In silico modeling of oxygen-enhanced MRI of specific ventilation.

Specific ventilation imaging (SVI) proposes that using oxygen-enhanced 1H MRI to capture signal change as subjects alternatively breathe room air and 100% O2 provides an estimate of specific ventilation distribution in the lung. How well this technique measures SV and the effect of currently adopted approaches of the technique on resulting SV measurement is open for further exploration. We investigated (1) How well does imaging a single sagittal lung slice represent whole lung SV? (2) What is the influence of pulmonary venous blood on the measured MRI signal and resultant SVI measure? and (3) How does inclusion of misaligned images affect SVI measurement? In this study, we utilized two patient-based in silico models of ventilation, perfusion, and gas exchange to address these questions for normal healthy lungs. Simulation results from the two healthy young subjects show that imaging a single slice is generally representative of whole lung SV distribution, with a calculated SV gradient within 90% of that calculated for whole lung distributions. Contribution of O2 from the venous circulation results in overestimation of SV at a regional level where major pulmonary veins cross the imaging plane, resulting in a 10% increase in SV gradient for the imaging slice. A worst-case scenario simulation of image misalignment increased the SV gradient by 11.4% for the imaged slice

Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance

The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vacciniabased method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with singletransfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P \u3c 0.05) or control (MDCKII-Co) cells (P \u3c 0.001). In vivo docetaxel transport studies in Slco1b2-/- mice showed approximately \u3e5.5-fold higher plasma concentrations (P \u3c 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P \u3c 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2-/- mice was 83% lower than WT mice (P \u3c 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics

A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.

Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers

The HST Key Project on the Extragalactic Distance Scale XXV. A Recalibration of Cepheid Distances to Type Ia Supernovae and the Value of the Hubble Constant

Cepheid-based distances to seven Type Ia supernovae (SNe)-host galaxies have been derived using the standard HST Key Project on the Extragalactic Distance Scale pipeline. For the first time, this allows for a transparent comparison of data accumulated as part of three different HST projects, the Key Project, the Sandage et al. Type Ia SNe program, and the Tanvir et al. Leo I Group study. Re-analyzing the Tanvir et al. galaxy and six Sandage et al. galaxies we find a mean (weighted) offset in true distance moduli of 0.12+/-0.07 mag -- i.e., 6% in linear distance -- in the sense of reducing the distance scale, or increasing H0. Adopting the reddening-corrected Hubble relations of Suntzeff et al. (1999), tied to a zero point based upon SNe~1990N, 1981B, 1998bu, 1989B, 1972E and 1960F and the photometric calibration of Hill et al. (1998), leads to a Hubble constant of H0=68+/-2(random)+/-5(systematic) km/s/Mpc. Adopting the Kennicutt et al. (1998) Cepheid period-luminosity-metallicity dependency decreases the inferred H0 by 4%. The H0 result from Type Ia SNe is now in good agreement, to within their respective uncertainties, with that from the Tully-Fisher and surface brightness fluctuation relations.Comment: Accepted for publication in The Astrophysical Journal. 62 pages, LaTeX, 9 Postscript figures. Also available at http://casa.colorado.edu/~bgibson/publications.htm

The HST Key Project on the Extragalactic Distance Scale. XXVIII. Combining the Constraints on the Hubble Constant

Since the launch of the Hubble Space Telescope nine years ago, Cepheid distances to 25 galaxies have been determined for the purpose of calibrating secondary distance indicators. A variety of these can now be calibrated, and the accompanying papers by Sakai, Kelson, Ferrarese, and Gibson employ the full set of 25 galaxies to consider the Tully-Fisher relation, the fundamental plane of elliptical galaxies, Type Ia supernovae, and surface brightness fluctuations. When calibrated with Cepheid distances, each of these methods yields a measurement of the Hubble constant and a corresponding measurement uncertainty. We combine these measurements in this paper, together with a model of the velocity field, to yield the best available estimate of the value of H_0 within the range of these secondary distance indicators and its uncertainty. The result is H_0 = 71 +/- 6 km/sec/Mpc. The largest contributor to the uncertainty of this 67% confidence level result is the distance of the Large Magellanic Cloud, which has been assumed to be 50 +/- 3 kpc

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation

Targeted next generation sequencing as a tool for precision medicine

Background: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1∗28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. Methods: A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. Results: Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1∗28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. Conclusions: PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine

The Vehicle, Spring 1999

Vol. 40, No. 2 Table of Contents Poetry Eve\u27s DaughterSylvia Whippopage 1 When We Wore Canoes On Our ShouldersMandy Watsonpage 2 This Is Not A Poem About GrandpaJake Tolbertpage 3 Old relationshipsBrandi Kinneypage 5 UntitledErin Winnerpage 6 BraverySylvia Whippopage 6 deep dark closetNicole Smithpage 7 Belly EarthTara Coburnpage 9 The River and FireJake Tolbertpage 10 UntitledAutumn Williamspage 12 Action PotentialKim Evanspage 13 Chimerical (a song for children)D.M. Attrapepage 14 UntitledAutumn Williamspage 16 UntitledMatthew Armstrongpage 18 Building YouSylvia Whippopage 19 RunningKim Evanspage 20 Walking Jenn to WorkJake Tolbertpage 22 Looking InKim Hunterpage 23 Void Between Me and WisconsinMandy Watsonpage 24 Artwork UntitledWendy Finchpage 4 MeditationJennifer Lundpage 8 UntitledSteve Drakepage 15 MemoriesJennifer Lundpage 21 UntitledKathryn Kolasinskipage 25 Prose FoundKim Hunterpage 26 A Day in the Life of William Baxter, DriverDaniel Fitzgeraldpage 32https://thekeep.eiu.edu/vehicle/1072/thumbnail.jp

The Vehicle, Spring 1999

Vol. 40, No. 2 Table of Contents Poetry Eve\u27s DaughterSylvia Whippopage 1 When We Wore Canoes On Our ShouldersMandy Watsonpage 2 This Is Not A Poem About GrandpaJake Tolbertpage 3 Old relationshipsBrandi Kinneypage 5 UntitledErin Winnerpage 6 BraverySylvia Whippopage 6 deep dark closetNicole Smithpage 7 Belly EarthTara Coburnpage 9 The River and FireJake Tolbertpage 10 UntitledAutumn Williamspage 12 Action PotentialKim Evanspage 13 Chimerical (a song for children)D.M. Attrapepage 14 UntitledAutumn Williamspage 16 UntitledMatthew Armstrongpage 18 Building YouSylvia Whippopage 19 RunningKim Evanspage 20 Walking Jenn to WorkJake Tolbertpage 22 Looking InKim Hunterpage 23 Void Between Me and WisconsinMandy Watsonpage 24 Artwork UntitledWendy Finchpage 4 MeditationJennifer Lundpage 8 UntitledSteve Drakepage 15 MemoriesJennifer Lundpage 21 UntitledKathryn Kolasinskipage 25 Prose FoundKim Hunterpage 26 A Day in the Life of William Baxter, DriverDaniel Fitzgeraldpage 32https://thekeep.eiu.edu/vehicle/1072/thumbnail.jp

Effect of Public Deliberation on Attitudes toward Return of Secondary Results in Genomic Sequencing

The increased use of genomic sequencing in clinical diagnostics and therapeutics makes imperative the development of guidelines and policies about how to handle secondary findings. For reasons both practical and ethical, the creation of these guidelines must take into consideration the informed opinions of the lay public. As part of a larger Clinical Sequencing Exploratory Research (CSER) consortium project, we organized a deliberative democracy (DD) session that engaged 66 participants in dialogue about the benefits and risks associated with the return of secondary findings from clinical genomic sequencing. Participants were educated about the scientific and ethical aspects of the disclosure of secondary findings by experts in medical genetics and bioethics, and then engaged in facilitated discussion of policy options for the disclosure of three types of secondary findings: 1) medically actionable results; 2) adult onset disorders found in children; and 3) carrier status. Participants’ opinions were collected via surveys administered one month before, immediately following, and one month after the DD session. Post DD session, participants were significantly more willing to support policies that do not allow access to secondary findings related to adult onset conditions in children (Χ2 (2, N = 62) = 13.300, p = 0.001) or carrier status (Χ2 (2, N = 60) = 11.375, p = 0.003). After one month, the level of support for the policy denying access to secondary findings regarding adult‐onset conditions remained significantly higher than the pre‐DD level, although less than immediately post‐DD (Χ2 (1, N = 60) = 2.465, p = 0.041). Our findings suggest that education and deliberation enhance public appreciation of the scientific and ethical complexities of genome sequencing.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/1/jgc40122-sup-0006.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/2/jgc40122.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/3/jgc40122-sup-0005.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/4/jgc40122-sup-0007.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/5/jgc40122-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/6/jgc40122-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/7/jgc40122-sup-0003.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/8/jgc40122-sup-0004.pd