Decreased olfactory discrimination is associated with impulsivity in healthy volunteers

In clinical populations, olfactory abilities parallel executive function, implicating shared neuroanatomical substrates within the ventral prefrontal cortex. In healthy individuals, the relationship between olfaction and personality traits or certain cognitive and behavioural characteristics remains unexplored. We therefore tested if olfactory function is associated with trait and behavioural impulsivity in nonclinical individuals. Eighty-three healthy volunteers (50 females) underwent quantitative assessment of olfactory function (odour detection threshold, discrimination, and identifcation). Each participant was rated for trait impulsivity index using the Barratt Impulsiveness Scale and performed a battery of tasks to assess behavioural impulsivity (Stop Signal Task, SST; Information Sampling Task, IST; Delay Discounting). Lower odour discrimination predicted high ratings in non-planning impulsivity (Barratt Non-Planning impulsivity subscale); both, lower odour discrimination and detection threshold predicted low inhibitory control (SST; increased motor impulsivity). These fndings extend clinical observations to support the hypothesis that defcits in olfactory ability are linked to impulsive tendencies within the healthy population. In particular, the relationship between olfactory abilities and behavioural inhibitory control (in the SST) reinforces evidence for functional overlap between neural networks involved in both processes. These fndings may usefully inform the stratifcation of people at risk of impulse-control-related problems and support planning early clinical interventions

In Vitro Transformation of Primary Human CD34+ Cells by AML Fusion Oncogenes: Early Gene Expression Profiling Reveals Possible Drug Target in AML

Different fusion oncogenes in acute myeloid leukemia (AML) have distinct clinical and laboratory features suggesting different modes of malignant transformation. Here we compare the in vitro effects of representatives of 4 major groups of AML fusion oncogenes on primary human CD34+ cells. As expected from their clinical similarities, MLL-AF9 and NUP98-HOXA9 had very similar effects in vitro. They both caused erythroid hyperplasia and a clear block in erythroid and myeloid maturation. On the other hand, AML1-ETO and PML-RARA had only modest effects on myeloid and erythroid differentiation. All oncogenes except PML-RARA caused a dramatic increase in long-term proliferation and self-renewal. Gene expression profiling revealed two distinct temporal patterns of gene deregulation. Gene deregulation by MLL-AF9 and NUP98-HOXA9 peaked 3 days after transduction. In contrast, the vast majority of gene deregulation by AML1-ETO and PML-RARA occurred within 6 hours, followed by a dramatic drop in the numbers of deregulated genes. Interestingly, the p53 inhibitor MDM2 was upregulated by AML1-ETO at 6 hours. Nutlin-3, an inhibitor of the interaction between MDM2 and p53, specifically inhibited the proliferation and self-renewal of primary human CD34+ cells transduced with AML1-ETO, suggesting that MDM2 upregulation plays a role in cell transformation by AML1-ETO. These data show that differences among AML fusion oncogenes can be recapitulated in vitro using primary human CD34+ cells and that early gene expression profiling in these cells can reveal potential drug targets in AML

High and low levels of an NTRK2-driven genetic profile affect motor- and cognition-associated frontal gray matter in prodromal Huntington’s disease

This study assessed how BDNF (brain-derived neurotrophic factor) and other genes involved in its signaling influence brain structure and clinical functioning in pre-diagnosis Huntington’s disease (HD). Parallel independent component analysis (pICA), a multivariate method for identifying correlated patterns in multimodal datasets, was applied to gray matter concentration (GMC) and genomic data from a sizeable PREDICT-HD prodromal cohort (N = 715). pICA identified a genetic component highlighting NTRK2, which encodes BDNF’s TrkB receptor, that correlated with a GMC component including supplementary motor, precentral/premotor cortex, and other frontal areas (p < 0.001); this association appeared to be driven by participants with high or low levels of the genetic profile. The frontal GMC profile correlated with cognitive and motor variables (Trail Making Test A (p = 0.03); Stroop Color (p = 0.017); Stroop Interference (p = 0.04); Symbol Digit Modalities Test (p = 0.031); Total Motor Score (p = 0.01)). A top-weighted NTRK2 variant (rs2277193) was protectively associated with Trail Making Test B (p = 0.007); greater minor allele numbers were linked to a better performance. These results support the idea of a protective role of NTRK2 in prodromal HD, particularly in individuals with certain genotypes, and suggest that this gene may influence the preservation of frontal gray matter that is important for clinical functioning.This project was supported by 1U01NS082074 (V.C. and J.T., co-principal investigators) from the National Institutes of Health, National Institute of Neurological Disorders and Stroke. The PREDICT-HD study was supported by NIH/NINDS grant 5R01NS040068 awarded to J.P.; CHDI Foundation, Inc., A3917 and 6266 awarded to J.P.; Cognitive and Functional Brain Changes in Preclinical Huntington’s Disease (HD) 5R01NS054893 awarded to J.P.; 4D Shape Analysis for Modeling Spatiotemporal Change Trajectories in Huntington’s 1U01NS082086; Functional Connectivity in Premanifest Huntington’s Disease 1U01NS082083; and Basal Ganglia Shape Analysis and Circuitry in Huntington’s Disease 1U01NS082085 awarded to Christopher A. Ross

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: a decade of the PREDICT-HD study

There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease