Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells

Candida glabrata : a review of its features and resistance

Candida species belong to the normal microbiota of the oral cavity and gastrointestinal and vaginal tracts, and are responsible for several clinical manifestations, from mucocutaneous overgrowth to bloodstream infections. Once believed to be non-pathogenic, Candida glabrata was rapidly blamable for many human diseases. Year after year, these pathological circumstances are more recurrent and problematic to treat, especially when patients reveal any level of immunosuppression. These difficulties arise from the capacity of C. glabrata to form biofilms and also from its high resistance to traditional antifungal therapies. Thus, this review intends to present an excerpt of the biology, epidemiology, and pathology of C. glabrata, and detail an approach to its resistance mechanisms based on studies carried out up to the present.The authors are grateful to strategic project PTDC/SAU-MIC/119069/2010 for the financial support to the research center and for Celia F. Rodrigues' grant

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The authors thank Charlotte Oomen for valuable comments on the manuscript.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4007-

Processing of spatial-frequency altered faces in schizophrenia: Effects of illness phase and duration

Low spatial frequency (SF) processing has been shown to be impaired in people with schizophrenia, but it is not clear how this varies with clinical state or illness chronicity. We compared schizophrenia patients (SCZ, n534), first episode psychosis patients (FEP, n522), and healthy controls (CON, n535) on a gender/facial discrimination task. Images were either unaltered (broadband spatial frequency, BSF), or had high or low SF information removed (LSF and HSF conditions, respectively). The task was performed at hospital admission and discharge for patients, and at corresponding time points for controls. Groups were matched on visual acuity. At admission, compared to their BSF performance, each group was significantly worse with low SF stimuli, and most impaired with high SF stimuli. The level of impairment at each SF did not depend on group. At discharge, the SCZ group performed more poorly in the LSF condition than the other groups, and showed the greatest degree of performance decline collapsed over HSF and LSF conditions, although the latter finding was not significant when controlling for visual acuity. Performance did not change significantly over time for any group. HSF processing was strongly related to visual acuity at both time points for all groups. We conclude the following: 1) SF processing abilities in schizophrenia are relatively stable across clinical state; 2) face processing abnormalities in SCZ are not secondary to problems processing specific SFs, but are due to other known difficulties constructing visual representations from degraded information; and 3) the relationship between HSF processing and visual acuity, along with known SCZ- and medication-related acuity reductions, and the elimination of a SCZ-related impairment after controlling for visual acuity in this study, all raise the possibility that some prior findings of impaired perception in SCZ may be secondary to acuity reductions

Bayesian Modeling of Perceived Surface Slant from Actively-Generated and Passively-Observed Optic Flow

We measured perceived depth from the optic flow (a) when showing a stationary physical or virtual object to observers who moved their head at a normal or slower speed, and (b) when simulating the same optic flow on a computer and presenting it to stationary observers. Our results show that perceived surface slant is systematically distorted, for both the active and the passive viewing of physical or virtual surfaces. These distortions are modulated by head translation speed, with perceived slant increasing directly with the local velocity gradient of the optic flow. This empirical result allows us to determine the relative merits of two alternative approaches aimed at explaining perceived surface slant in active vision: an “inverse optics” model that takes head motion information into account, and a probabilistic model that ignores extra-retinal signals. We compare these two approaches within the framework of the Bayesian theory. The “inverse optics” Bayesian model produces veridical slant estimates if the optic flow and the head translation velocity are measured with no error; because of the influence of a “prior” for flatness, the slant estimates become systematically biased as the measurement errors increase. The Bayesian model, which ignores the observer's motion, always produces distorted estimates of surface slant. Interestingly, the predictions of this second model, not those of the first one, are consistent with our empirical findings. The present results suggest that (a) in active vision perceived surface slant may be the product of probabilistic processes which do not guarantee the correct solution, and (b) extra-retinal signals may be mainly used for a better measurement of retinal information

Actinic Skin Damage and Mortality - the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study

BACKGROUND: Exposure to sunlight may decrease the risk of several diseases through the synthesis of vitamin D, whereas solar radiation is the main cause of some skin and eye diseases. However, to the best of our knowledge, the association of sun-induced skin damage with mortality remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: Subjects were 8472 white participants aged 25-74 years in the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Cardiovascular disease mortality, cancer mortality, and all-cause mortality were obtained by either a death certificate or a proxy interview, or both. Actinic skin damage was examined and recorded by the presence and severity (absent, minimal, moderate, or severe) of overall actinic skin damage and its components (i.e., fine telangiectasia, solar elastosis, and actinic keratoses). Cox regression and Kaplan-Meier methods were applied to explore the associations. A total of 672 cancer deaths, 1500 cardiovascular disease deaths, and 2969 deaths from all causes were documented through the follow-up between 1971 and 1992. After controlling for potential confounding variables, severe overall actinic skin damage was associated with a 45% higher risk for all-cause mortality (95% CI: 1.22, 1.72; P<0.001), moderate overall skin damage with a 20% higher risk (95% CI: 1.08., 1.32; P<0.001), and minimal overall skin damage with no significant mortality difference, when compared to those with no skin damage. Similar results were obtained for all-cause mortality with fine telangiectasia, solar elastosis, and actinic keratoses. The results were similar for cancer and cardiovascular disease mortality. CONCLUSIONS: The present study gives an indication of an association of actinic skin damage with cardiovascular disease, cancer and all-cause mortality in white subjects. Given the lack of support in the scientific literature and potential unmeasured confounding factors, this finding should be interpreted with caution. More independent studies are needed before any practical recommendations can be made

Identification of sumoylation targets, combined with inactivation of SMT3, reveals the impact of sumoylation upon growth, morphology, and stress resistance in the pathogen Candida albicans

Peer reviewedPublisher PD

Euclid II. The VIS instrument

This paper presents the specification, design, and development of the Visible Camera (VIS) on the European Space Agency's mission. VIS is a large optical-band imager with a field of view of 0.54 deg$^2$ sampled at with an array of 609 Megapixels and a spatial resolution of . It will be used to survey approximately 14 000 deg$^2$ of extragalactic sky to measure the distortion of galaxies in the redshift range $z=0.1$--1.5 resulting from weak gravitational lensing, one of the two principal cosmology probes leveraged by With photometric redshifts, the distribution of dark matter can be mapped in three dimensions, and the extent to which this has changed with look-back time can be used to constrain the nature of dark energy and theories of gravity. The entire VIS focal plane will be transmitted to provide the largest images of the Universe from space to date, specified to reach AB with a signal-to-noise ratio S/N in a single broad E (r+i+z)$band over a six-year survey. The particularly challenging aspects of the instrument are the control and calibration of observational biases, which lead to stringent performance requirements and calibration regimes. With its combination of spatial resolution, calibration knowledge, depth, and area covering most of the extra-Galactic sky, VIS will also provide a legacy data set for many other fields. This paper discusses the rationale behind the conception of VIS and describes the instrument design and development, before reporting the prelaunch performance derived from ground calibrations and brief results from the in-orbit commissioning. VIS should reach fainter than AB =25$ with $S/N 10$ for galaxies with a full width at half maximum of in a diameter aperture over the Wide Survey, and $m_ AB for a Deep Survey that will cover more than 50 deg$^2$. The paper also describes how the instrument works with the telescope and survey, and with the science data processing, to extract the cosmological information