the most precise to date. In the dimuon invariant mass squared range 1.00-6.00  GeV2/c4, the results are A(FB)=-0.06(-0.14)(+0.13)±0.04, F(L)=0.55±0.10±0.03, and dB/dq2=(0.42±0.06±0.03)×10(-7)  c4/GeV2. In each case, the first error is statistical and the second systematic.
Surveillance for Ocular Hypertension: an Evidence Synthesis and Economic Evaluation
To determine effective and efficient monitoring criteria for ocular hypertension [raised intraocular pressure (IOP)] through (i) identification and validation of glaucoma risk prediction models; and (ii) development of models to determine optimal surveillance pathways.
Current Research with Cochlear Implants at Arizona State University
In this article we review, and discuss the clinical implications of, five projects currently underway in the Cochlear Implant Laboratory at Arizona State University. The projects are (1) norming the AzBio sentence test, (2) comparing the performance of bilateral and bimodal cochlear implant (CI) patients in realistic listening environments, (3) accounting for the benefit provided to bimodal patients by low-frequency acoustic stimulation, (4) assessing localization by bilateral hearing aid patients and the implications of that work for hearing preservation patients, and (5) studying heart rate variability as a possible measure for quantifying the stress of listening via an implant. The long-term goals of the laboratory are to improve the performance of patients fit with cochlear implants and to understand the mechanisms, physiological or electronic, that underlie changes in performance. We began our work with cochlear implant patients in the mid-1980s and received our first grant from the National Institutes of Health (NIH) for work with implanted patients in 1989. Since that date our work with cochlear implant patients has been funded continuously by the NIH. In this report we describe some of the research currently being conducted in our laboratory.
Genome-Wide Association Study for Ovarian Cancer Susceptibility Using Pooled DNA
Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.
Future Directions for Cardiovascular Disease Comparative Effectiveness Research: Report of a Workshop Sponsored by the National Heart, Lung, and Blood Institute
Comparative effectiveness research (CER) aims to provide decision makers with the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart, Lung, and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address 8 clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.
The Origin and Evolution of Mutations in Acute Myeloid Leukemia
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.
IL-3 and TNFα Increase Thymic Stromal Lymphopoietin Receptor (TSLPR) Expression on Eosinophils and Enhance TSLP-stimulated Degranulation
Thymic stromal lymphopoietin (TSLP) and eosinophils are prominent components of allergic inflammation. Therefore, we sought to determine whether TSLP could activate eosinophils, focusing on measuring the regulation of TSLPR expression on eosinophils and degranulation in response to TSLP, as well as other eosinophil activation responses.
An Extreme Case of Plant-Insect Codiversification: Figs and Fig-Pollinating Wasps
It is thought that speciation in phytophagous insects is often due to colonization of novel host plants, because radiations of plant and insect lineages are typically asynchronous. Recent phylogenetic comparisons have supported this model of diversification for both insect herbivores and specialized pollinators. An exceptional case where contemporaneous plant-insect diversification might be expected is the obligate mutualism between fig trees (Ficus species, Moraceae) and their pollinating wasps (Agaonidae, Hymenoptera). The ubiquity and ecological significance of this mutualism in tropical and subtropical ecosystems has long intrigued biologists, but the systematic challenge posed by >750 interacting species pairs has hindered progress toward understanding its evolutionary history. In particular, taxon sampling and analytical tools have been insufficient for large-scale cophylogenetic analyses. Here, we sampled nearly 200 interacting pairs of fig and wasp species from across the globe. Two supermatrices were assembled: on an average, wasps had sequences from 77% of 6 genes (5.6 kb), figs had sequences from 60% of 5 genes (5.5 kb), and overall 850 new DNA sequences were generated for this study. We also developed a new analytical tool, Jane 2, for event-based phylogenetic reconciliation analysis of very large data sets. Separate Bayesian phylogenetic analyses for figs and fig wasps under relaxed molecular clock assumptions indicate Cretaceous diversification of crown groups and contemporaneous divergence for nearly half of all fig and pollinator lineages. Event-based cophylogenetic analyses further support the codiversification hypothesis. Biogeographic analyses indicate that the present-day distribution of fig and pollinator lineages is consistent with a Eurasian origin and subsequent dispersal, rather than with Gondwanan vicariance. Overall, our findings indicate that the fig-pollinator mutualism represents an extreme case among plant-insect interactions of coordinated dispersal and long-term codiversification. [Biogeography; coevolution; cospeciation; host switching; long-branch attraction; phylogeny.].
The Aromatase Gene (CYP19A1) Variants and Circulating Hepatocyte Growth Factor in Postmenopausal Women
Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations.
Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
