The Indiana Center for Breast Cancer Research: Progress towards a SPORE Proposal

poster abstractAbstract The Indiana Center for Breast Cancer Research (ICBCR) was funded under the IUPUI Signature Center Initiative in 2010. Its mission is to address the full range of prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts to date towards applying for a National Cancer Institute Specialized Program of Research Excellence (SPORE) in January 2013. The proposed IU Breast Cancer SPORE will include 4-5 individual research projects, 3 cores, developmental research and career development programs. The SPORE Biostatistics and Bioinformatics core has developed the Breast Cancer Prognostics Database (BCDB), an online tool to study prognostic implications of genes of interest in publically available breast cancer databases. The BCDB can be used to study overall, recurrence free and metastasis free survival in large patient series. Supporting the SPORE Biospecimen/Pathology core, the IU Breast Cancer Tissue Bank includes a total sample of N = 500 cases with 30% non-Caucasian cases from Wishard Memorial Hospital. Currently there are N = 333 cases with tissue microarray data and complete clinical data with an additional 200 cases pending tissue confirmation. Dr. Clark D. Wells together with S. Badve and G. Sandusky are collaborating on the project: “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”, a candidate SPORE individual research project. This project is investigating localized protein expression in paraffin-embedded tissues to associate expression levels with disease subtype and patient outcome. Dr. David P. Gilley together with N. Kannan, N. Huda, L. Tu, R. Droumeva, R. Brinkman, J. Emerman, S. Abe, and C. Eaves, are collaborating on the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”, a candidate SPORE developmental research project. This project is investigating the relationship between telomere dysfunction and breast cancer tumorigenesis. These SPORE projects and cores were discussed at the IUSCC Breast Cancer Program retreat held on 1/13/12. Two additional planning meetings were held on 1/5 and 2/23. A timeline was generated to include final project selection in April, internal review in June, external review in August-September, and draft completion by 12/1, to meet the 1/20/13 NIH receipt deadline

GREAT3 results I: systematic errors in shear estimation and the impact of real galaxy morphology

We present first results from the third GRavitational lEnsing Accuracy Testing (GREAT3) challenge, the third in a sequence of challenges for testing methods of inferring weak gravitational lensing shear distortions from simulated galaxy images. GREAT3 was divided into experiments to test three specific questions, and included simulated space- and ground-based data with constant or cosmologically-varying shear fields. The simplest (control) experiment included parametric galaxies with a realistic distribution of signal-to-noise, size, and ellipticity, and a complex point spread function (PSF). The other experiments tested the additional impact of realistic galaxy morphology, multiple exposure imaging, and the uncertainty about a spatially-varying PSF; the last two questions will be explored in Paper II. The 24 participating teams competed to estimate lensing shears to within systematic error tolerances for upcoming Stage-IV dark energy surveys, making 1525 submissions overall. GREAT3 saw considerable variety and innovation in the types of methods applied. Several teams now meet or exceed the targets in many of the tests conducted (to within the statistical errors). We conclude that the presence of realistic galaxy morphology in simulations changes shear calibration biases by $\sim 1$ per cent for a wide range of methods. Other effects such as truncation biases due to finite galaxy postage stamps, and the impact of galaxy type as measured by the S\'{e}rsic index, are quantified for the first time. Our results generalize previous studies regarding sensitivities to galaxy size and signal-to-noise, and to PSF properties such as seeing and defocus. Almost all methods' results support the simple model in which additive shear biases depend linearly on PSF ellipticity.Comment: 32 pages + 15 pages of technical appendices; 28 figures; submitted to MNRAS; latest version has minor updates in presentation of 4 figures, no changes in content or conclusion

Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain

Stem cell transplantation promises new hope for the treatment of stroke although significant questions remain about how the grafted cells elicit their effects. One hypothesis is that transplanted stem cells enhance endogenous repair mechanisms activated after cerebral ischaemia. Recognizing that bilateral reorganization of surviving circuits is associated with recovery after stroke, we investigated the ability of transplanted human neural progenitor cells to enhance this structural plasticity. Our results show the first evidence that human neural progenitor cell treatment can significantly increase dendritic plasticity in both the ipsi- and contralesional cortex and this coincides with stem cell-induced functional recovery. Moreover, stem cell-grafted rats demonstrated increased corticocortical, corticostriatal, corticothalamic and corticospinal axonal rewiring from the contralesional side; with the transcallosal and corticospinal axonal sprouting correlating with functional recovery. Furthermore, we demonstrate that axonal transport, which is critical for both proper axonal function and axonal sprouting, is inhibited by stroke and that this is rescued by the stem cell treatment, thus identifying another novel potential mechanism of action of transplanted cells. Finally, we established in vitro co-culture assays in which these stem cells mimicked the effects observed in vivo. Through immunodepletion studies, we identified vascular endothelial growth factor, thrombospondins 1 and 2, and slit as mediators partially responsible for stem cell-induced effects on dendritic sprouting, axonal plasticity and axonal transport in vitro. Thus, we postulate that human neural progenitor cells aid recovery after stroke through secretion of factors that enhance brain repair and plasticity

Linking Auxin with Photosynthetic Rate via Leaf Venation

International audienceLand plants lose vast quantities of water to the atmosphere during photosynthetic gas exchange. In angiosperms, a complex network of veins irrigates the leaf, and it is widely held that the density and placement of these veins determines maximum leaf hydraulic capacity and thus maximum photosynthetic rate. This theory is largely based on interspecific comparisons and has never been tested using vein mutants to examine the specific impact of leaf vein morphology on plant water relations. Here we characterize mutants at the Crispoid (Crd) locus in pea (Pisum sativum), which have altered auxin homeostasis and activity in developing leaves, as well as reduced leaf vein density and aberrant placement of free-ending veinlets. This altered vein phenotype in crd mutant plants results in a significant reduction in leaf hydraulic conductance and leaf gas exchange. We find Crispoid to be a member of the YUCCA family of auxin biosynthetic genes. Our results link auxin biosynthesis with maximum photosynthetic rate through leaf venation and substantiate the theory that an increase in the density of leaf veins coupled with their efficient placement can drive increases in leaf photosynthetic capacity

The Dementia Care Study (D-Care): Recruitment Strategies and Demographic Characteristics of Participants in a Pragmatic Randomized Trial of Dementia Care

INTRODUCTION: Pragmatic research studies that include diverse dyads of persons living with dementia (PLWD) and their family caregivers are rare. METHODS: Community-dwelling dyads were recruited for a pragmatic clinical trial evaluating three approaches to dementia care. Four clinical trial sites used shared and site-specific recruitment strategies to enroll health system patients. RESULTS: Electronic health record (EHR) queries of patients with a diagnosis of dementia and engagement of their clinicians were the main recruitment strategies. A total of 2176 dyads were enrolled, with 80% recruited after the onset of the pandemic. PLWD had a mean age of 80.6 years (SD 8.5), 58.4% were women, and 8.8% were Hispanic/Latino, and 11.9% were Black/African American. Caregivers were mostly children of the PLWD (46.5%) or spouses/partners (45.2%), 75.8% were women, 9.4% were Hispanic/Latino, and 11.6% were Black/African American. DISCUSSION: Health systems can successfully enroll diverse dyads in a pragmatic clinical trial

Reliability and validity of two fitness tracker devices in the laboratory and home environment for older community-dwelling people

© 2018 The Author(s). Background: Two-thirds of older Australians are sedentary. Fitness trackers have been popular with younger people and may encourage older adults to become more active. Older adults may have different gait patterns and as such it is important to establish whether fitness trackers are valid and reliable for this population. The aim of the study was to test the reliability and validity of two fitness trackers (Fitbit Flex and ChargeHR) by step count when worn by older adults. Reliability and validity were tested in two conditions: 1) in the laboratory using a two-minute-walk-test (2MWT) and 2) in a free-living environment. Methods: Two 2MWTs were completed while wearing the fitness trackers. Participants were videoed during each test. Participants were then given one fitness tracker and a GENEactiv accelerometer to wear at home for 14-days. Results: Thirty-one participants completed two 2MWTs and 30 completed the free-living procedure. Intra Class Correlation's of the fitness trackers with direct observation of steps (criterion validity) was high (ICC:0.86,95%CI:0.76,0.93). However, both fitness trackers underestimated steps. Excellent test-retest reliability (ICC = 0.75) was found between the two 2MWTs for each device, particularly the ChargeHR devices. Good strength of agreement was found for total distance and steps (fitness tracker) and moderate-to-vigorous physical activity (GENEactiv) for the free-living environment (Spearman Rho's 0.78 and 0.74 respectively). Conclusion: Reliability and validity of the Flex and ChargeHR when worn by older adults is good, however both devices underestimated step count within the laboratory environment. These fitness trackers appear suitable for consumer use and promoting physical activity for older adults

An Ultra-High Discrimination Y Chromosome Short Tandem Repeat Multiplex DNA Typing System

In forensic casework, Y chromosome short tandem repeat markers (Y-STRs) are often used to identify a male donor DNA profile in the presence of excess quantities of female DNA, such as is found in many sexual assault investigations. Commercially available Y-STR multiplexes incorporating 12–17 loci are currently used in forensic casework (Promega's PowerPlex® Y and Applied Biosystems' AmpFlSTR® Yfiler®). Despite the robustness of these commercial multiplex Y-STR systems and the ability to discriminate two male individuals in most cases, the coincidence match probabilities between unrelated males are modest compared with the standard set of autosomal STR markers. Hence there is still a need to develop new multiplex systems to supplement these for those cases where additional discriminatory power is desired or where there is a coincidental Y-STR match between potential male participants. Over 400 Y-STR loci have been identified on the Y chromosome. While these have the potential to increase the discrimination potential afforded by the commercially available kits, many have not been well characterized. In the present work, 91 loci were tested for their relative ability to increase the discrimination potential of the commonly used ‘core’ Y-STR loci. The result of this extensive evaluation was the development of an ultra high discrimination (UHD) multiplex DNA typing system that allows for the robust co-amplification of 14 non-core Y-STR loci. Population studies with a mixed African American and American Caucasian sample set (n = 572) indicated that the overall discriminatory potential of the UHD multiplex was superior to all commercial kits tested. The combined use of the UHD multiplex and the Applied Biosystems' AmpFlSTR® Yfiler® kit resulted in 100% discrimination of all individuals within the sample set, which presages its potential to maximally augment currently available forensic casework markers. It could also find applications in human evolutionary genetics and genetic genealogy

GREAT3 results - I. Systematic errors in shear estimation and the impact of real galaxy morphology

We present first results from the third GRavitational lEnsing Accuracy Testing (GREAT3) challenge, the third in a sequence of challenges for testing methods of inferring weak gravitational lensing shear distortions from simulated galaxy images. GREAT3 was divided into experiments to test three specific questions, and included simulated space- and ground-based data with constant or cosmologically varying shear fields. The simplest (control) experiment included parametric galaxies with a realistic distribution of signal-to-noise, size, and ellipticity, and a complex point spread function (PSF). The other experiments tested the additional impact of realistic galaxy morphology, multiple exposure imaging, and the uncertainty about a spatially varying PSF; the last two questions will be explored in Paper II. The 24 participating teams competed to estimate lensing shears to within systematic error tolerances for upcoming Stage-IV dark energy surveys, making 1525 submissions overall. GREAT3 saw considerable variety and innovation in the types of methods applied. Several teams now meet or exceed the targets in many of the tests conducted (to within the statistical errors). We conclude that the presence of realistic galaxy morphology in simulations changes shear calibration biases by ∼1percent for a wide range of methods. Other effects such as truncation biases due to finite galaxy postage stamps, and the impact of galaxy type as measured by the Sérsic index, are quantified for the first time. Our results generalize previous studies regarding sensitivities to galaxy size and signal-to-noise, and to PSF properties such as seeing and defocus. Almost all methods' results support the simple model in which additive shear biases depend linearly on PSF ellipticit