Is Evaluative Conditioning Moderated by Big Five Personality Traits?

Evaluative conditioning (EC), a change in liking of a stimulus due to its paired presentation with a positive or negative stimulus, is a key concept in attitude formation. The present article examines to what extent EC effects are moderated by Big Five personality. For this purpose, 567 participants completed an EC procedure and the Big Five Inventory. People high on neuroticism and agreeableness showed stronger EC effects than people low on those personality traits. In conclusion, attitude formation via EC depends in part on Big Five personality. This novel insight has important ramifications for EC research and personality research. As to EC research, the moderation by neuroticism suggests that EC effects intensify with an increased focus on valent stimuli. As to personality research, our findings reinforce the fundamental nature of the Big Five because they are evidentially able to moderate such basic learning phenomena as EC.

The Impact of Maintenance Lenalidomide on the Mutational Status of the Myeloma Clone at Relapse in the NCRI Myeloma XI Trial for Newly Diagnosed Multiple Myeloma Patients (NDMM)

Introduction With a multifactorial mechanism of action and excellent PFS associated with prolonged exposure, lenalidomide (len) is an attractive candidate for maintenance therapy. Len exerts its action by interaction with cereblon (CRBN) which forms a ubiquitin ligase complex with cullin-4A (CUL4), damaged DNA binding protein 1 (DDB1) and regulator of cullins 1 (ROC1). Downstream effects are mediated via Ikaros, Aiolos, MYC, IRF4, basigin (BSG) and solute carrier family 16 member 1 (SLC16A1). The impact of selective pressure on MM clonal architecture and mutational load has not been assessed. Although not a DNA damaging agent there is an apparent effect of maintenance len increasing the risk of second cancers and a suggestion that it could select for aggressive clones in high risk disease. We addressed the hypothesis that len may increase the rate of mutation at relapse by performing whole exome sequencing (WES) on 70 paired presentation/relapse samples from patients enrolled to the Myeloma XI trial (MXI), 35 of whom received maintenance Len and 35 not. Methods WES was performed to a median depth of 125x on 70 presentation/relapse pairs from patients enrolled to the MXI trial. MXI is a phase III study comparing thalidomide, len and bortezomib induction combinations and len vs observation maintenance treatment in both transplant eligible (TE) and transplant non-eligible (TNE) NDMM patients. We selected patients who had completed induction +/- ASCT and been randomised to receive maintenance therapy with len or observation. All patients had disease progression determined by IMWG criteria at the time of the relapse sample. Of the 70 patients, 30 were enrolled in the TE pathway and 40 in the TNE pathway. The median time to relapse following maintenance randomisation was 323 days (296 len vs 325 observation). 35 patients (50%) achieved a CR as their best response, 26 (37%) a VGPR and 9 (13%) a PR. The median age was 66 and 69 for those receiving len and those being observed respectively. High risk disease status was confirmed in 33 (47%) patients at presentation (≥ 1of t(4;14), t(14;16), t(14;20), +1q, -17p, -1p). Results The median number of non-silent mutations (NSM) found at presentation and relapse was 37 and 41 respectively (p=0.25). In patients receiving len maintenance the median number of NSM at presentation was 37 vs 34 at relapse (p=0.69). In those being observed the median number of NSM at presentation was 42 vs 52 at relapse (p=0.21). Mutations in genes important in myeloma pathogenesis seen in more than one patient at presentation included KRAS (16), NRAS (14), DIS3 (6), HIST1H1E (2), RB1 (2), EGR1 (2), TP53 (2) and FAM46C (2). These were seen in a total of 37 (53%) patients. One patient had both an NRAS and KRAS mutation. At relapse 7 patients lost mutations (NRAS (3), KRAS (3), DIS3 (1)) and 6 patients gained mutations (KRAS (2), NRAS (2), TP53 (1), FAM46C(1)). Paired presentation/relapse copy number (CN) data (MLPA) was available for 38 patients (54%). At relapse there was evidence of a change in CN status with 5 (13%) patients gaining CN changes associated with high risk (gain 1q (4), del 17p (1). Six patients (9%) were found to have mutations in genes associated with len action; CRBN (1), IRF4 (1), DDB1 (2), SLC16A1 (2). No mutations were found in Ikaros, Aiolos, ROC1, CUL4 or BSG. The CRBN mutation was found at relapse only, in a patient who had achieved a CR and undergone 232 days of len maintenance. The IRF4 mutation was seen at presentation and relapse in a patient who achieved CR and received 754 days of len prior to relapse. Both patients with DDB1 mutations received len induction, ASCT, achieved CR and were randomised to observation. In one patient the mutation was seen at presentation and relapse whilst in the other only at relapse. Both patients with mutations in SLC16A1 were treated with len induction and ASCT to CR. In one patient, randomised to observation the mutation was seen at both time points and they relapsed after 156 days. The other, with the mutation present at presentation only was randomised to len maintenance and relapsed after 256 days. Conclusions This is the largest study comparing the genetics of presentation/relapse myeloma in a len treated population. Overall, the number of mutations at presentation vs relapse remained stable. We show that len does not affect the mutational load at relapse but may select for mutations conferring len resistance although at present further analysis is required to confirm this. Disclosures Jones: Celgene: Honoraria, Research Funding. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Cook:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:BMS: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Chugai: Consultancy. Jackson:Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment.

Single-Cell Genetic Analysis Reveals The Genetic Composition Of Founder Clones, Phylogenetic Patterns Of Branching and Parallel Evolution, and Clonal Fluctuations Following Patient Treatment In Multiple Myeloma

Multiple Myeloma (MM) is a proliferation of aberrant plasma cells in the bone marrow. Ig translocations or hyperdiploidy are MM initiating events present in all clonal cells in contrast to other secondary lesions involved in progression (e.g. RASmutations), which may be subclonal. We and others have recently described the presence of different tumour clonal populations—a phenomenon called intra-tumour heterogeneity—in MM, yet the phylogenetic relationships of the tumour subclones remains to be fully elucidated. To describe the intra-tumour heterogeneity and tumour phylogenies in a series of t(11;14) MM patients characterised by KRAS/NRAS/BRAF mutations, we combined whole-exome sequencing and single-cell genetic analysis. A novel approach for single-cell multiplex-qPCR analysis using nano-fluidic arrays (Fluidigm) was followed in 100-250 single-cells per sample. The t(11;14) breakpoint was defined using Ig regions-targeted massively-parallel sequencing. Taqman assays specific for detection of the t(11;14) breakpoints and for mutations in selected genes were custom-made designed. Copy number assays for chromosomal regions of interest were also used. This strategy allowed us: first, to report the presence of the t(11;14), mutations and copy number aberrations (gains/losses) at the single-cell level; second, to define subclonal populations; and third, to delineate the most plausible sequence of events for each case. An additional series of 14 MM patients with paired-samples at presentation/relapse was included for the study of the effect of treatment in clonal architecture. Lastly, to analyse the engraftment-ability of subclonal populations, we injected 1x106 CD138+ cells from one of the patient-samples at diagnosis into the tibia of NOD/SCIDyc(null)-mice and compared the engrafted-myeloma with the paired presentation-relapse samples. We demonstrate that MM is comprised of 2-6 clones, related through a linear (3/7 cases) or a branching (4/7) phylogeny. The t(11;14) was seen in 91-100% of tumour cells, supporting its aetiological role as a MM initiating event. For the first time in MM, we describe a parallel evolutionary pattern in two samples that carried double hits in KRAS or KRAS/NRAS. These mutations were acquired separately in two divergent clonal lineages, which were derived from the same ancestor but evolved independently. We suggest that RAS is a true driver mutation in MM as such alterations seem to provide clonal advantages for myeloma subclones in the bone marrow environment. We also report the concomitant acquisition of RAS mutations and IRF4p.K123R mutation in 2% (9/453) screened MM patients. This finding suggests a collaborative effect provided by the mutations in both pathways to trigger myeloma development. We examine the ability of subclonal populations to survive patient treatment by the analysis of paired presentation-relapse samples. Not only did the intra-tumour heterogeneity shift in the transition to relapse meaning that subclonal populations fluctuated during treatment, but also new clones emerged from early and late subclones formerly described at diagnosis. To note, some of these new subclones acquired mutations in KRAS/BRAF during transition, likely leading to relapse. In parallel, we tested the ability to recapitulate the disease in NOD/SCIDyc(null)-mice. Engrafted-myelomas also had clonal fluctuations with 1/3 clones shown at patient-diagnosis neither found at relapse, nor in the engrafted-MM. This missing clone was similarly outcompeted by the other clones during patient treatment and xeno-transplantation. Altogether, these results suggest that subclonal populations have different abilities to survive treatment or xeno-transplantation and hence, to lead to relapse or reconstitution of myeloma by the generation of new clonal subpopulations. We confirm the existence of distinct MM subclones that are related through a linear or a branching phylogeny, with examples of parallel evolution for alteration of the RAS/MAPK pathway. Myeloma subclones are subject of a selection process involving clonal extinction and clonal tides, similar to the theory of Natural Selection by Charles Darwin. In conclusion, intra-tumour heterogeneity is an elementary foundation for Darwinian selection underlying both disease progression and the development of treatment resistance in MM. Disclosures: No relevant conflicts of interest to declare.

Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors

FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate. We have studied FLT3 mutations in paired presentation and relapse samples to ascertain the biology of these mutations and to evaluate whether they can be used as markers of minimal residual disease. At diagnosis, 24 patients were wild-type FLT3, and 4 acquired a FLT3 mutation at relapse (2 D835+, 2 ITD+), with a further patient acquiring an ITD at second relapse. Of 20 patients positive at diagnosis (18 ITD+, 2 D835+), 5 who were all originally ITD+ had no detectable mutation at relapse, as determined by a sensitive radioactive polymerase chain reaction. One of these patients had acquired an N-Ras mutation not detectable at presentation. Furthermore, another patient had a completely different ITD at relapse, which could not be detected in the presentation sample. These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease.

Deactivation of Sensory-Specific Cortex by Cross-Modal Stimuli

Visual and auditory cortices traditionally have been considered to be “modality-specific.” Thus, their activity has been thought to be unchanged by information in other sensory modalities. However, using functional magnetic resonance imaging (fMRI), the present experiments revealed that ongoing activity in the visual cortex could be modulated by auditory information and ongoing activity in the auditory cortex could be modulated by visual information. In both cases, this cross-modal modulation of activity took the form of deactivation. Yet, the deactivation response was not evident in either cortical area during the paired presentation of visual and auditory stimuli. These data suggest that cross-modal inhibitory processes operate within traditional modality-specific cortices and that these processes can be switched on or off in different circumstances.