Widespread alteration of protein autoinhibition in human cancers.

Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.

Modelling MR and clinical features in grade II/III astrocytomas to predict IDH mutation status.

BACKGROUND AND PURPOSE: There is increasing evidence that many IDH wildtype (IDHwt) astrocytomas have a poor prognosis and although MR features have been identified, there remains diagnostic uncertainty in the clinic. We have therefore conducted a comprehensive analysis of conventional MR features of IDHwt astrocytomas and performed a Bayesian logistic regression model to identify critical radiological and basic clinical features that can predict IDH mutation status. MATERIALS AND METHODS: 146 patients comprising 52 IDHwt astrocytomas (19 WHO Grade II diffuse astrocytomas (A II) and 33 WHO Grade III anaplastic astrocytomas (A III)), 68 IDHmut astrocytomas (53 A II and 15 A III) and 26 GBM were studied. Age, sex, presenting symptoms and Overall Survival were recorded. Two neuroradiologists assessed 23 VASARI imaging descriptors of MRI features and the relation between IDH mutation status and MR and basic clinical features was modelled by Bayesian logistic regression, and survival by Kaplan-Meier plots. RESULTS: The features of greatest predictive power for IDH mutation status were, age at presentation (OR = 0.94 +/-0.03), tumour location within the thalamus (OR = 0.15 +/-0.25), involvement of speech receptive areas (OR = 0.21 +/-0.26), deep white matter invasion of the brainstem (OR = 0.10 +/-0.32), and T1/FLAIR signal ratio (OR = 1.63 +/-0.64). A logistic regression model based on these five features demonstrated excellent out-of-sample predictive performance (AUC = 0.92 +/-0.07; balanced accuracy 0.81 +/-0.09). Stepwise addition of further VASARI variables did not improve performance. CONCLUSION: Five demographic and VASARI features enable excellent individual prediction ofIDH mutation status, opening the way to identifying patients with IDHwt astrocytomas for earlier tissue diagnosis and more aggressive management.

Probabilistic electrical stimulation mapping of human medial frontal cortex.

The medial frontal cortex remains functionally ill-understood; this is reflected by the heterogeneity of behavioural outcomes following damage to the region. We aim to use the rich information provided by extraoperative direct electrical cortical stimulation to enhance our understanding of its functional anatomy. Examining a cohort of 38 epilepsy patients undergoing direct electrical cortical stimulation in the context of presurgical evaluation, we reviewed stimulation findings and classified them in a behavioural framework (positive motor, negative motor, somatosensory, speech disturbances, and "other"). The spatially discrete cortical stimulation-derived data points were then transformed into continuous probabilistic maps, thereby enabling the voxel-wise spatial inference widely used in the analysis of functional and structural imaging data. A functional map of stimulation findings of the medial wall emerged. Positive motor responses occurred in 141 stimulations (31.2%), anatomically located on the paracentral lobule (threshold at p<.05), extending no further than the vertical anterior commissure (VCA) line. Thirty negative motor responses were observed (6.6%), localised to the VCA line (at p < .001 uncorrected). In 43 stimulations (9.5%) a somatosensory response localised to the caudal cingulate zone (at p < .001 uncorrected), with a second region posterior to central sulcus. Speech disturbances were elicited in 38 stimulations (8.4%), more commonly but not exclusively from the language fMRI dominant side, just anterior to VCA (p < .001 uncorrected). In only 2 stimulations, the patient experienced a subjective "urge" to move in the absence of overt movement. Classifying motor behaviour along the dimensions of effector, and movement vs arrest, we derive a wholly data-driven stimulation map of the medial wall, powered by the largest number of stimulations of the region reported (n = 452) in patients imaged with MRI. This model and the underlying data provide a robust framework for understanding the architecture of the region through the joint analysis of disruptive and correlative anatomical maps.

The Parkinsonian Subthalamic Network: Measures of Power, Linear, and Non-linear Synchronization and their Relationship to L-DOPA Treatment and OFF State Motor Severity.

In this paper we investigated the dopaminergic modulation of neuronal interactions occurring in the subthalamic nucleus (STN) during Parkinson's disease (PD). We utilized linear measures of local and long range synchrony such as power and coherence, as well as Detrended Fluctuation Analysis for Phase Synchrony (DFA-PS)- a recently developed non-linear method that computes the extent of long tailed autocorrelations present in the phase interactions between two coupled signals. Through analysis of local field potentials (LFPs) taken from the STN we seek to determine changes in the neurodynamics that may underpin the pathophysiology of PD in a group of 12 patients who had undergone surgery for deep brain stimulation. We demonstrate up modulation of alpha-theta (5-12 Hz) band power in response to L-DOPA treatment, whilst low beta band power (15-20 Hz) band-power is suppressed. We also find evidence for significant local connectivity within the region surrounding STN although there was evidence for its modulation via administration of L-DOPA. Further to this we present evidence for a positive correlation between the phase ordering of bilateral STN interactions and the severity of bradykinetic and rigidity symptoms in PD. Although, the ability of non-linear measures to predict clinical state did not exceed standard measures such as beta power, these measures may help identify the connections which play a role in pathological dynamics.

A legion of potential regulatory sRNAs exists beyond the typical microRNAs microcosm.

Post ENCODE, regulatory sRNAs (rsRNAs) like miRNAs have established their status as one of the core regulatory elements of cell systems. However, large number of rsRNAs are compromised due to traditional approaches to identify miRNAs, limiting the otherwise vast world of rsRNAs mainly to hair-pin loop bred typical miRNAs. The present study has analyzed for the first time a huge volume of sequencing data from 4997 individuals and 25 cancer types to report 11 234 potentially regulatory small RNAs which appear to have deep reaching impact. The rsRNA-target interactions have been studied and validated extensively using experimental data from AGO-crosslinking, DGCR8 knockdown, CLASH, proteome and expression data. A subset of such interactions was also validated independently in the present study using multiple cell lines, by qPCR. Several of the potential rsRNAs have emerged as a critical cancer biomarker controlling some important spots of cell system. The entire study has been presented into an interactive info-analysis portal handling more than 260 GB of processed data. The possible degree of cell system regulation by sRNAs appears to be much higher than previously assumed.

The regulatory epicenter of miRNAs.

miRNAs are small non-coding RNAs with average length of ~21 bp. miRNA formation seems to be dependent upon multiple factors besides Drosha and Dicer, in a tissue/stage-specific manner, with interplay of several specific binding factors. In the present study, we have investigated transcription factor binding sites in and around the genomic sequences of precursor miRNAs and RNA-binding protein (RBP) sites in miRNA precursor sequences, analysed and tested in comprehensive manner. Here, we report that miRNA precursor regions are positionally enriched for binding of transcription factors as well as RBPs around the 3' end of mature miRNA region in 5' arm. The pattern and distribution of such regulatory sites appears to be a characteristic of precursor miRNA sequences when compared with non-miRNA sequences as negative dataset and tested statistically.When compared with 1 kb upstreamregions, a sudden sharp peak for binding sites arises in the enriched zone near the mature miRNA region. An expression-data-based correlation analysis was performed between such miRNAs and their corresponding transcription factors and RBPs for this region. Some specific groups of binding factors and associated miRNAs were identified. We also identified some of the overrepresented transcription factors and associated miRNAs with high expression correlation values which could be useful in cancer-related studies. The highly correlated groups were found to host experimentally validated composite regulatory modules, in which Lmo2-GATA1 appeared as the predominant one. For many of RBP-miRNAs associations, coexpression similarity was also evident among the associated miRNA common to given RBPs, supporting the Regulon model, suggesting a common role and common control of these miRNAs by the associated RBPs. Based on our findings, we propose that the observed characteristic distribution of regulatory sites in precursor miRNA sequence regions could be critical inmiRNA transcription, processing, stability and formation and are important for therapeutic studies. Our findings also support the recently proposed theory of self-sufficient mode of transcription by miRNAs, which states that miRNA transcription can be carried out in host-independent mode too.