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.Peer reviewe

Personality psychology: Lexical approaches, assessment methods, and trait concepts reveal only half of the story—Why it is time for a paradigm shift

This article develops a comprehensive philosophy-of-science for personality psychology that goes far beyond the scope of the lexical approaches, assessment methods, and trait concepts that currently prevail. One of the field’s most important guiding scientific assumptions, the lexical hypothesis, is analysed from meta-theoretical viewpoints to reveal that it explicitly describes two sets of phenomena that must be clearly differentiated: 1) lexical repertoires and the representations that they encode and 2) the kinds of phenomena that are represented. Thus far, personality psychologists largely explored only the former, but have seriously neglected studying the latter. Meta-theoretical analyses of these different kinds of phenomena and their distinct natures, commonalities, differences, and interrelations reveal that personality psychology’s focus on lexical approaches, assessment methods, and trait concepts entails a) erroneous meta-theoretical assumptions about what the phenomena being studied actually are, and thus how they can be analysed and interpreted, b) that contemporary personality psychology is largely based on everyday psychological knowledge, and c) a fundamental circularity in the scientific explanations used in trait psychology. These findings seriously challenge the widespread assumptions about the causal and universal status of the phenomena described by prominent personality models. The current state of knowledge about the lexical hypothesis is reviewed, and implications for personality psychology are discussed. Ten desiderata for future research are outlined to overcome the current paradigmatic fixations that are substantially hampering intellectual innovation and progress in the field

Challenges in assessing personality of individuals with Gender Dysphoria with the SWAP-200

Background Personality assessment can be useful to better understand the complexity of transgender and transsexual people. In particular, the Shedler Westen Assessment Procedure-200 (SWAP-200) is a measure that provides an accurate dimensional evaluation of personality. When assessing gender non-conforming people, however, clinicians can encounter some difficulties in giving appropriate ratings to all the items. Purpose of the review A brief guide to the use of SWAP-200 with transgender patients is provided, taking into account three areas of psychological functioning: identity, relationships and sexuality. The authors review, one by one, the SWAP-200 items related to these areas, and, relying on their clinical experience and on scientific literature on Gender Dysphoria, they propose recommendations for making personality diagnoses meaningful. Conclusion This paper facilitates a better clinical understanding of transgender people, and help clinicians to be more knowledgeable in the assessment of this heterogeneous population

Comparing six commercial autosomal STR kits in a large Dutch population sample

Regularly, STR results obtained with different PCR amplification kits are compared, for instance with old cases, when revisiting cold cases or when addressing cross-border crimes. It is known that differences in primer design for the same loci in different kits may give rise to null alleles or shifted alleles. In this study, the genotyping results of 2085 Dutch male samples were compared for six autosomal STR kits (Promega's PowerPlex (R) 16, ESX-16 and ESI-17 Systems, Qiagen's Investigator (R) ESSplex Kit and Applied Biosystems' AmpFlSTR (R) Identifiler and NGM PCR Amplification Kits). A total of 19 discordant autosomal genotyping results were obtained that were examined by sequence analysis using Roche-454 next generation sequencing and/or Sanger sequencing. A further 25 discordances were found and sequenced for the Amelogenin locus. The 24 samples showing the same primer binding site mutation at the Amelogenin locus were subjected to X-STR analysis in order to assess whether they could share a common origin, which appeared not to be the case. Based on the sequencing results, we set the final genotypes and determined the allele frequencies of 23 autosomal STRs for the Dutch reference database. (C) 2014 The Authors. Published by Elsevier Ireland Ltd. All rights reserved

Personality and Attachment in Transsexual Adults

Abstract The main aim of this study was to investigate the associations between personality features and attachment patterns in transsexual adults.We explored mental representations of attachment, assessed personality traits, and possible personality disorders. Forty-four individuals diagnosed with gender identity disorder (now gender dysphoria), 28 male-to-female and 16 female-to-male,were evaluated using the Shedler–Westen assessment procedure-200 (SWAP-200) to assess personality traits and disorders; the adult attachment interview was used to evaluate their attachment state-of-mind. With respect to attachment, our sample differed both from normative samples because of the high percentage of disorganized states of mind (50% of the sample), and from clinical samples for the conspicuous percentage of secure states of mind (37%). Furthermore, we found that only 16% of our sample presented a personality disorder, while 50%showed a high level of functioning according to the SWAP-200 scales. In order to find latent subgroups that shared personality characteristics,we performed a Q-factor analysis. Three personality clusters then emerged: Healthy Functioning (54% of the sample); Depressive/Introverted (32%) and Histrionic/Extroverted (14%). These data indicate that in terms of personality and attachment, GD individuals are a heterogeneous sample and show articulate and diverse types with regard to these constructs

Assessing the Firing Properties of the Electrically Stimulated Auditory Nerve Using a Convolution Model

The electrically evoked compound action potential (eCAP) is a routinely performed measure of the auditory nerve in cochlear implant users. Using a convolution model of the eCAP, additional information about the neural firing properties can be obtained, which may provide relevant information about the health of the auditory nerve. In this study, guinea pigs with various degrees of nerve degeneration were used to directly relate firing properties to nerve histology. The same convolution model was applied on human eCAPs to examine similarities and ultimately to examine its clinical applicability. For most eCAPs, the estimated nerve firing probability was bimodal and could be parameterised by two Gaussian distributions with an average latency difference of 0.4 ms. The ratio of the scaling factors of the late and early component increased with neural degeneration in the guinea pig. This ratio decreased with stimulation intensity in humans. The latency of the early component decreased with neural degeneration in the guinea pig. Indirectly, this was observed in humans as well, assuming that the cochlear base exhibits more neural degeneration than the apex. Differences between guinea pigs and humans were observed, among other parameters, in the width of the early component: very robust in guinea pig, and dependent on stimulation intensity and cochlear region in humans. We conclude that the deconvolution of the eCAP is a valuable addition to existing analyses, in particular as it reveals two separate firing components in the auditory nerve