Recombination phenotypes of the NCI-60 collection of human cancer cells

<p>Abstract</p> <p>Background</p> <p>The NCI-60 is a collection of tumor cell lines derived from a variety of human adult cancer tissue types and is commonly used for genetic analysis and screening of potential chemotherapeutic agents. We wanted to understand the contributions of specific mechanisms of genomic instability to the etiology of cancers represented by the NCI-60.</p> <p>Results</p> <p>We screened the NCI-60 for dysregulated homologous recombination by using the gene cluster instability (GCI) assay we pioneered, and for defects in base excision repair by sensitivity to 5-hydroxymethyl-2'-deoxyuridine (hmdUrd). We identified subsets of the NCI-60 lines that either displayed the characteristic molecular signature of GCI or were sensitive to hmdUrd. With the exception of the NCI-H23 lung cancer line, these phenotypes were not found to overlap. None of the lines examined in either subset exhibited significant changes in the frequency of sister chromatid exchanges (SCE), neither did any of the lines in either subset exhibit microsatellite instability (MSI) indicative of defects in DNA mismatch repair.</p> <p>Conclusions</p> <p>Gene cluster instability, sensitivity to hmdUrd and sister chromatid exchange are mechanistically distinct phenomena. Genomic instability in the NCI-60 appears to involve only one mechanism of instability for each individual cell line.</p

Frameless Image-Guided Radiosurgery for Trigeminal Neuralgia

Background: Frameless image-guided radiosurgery (IGRS) is a safe and effective noninvasive treatment for trigeminal neuralgia (TN). This study evaluates the use of frameless IGRS to treat patients with refractory TN. Methods: We reviewed the records of 20 patients diagnosed with TN who underwent frameless IGRS treatments between March 2012 and December 2013. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. The initial setup uncertainty from simulation to treatment and the patient intrafraction uncertainty were measured. The median follow-up was 32 months. Results: All patients\u27 pain was BNI Grade IV or V before the frameless IGRS treatment. The mean intrafraction shift was 0.43 mm (0.28-0.76 mm), and the maximum intrafraction shift was 0.95 mm (0.53-1.99 mm). At last follow-up, 8 (40%) patients no longer required medications (BNI 1 or 2), 11 (55%) patients were pain free but required medication (BNI 3), and 1 (5%) patient had no pain relief (BNI 5). Patients who did not have prior surgery had a higher odds ratio for pain relief compared to patients who had prior surgery (14.9, P = 0.0408). Conclusions: Frameless IGRS provides comparable dosimetric and clinical outcomes to frame-based SRS in a noninvasive fashion for patients with medically refractory TN

Dexamethasone Administration During Definitive Radiation and Temozolomide Renders a Poor Prognosis in a Retrospective Analysis of Newly Diagnosed Glioblastoma Patients

BACKGROUND: Dexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration. METHODS: We reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m2). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV. RESULTS: With a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p  = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p  = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045). CONCLUSIONS: Our results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered

Characterizing Transition Temperature Gas in the Galactic Corona

We present a study of the properties of the transition temperature (T~10^5 K) gas in the Milky Way corona, based on measurements of OVI, NV, CIV, SiIV and FeIII absorption lines seen in the far ultraviolet spectra of 58 sightlines to extragalactic targets, obtained with Far-Ultraviolet Spectroscopic Explorer (FUSE) and Space Telescope Imaging Spectrograph. In many sightlines the Galactic absorption profiles show multiple components, which are analyzed separately. We find that the highly-ionized atoms are distributed irregularly in a layer with a scaleheight of about 3 kpc, which rotates along with the gas in the disk, without an obvious gradient in the rotation velocity away from the Galactic plane. Within this layer the gas has randomly oriented velocities with a dispersion of 40-60 km/s. On average the integrated column densities are log N(OVI)=14.3, log N(NV)=13.5, log N(CIV)=14.2, log N(SiIV)=13.6 and log N(FeIII)=14.2, with a dispersion of just 0.2 dex in each case. In sightlines around the Galactic Center and Galactic North Pole all column densities are enhanced by a factor ~2, while at intermediate latitudes in the southern sky there is a deficit in N(OVI) of about a factor 2, but no deficit for the other ions. We compare the column densities and ionic ratios to a series of theoretical predictions: collisional ionization equilibrium, shock ionization, conductive interfaces, turbulent mixing, thick disk supernovae, static non-equilibrium ionization (NIE) radiative cooling and an NIE radiative cooling model in which the gas flows through the cooling zone. None of these models can fully reproduce the data, but it is clear that non-equilibrium ionization radiative cooling is important in generating the transition temperature gas.Comment: 99 pages, 11 figures, with appendix on Cooling Flow model; only a sample of 5 subfigures of figure 2 included - full set of 69 available through Ap

Farmer perceptions of legumes and their functions in smallholder farming systems in east Africa

Legumes play an important role in sub-Saharan Africa (SSA) farming systems through the provision of food, feed, fuel, income and a range of biophysical benefits, such as soil fertility enhancement and erosion control. However, their full potential is not being realized. The purpose of this study was to assess farmers’ perceptions and knowledge towards legumes and the rationale of farmers for current legume production practices using a survey of 268 farmers in the Democratic Republic of Congo and Kenya. Most of the farmers had some knowledge of legumes and their characteristics. However, they had little knowledge of some key functions, including soil erosion control and soil fertility improvement. Most farmers relied on radio and other farmers for legume-related information. Farmers with relatively large livestock holdings ranked provision of livestock feed as an important legume function. We conclude that farmers put more value on short-term benefits of legumes including food and income than long-term benefits such as natural resource management and thus grain legumes are more readily identified by farmers than forage species. Also, we conclude that farmers require more than just information about legumes to increase uptake, they also require improved market access to procure inputs and sell products to realize other benefits that are associated with growing legumes

Vision Care Utilization and Insurance Coverage Prior to and Following Medicaid Expansion in Ohio

Background: Increased access and utilization of vision care services has the potential to reduce preventable vision loss. The state of Ohio has been uniquely proactive when collecting vision-oriented data through population health surveys, including the Behavioral Risk Factor Surveillance System (BRFSS). These data can be used to better understand vision care utilization patterns and access to insurance. Methods: Responses to 3 items administered in the Ohio BRFSS that assess vision care utilization and insurance coverage were compared between 2 different administration periods, 2005-2011 and 2018-2019, using chi-square tests. Comparable data from 2 items assessing eye care utilization were available in 2005-2011 and 2019. Comparable data for insurance coverage were available in 2005-2011 and in 2018-2019. Responses were further stratified by population characteristics, including age, gender, household income, and education level. Results: The percentages of those reporting eye exams in the previous year were not significantly different between 2005-2011 and 2019 (chi-square, p = 0.06). In Ohio, the primary reason for not seeing a vision care provider in the past 12 months was “No reason to go” in 2005-2011 and in 2019. The second most common reason for not seeing a vision care provider in the past 12 months was “Cost/insurance,” which decreased between 2005-2011 and 2019 (chi-square, p &lt;0.001). Insurance coverage for eye care increased between 2005-2011 and 2018-2019 (chi-square, p &lt;0.001). Important differences were found within the demographic stratification. Conclusion: Population health surveillance data provide useful insight into vision care utilization and insurance coverage. Despite the increase in insurance coverage, eye care provider utilization remains relatively stable

Spatial factor analysis: a new tool for estimating joint species distributions and correlations in species range

1. Predicting and explaining the distribution and density of species is one of the oldest concerns in ecology. Species distributions can be estimated using geostatistical methods, which estimate a latent spatial variable explaining observed variation in densities, but geostatistical methods may be imprecise for species with low densities or few observations. Additionally, simple geostatistical methods fail to account for correlations in distribution among species and generally estimate such cross-correlations as a post hoc exercise. 2. We therefore present spatial factor analysis (SFA), a spatial model for estimating a low-rank approximation to multivariate data, and use it to jointly estimate the distribution of multiple species simultaneously. We also derive an analytic estimate of cross-correlations among species from SFA parameters. 3. As a first example, we show that distributions for 10 bird species in the breeding bird survey in 2012 can be parsimoniously represented using only five spatial factors. As a second case study, we show that forward prediction of catches for 20 rockfishes (Sebastes spp.) off the U.S. West Coast is more accurate using SFA than analysing each species individually. Finally, we show that single-species models give a different picture of cross-correlations than joint estimation using SFA. 4. Spatial factor analysis complements a growing list of tools for jointly modelling the distribution of multiple species and provides a parsimonious summary of cross-correlation without requiring explicit declaration of habitat variables. We conclude by proposing future research that would model species cross-correlations using dissimilarity of species' traits, and the development of spatial dynamic factor analysis for a low-rank approximation to spatial time-series data

Mechanical unloading activates FoxO3 to trigger Bnip3‐dependent cardiomyocyte atrophy

BACKGROUND: Mechanical assist device therapy has emerged recently as an important and rapidly expanding therapy in advanced heart failure, triggering in some patients a beneficial reverse remodeling response. However, mechanisms underlying this benefit are unclear. METHODS AND RESULTS: In a model of mechanical unloading of the left ventricle, we observed progressive myocyte atrophy, autophagy, and robust activation of the transcription factor FoxO3, an established regulator of catabolic processes in other cell types. Evidence for FoxO3 activation was similarly detected in unloaded failing human myocardium. To determine the role of FoxO3 activation in cardiac muscle in vivo, we engineered transgenic mice harboring a cardiomyocyte‐specific constitutively active FoxO3 mutant (caFoxO3(flox);αMHC‐Mer‐Cre‐Mer). Expression of caFoxO3 triggered dramatic and progressive loss of cardiac mass, robust increases in cardiomyocyte autophagy, declines in mitochondrial biomass and function, and early mortality. Whereas increases in cardiomyocyte apoptosis were not apparent, we detected robust increases in Bnip3 (Bcl2/adenovirus E1B 19‐kDa interacting protein 3), an established downstream target of FoxO3. To test the role of Bnip3, we crossed the caFoxO3(flox);αMHC‐Mer‐Cre‐Mer mice with Bnip3‐null animals. Remarkably, the atrophy and autophagy phenotypes were significantly blunted, yet the early mortality triggered by FoxO3 activation persisted. Rather, declines in cardiac performance were attenuated by proteasome inhibitors. Consistent with involvement of FoxO3‐driven activation of the ubiquitin‐proteasome system, we detected time‐dependent activation of the atrogenes program and sarcomere protein breakdown. CONCLUSIONS: In aggregate, these data point to FoxO3, a protein activated by mechanical unloading, as a master regulator that governs both the autophagy‐lysosomal and ubiquitin‐proteasomal pathways to orchestrate cardiac muscle atrophy