Mutational Analysis of Ionizing Radiation Induced Neoplasms

SummaryIonizing radiation (IR) is a mutagen that promotes tumorigenesis in multiple exposure contexts. One severe consequence of IR is the development of second malignant neoplasms (SMNs), a radiotherapy-associated complication in survivors of cancers, particularly pediatric cancers. SMN genomes are poorly characterized, and the influence of genetic background on genotoxin-induced mutations has not been examined. Using our mouse models of SMNs, we performed whole exome sequencing of neoplasms induced by fractionated IR in wild-type and Nf1 mutant mice. Using non-negative matrix factorization, we identified mutational signatures that did not segregate by genetic background or histology. Copy-number analysis revealed recurrent chromosomal alterations and differences in copy number that were background dependent. Pathway analysis identified enrichment of non-synonymous variants in genes responsible for cell assembly and organization, cell morphology, and cell function and maintenance. In this model system, ionizing radiation and Nf1 heterozygosity each exerted distinct influences on the mutational landscape

Detection of Dynamic Spatiotemporal Response to Periodic Chemical Stimulation in a Xenopus Embryonic Tissue

Embryonic development is guided by a complex and integrated set of stimuli that results in collective system-wide organization that is both time and space regulated. These regulatory interactions result in the emergence of highly functional units, which are correlated to frequency-modulated stimulation profiles. We have determined the dynamic response of vertebrate embryonic tissues to highly controlled, time-varying localized chemical stimulation using a microfluidic system with feedback control. Our approach has enabled localized spatiotemporal manipulation of the steroid hormone dexamethasone (DEX) in Animal Cap (AC) tissues isolated from gastrulating Xenopus embryos. Using this approach we investigated cell-scale responses to precisely controlled stimulation by tracking the redistribution of a GFP-tagged DEX-reporter constructed from the human glucocorticoid receptor (GR). We exposed defined regions of a single AC explant to different stimulation conditions—continuous stimulation, periodic stimulation, and no stimulation. We observed collective behavior of the GR transport into the nucleus was first-order. Furthermore, the dynamic response was well-modeled by a first-order differential equation with a single time derivative. The model predicted that responses to periodic stimulations closely matched the results of the frequency-based experiments. We find that stimulation with localized bursts versus continuous stimulation can result in highly distinct responses. This finding is critical as controlled space and time exposure to growth factors is a hallmark of complex processes in embryonic development. These complex responses to cellular signaling and transport machinery were similar to emergent behaviors in other complex systems, suggesting that even within a complex embryonic tissue, the overall system can converge toward a predictive first-order response

Alkene anti-dihydroxylation with malonoyl peroxides

Malonoyl peroxide 1, prepared in a single step from the commercially available diacid, is an effective reagent for the anti-dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of acetic acid at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (35-92%) with up to 13:1 anti-selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed

The XMM Cluster Survey: Evidence for energy injection at high redshift from evolution of the X-ray luminosity-temperature relation

We measure the evolution of the X-ray luminosity-temperature (L_X-T) relation since z~1.5 using a sample of 211 serendipitously detected galaxy clusters with spectroscopic redshifts drawn from the XMM Cluster Survey first data release (XCS-DR1). This is the first study spanning this redshift range using a single, large, homogeneous cluster sample. Using an orthogonal regression technique, we find no evidence for evolution in the slope or intrinsic scatter of the relation since z~1.5, finding both to be consistent with previous measurements at z~0.1. However, the normalisation is seen to evolve negatively with respect to the self-similar expectation: we find E(z)^{-1} L_X = 10^{44.67 +/- 0.09} (T/5)^{3.04 +/- 0.16} (1+z)^{-1.5 +/- 0.5}, which is within 2 sigma of the zero evolution case. We see milder, but still negative, evolution with respect to self-similar when using a bisector regression technique. We compare our results to numerical simulations, where we fit simulated cluster samples using the same methods used on the XCS data. Our data favour models in which the majority of the excess entropy required to explain the slope of the L_X-T relation is injected at high redshift. Simulations in which AGN feedback is implemented using prescriptions from current semi-analytic galaxy formation models predict positive evolution of the normalisation, and differ from our data at more than 5 sigma. This suggests that more efficient feedback at high redshift may be needed in these models.Comment: Accepted for publication in MNRAS; 12 pages, 6 figures; added references to match published versio

Transverse beam compression on the Paul trap simulator experiment

The Paul trap simulator experiment is a compact laboratory Paul trap that simulates a long, thin charged-particle bunch coasting through a kilometers-long magnetic alternating-gradient (AG) transport system by putting the physicist in the beam's frame of reference. The transverse dynamics of particles in both systems are described by similar equations, including all nonlinear space-charge effects. The time-dependent quadrupolar electric fields created by the confinement electrodes of a linear Paul trap correspond to the axially dependent magnetic fields applied in the AG system. Results are presented for experiments in which the lattice period and strength are changed over the course of the experiment to transversely compress a beam with an initial depressed tune of 0.9. Instantaneous and smooth changes are considered. Emphasis is placed on determining the conditions that minimize the emittance growth and the number of halo particles produced by the beam compression process. Both the results of particle-in-cell simulations performed with the warp code and envelope equation solutions agree well with the experimental dataclose9

Experiments on transverse compression of a long charge bunch in a linear Paul trap

The transverse compression of a long charge bunch is investigated in the Paul trap simulator experiment ( PTSX), which is a linear Paul trap that simulates the nonlinear transverse dynamics of an intense charged particle beam propagating through an equivalent kilometers- long magnetic alternating- gradient ( AG) focusing system. Changing the voltage amplitude at fixed focusing frequency in the PTSX device corresponds to changing the field gradient of the quadrupole magnets with fixed axial periodicity in the AG transport system. In this work, we present experimental results on transverse compression of the charge bunch in which the amplitude of the applied oscillatory focusing voltage is changed instantaneously, and adiabatically. The experimental data are also compared with analytical estimates and 2D WARP particle- in- cell simulationsclose6

Handedness and behavioural inhibition system/behavioural activation system (BIS/BAS) scores: A replication and extension of Wright, Hardie, and Wilson (2009)

The Annett Hand Preference Questionnaire (AHPQ) as modified by Briggs and Nebes was administered along with Carver and White's behavioural inhibition system (BIS) and behavioural activation system (BAS) scale and a shortened form of the Big Five personality questionnaire to 92 university students. After eliminating the data from five respondents who reported having changed handedness and one outlier, there was a significant sex difference in mean BIS scores, with females (n = 43) scoring higher than males (n = 43). Replicating the results of Wright, Hardie and Wilson, non-right-handers (n = 36) had significantly higher mean BIS score than right-handers (n = 50). Controlling for sex of participant, neuroticism and BAS sub-scale scores in hierarchical regression analyses left this BIS effect substantially unaffected. There was no handedness or sex difference on any of the three BAS sub-scales. Further analyses revealed no association between strength, as distinct from direction, of handedness and BIS (or BAS) scores. The findings are discussed with reference to recent developments in reinforcement sensitivity theory on which BIS/BAS variables are based

Addressing cancer survivors\u27 cardiovascular health using the Automated Heart Health Assessment (AH-HA) EHR tool: Initial protocol and modifications to address COVID-19 challenges

BACKGROUND: The purpose of this paper is to describe the Automated Heart-Health Assessment (AH-HA) study protocol, which demonstrates an agile approach to cancer care delivery research. This study aims to assess the effect of a clinical decision support tool for cancer survivors on cardiovascular health (CVH) discussions, referrals, completed visits with primary care providers and cardiologists, and control of modifiable CVH factors and behaviors. The COVID-19 pandemic has caused widespread disruption to clinical trial accrual and operations. Studies conducted with potentially vulnerable populations, including cancer survivors, must shift towards virtual consent, data collection, and study visits to reduce risk for participants and study staff. Studies examining cancer care delivery innovations may also need to accommodate the increased use of virtual visits. METHODS/DESIGN: This group-randomized, mixed methods study will recruit 600 cancer survivors from 12 National Cancer Institute Community Oncology Research Program (NCORP) practices. Survivors at intervention sites will use the AH-HA tool with their oncology provider; survivors at usual care sites will complete routine survivorship visits. Outcomes will be measured immediately after the study visit, with follow-up at 6 and 12 months. The study was amended during the COVID-19 pandemic to allow for virtual consent, data collection, and intervention options, with the goal of minimizing participant-staff in-person contact and accommodating virtual survivorship visits. CONCLUSIONS: Changes to the study protocol and procedures allow important cancer care delivery research to continue safely during the COVID-19 pandemic and give sites and survivors flexibility to conduct study activities in-person or remotely