The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL. Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors. From whole transcriptome sequencing, we observed striking expressional activity of the entire C19MC region. Concordantly, in 7 of 7 samples undergoing miRNAseq, we observed hyperexpression of the miRNAs within this cluster to levels >100 fold compared to matched normal tissue or a non-C19MC amplified cancer cell line. Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression. We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs. Using RNA-seq we identified that pathways relevant to cellular differentiation as well as mRNA translation machinery are transcriptionally enriched in UESL. In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC hyperexpression via chromosomal structural event with TP53 mutation or loss as highly recurrent genomic features of UESL.

Actigraphic patterns, impulsivity and mood instability in bipolar disorder, borderline personality disorder and healthy controls.

OBJECTIVES: To differentiate the relation between the structure and timing of rest-activity patterns and symptoms of impulsivity and mood instability in bipolar disorder (BD), borderline personality disorder (BPD) and healthy controls (HC). METHODS: Eighty-seven participants (31 BD, 21 BPD and 35 HC) underwent actigraph monitoring for 28 days as part of the Automated Monitoring of Symptom Severity (AMoSS) study. Impulsivity was assessed at study entry using the BIS-11. Mood instability was subsequently longitudinally monitored using the digital Mood Zoom questionnaire. RESULTS: BPD participants show several robust and significant correlations between non-parametric circadian rest-activity variables and worsened symptoms. Impulsivity was associated with low interdaily stability (r = -0.663) and weak amplitude (r = -0.616). Mood instability was associated with low interdaily stability (r = -0.773), greater rhythm fragmentation (r = 0.662), weak amplitude (r = -0.694) and later onset of daily activity (r = 0.553). These associations were not present for BD or HCs. Classification analysis using actigraphic measures determined that later L5 onset reliably distinguished BPD from BD and HC but did not sufficiently discriminate between BD and HC. CONCLUSIONS: Rest-activity pattern disturbance indicative of perturbed sleep and circadian function is an important predictor of symptom severity in BPD. This appears to validate the greater subjective complaints of BPD individuals that are sometimes regarded as exaggerated by clinicians. We suggest that treatment strategies directed towards improving sleep and circadian entrainment may in the future be investigated in BPD.

Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.

Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.

Vitamin D, bone mineral density and risk of fracture in people with intellectual disabilities.

BACKGROUND: People with intellectual disabilities (IDs) have very high rates of osteoporosis and fractures, to which their widespread vitamin D deficiency and other factors could contribute. We aimed to assess in people with IDs previously treated for vitamin D deficiency (1) long-term adherence to vitamin D supplementation and (2) bone mineral density (BMD), as an indicator for risk of fractures, according to vitamin D supplementation and other factors. METHOD: We recorded height, weight, medical, pharmacological, dietary and lifestyle assessment. Blood sample were taken for vitamin D and related analytes. dual-energy X-ray absorptiometry for BMD was performed. RESULTS: Of 51 study participants (mean [standard deviation, SD] age 51.5 [13.6] years, 57% male), 41 (80.4%) were taking vitamin D and 10 were not. Mean [SD] serum vitamin D was 81.3 [21.3] vs. 25.2 [10.2] nmol/L (P < 0.0001), respectively. Thirty-six participants underwent a dual-energy X-ray absorptiometry scan, which showed osteoporosis in 23.7% and osteopenia in 52.6%. Participants on vitamin D had higher BMD than those who were not, a statistically significant difference when confounders (lack of mobility and hypogonadism) were removed. BMD was significantly different according to mobility, particularly in wheelchair users, in whom hip BMD was 33% lower (P < 0.0001) than in participants with normal mobility. Participants still taking vitamin D showed a 6.1% increase in BMD at the spine (P = 0.003) after mean [SD] 7.4 [1.5] years vitamin D treatment. CONCLUSIONS: In people with IDs and previous vitamin D deficiency, BMD increases on long-term vitamin D supplementation. However, additional strategies must be considered for osteoporosis and fracture prevention in this population.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression.

CF3DODA-Me induces apoptosis, degrades Sp1, and blocks the transformation phase of the blebbishield emergency program.

Cancer stem cells are capable of undergoing cellular transformation after commencement of apoptosis through the blebbishield emergency program in a VEGF-VEGFR2-dependent manner. Development of therapeutics targeting the blebbishield emergency program would thus be important in cancer therapy. Specificity protein 1 (Sp1) orchestrates the transcription of both VEGF and VEGFR2; hence, Sp1 could act as a therapeutic target. Here, we demonstrate that CF3DODA-Me induced apoptosis, degraded Sp1, inhibited the expression of multiple drivers of the blebbishield emergency program such as VEGFR2, p70S6K, and N-Myc through activation of caspase-3, inhibited reactive oxygen species; and inhibited K-Ras activation to abolish transformation from blebbishields as well as transformation in soft agar. These findings confirm CF3DODA-Me as a potential therapeutic candidate that can induce apoptosis and block transformation from blebbishields.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial.

OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.

Smac mimetic with TNF-α targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields.

Cancer cells are capable of sphere formation (transformation) through reactive oxygen species (ROS) and glycolysis shift. Transformation is linked to tumorigenesis and therapy resistance, hence targeting regulators of ROS and glycolysis is important for cancer therapeutic candidates. Here, we demonstrate that Smac mimetic AZ58 in combination with tumour necrosis factor-α (TNF-α) was able to inhibit the production of ROS, inhibit glycolysis through Pim-1 kinase-mediated Ser-112 phosphorylation of BAD, and increase depolarization of mitochondria. We also identified mitochondrial isoforms of Pim-1 kinase that were targeted for degradation by AZ58 in combination with TNF-α or AZ58 in combination with Fas ligand (FasL) plus cycloheximide (CHX) through caspase-3 to block transformation. Our study demonstrates that Smac mimetic in combination with TNF-α is an ideal candidate to target Pim-1 expression, inhibit ROS production and to block transformation from blebbishields.

Pim kinase isoforms: devils defending cancer cells from therapeutic and immune attacks.

Pim kinases are being implicated in oncogenic process in various human cancers. Pim kinases primarily deal with three broad categories of functions such as tumorigenesis, protecting cells from apoptotic signals and evading immune attacks. Here in this review, we discuss the regulation of Pim kinases and their expression, and how these kinases defend cancer cells from therapeutic and immune attacks with special emphasis on how Pim kinases maintain their own expression during apoptosis and cellular transformation, defend mitochondria during apoptosis, defend cancer cells from immune attack, defend cancer cells from therapeutic attack, choose localization, self-regulation, activation of oncogenic transcription, metabolic regulation and so on. In addition, we also discuss how Pim kinases contribute to tumorigenesis by regulating cellular transformation and glycolysis to reinforce the importance of Pim kinases in cancer and cancer stem cells.

Associations between mood instability and emotional processing in a large cohort of bipolar patients.

BACKGROUND: Aberrant emotional biases have been reported in bipolar disorder (BD), but results are inconsistent. Despite the clinical relevance of chronic mood variability in BD, there is no previous research investigating how the extent of symptom fluctuations in bipolar disorder might relate to emotional biases. This exploratory study investigated, in a large cohort of bipolar patients, whether instability in weekly mood episode symptoms and other clinical and demographic factors were related to emotional bias as measured in a simple laboratory task. METHOD: Participants (N = 271, BDI = 206, BDII = 121) completed an 'emotional categorization and memory' task. Weekly self-reported symptoms of depression and mania were collected prospectively. In linear regression analyses, associations between cognitive bias and mood variability were explored together with the influence of demographic and clinical factors, including current medication. RESULTS: Greater accuracy in the classification of negative words relative to positive words was associated with greater instability in depressive symptoms. Furthermore, greater negative bias in free recall was associated with higher instability in manic symptoms. Participants diagnosed with BDII, compared with BDI, showed overall better word recognition and recall. Current antipsychotic use was associated with reduced instability in manic symptoms but this did not impact on emotional processing performance. CONCLUSIONS: Emotional processing biases in bipolar disorder are related to instability in mood. These findings prompt further investigation into the underpinnings as well as clinical significance of mood instability.

Borderline personality disorder, but not euthymic bipolar disorder, is associated with a failure to sustain reciprocal cooperative behaviour: implications for spectrum models of mood disorders.

BACKGROUND: Borderline personality disorder (BPD) and bipolar disorder (BD) have overlapping clinical presentations and symptoms - sources of persistent clinical confusion. Game-theory can characterize how social function might be sub-optimal in the two disorders and move the field beyond the anecdotal description of clinical history. Here, we tested the hypothesis that BPD and BD can be distinguished on the basis of diminished reciprocal altruism in iterated Prisoner's Dilemma (PD) games. METHOD: Twenty females with BPD, 20 females with euthymic BD and 20 healthy (non-clinical) females, matched for age and cognitive ability, were assessed for Axis-I and personality disorders, and completed psychometric measures of state affect, impulsivity and hostility. Participants completed two iterated PD games and a test of gaze-cueing. RESULTS: In the PD games, BPD participants failed to show statistically stable preferences to cooperate with social partners (playing tit-for-tat) and made significantly fewer cooperative responses compared to BD or controls (ANOVA main effect p = 0.03, post-hoc Tukey p < 0.05 for both comparisons). BPD participants were also less likely to sustain cooperation following experiences involving mutual cooperation than the other groups. Neither BPD nor BD participants demonstrated impairments in shifting visual attention on the basis of other peoples' gaze. CONCLUSIONS: These data indicate that BPD is (selectively) associated with difficulties in establishing, and then maintaining, reciprocal cooperation, involving altruism. These difficulties are not seen in euthymic BD. Our data support the differentiation of BPD from BD and offer fresh insights into the social difficulties experienced by individuals with diagnoses of BPD.

Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels.

BACKGROUND: Oxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers. METHOD: Blood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period. RESULTS: Compared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness. CONCLUSIONS: Plasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Nonlinear time-series approaches in characterizing mood stability and mood instability in bipolar disorder.

Bipolar disorder is a psychiatric condition characterized by episodes of elevated mood interspersed with episodes of depression. While treatment developments and understanding the disruptive nature of this illness have focused on these episodes, it is also evident that some patients may have chronic week-to-week mood instability. This is also a major morbidity. The longitudinal pattern of this mood instability is poorly understood as it has, until recently, been difficult to quantify. We propose that understanding this mood variability is critical for the development of cognitive neuroscience-based treatments. In this study, we develop a time-series approach to capture mood variability in two groups of patients with bipolar disorder who appear on the basis of clinical judgement to show relatively stable or unstable illness courses. Using weekly mood scores based on a self-rated scale (quick inventory of depressive symptomatology-self-rated; QIDS-SR) from 23 patients over a 220-week period, we show that the observed mood variability is nonlinear and that the stable and unstable patient groups are described by different nonlinear time-series processes. We emphasize the necessity in combining both appropriate measures of the underlying deterministic processes (the QIDS-SR score) and noise (uncharacterized temporal variation) in understanding dynamical patterns of mood variability associated with bipolar disorder.

Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis.

Metastasis is a pivotal event that accelerates the prognosis of cancer patients towards mortality. Therapies that aim to induce cell death in metastatic cells require a more detailed understanding of the metastasis for better mitigation. Towards this goal, we discuss the details of two distinct but overlapping pathways of metastasis: a classical reversible epithelial-to-mesenchymal transition (hybrid-EMT)-driven transport pathway and an alternative cell death process-driven blebbishield metastatic-witch (BMW) transport pathway involving reversible cell death process. The knowledge about the EMT and BMW pathways is important for the therapy of metastatic cancers as these pathways confer drug resistance coupled to immune evasion/suppression. We initially discuss the EMT pathway and compare it with the BMW pathway in the contexts of coordinated oncogenic, metabolic, immunologic, and cell biological events that drive metastasis. In particular, we discuss how the cell death environment involving apoptosis, ferroptosis, necroptosis, and NETosis in BMW or EMT pathways recruits immune cells, fuses with it, migrates, permeabilizes vasculature, and settles at distant sites to establish metastasis. Finally, we discuss the therapeutic targets that are common to both EMT and BMW pathways.

A comprehensive review and model of putative prodromal features of bipolar affective disorder.

BACKGROUND: Identifying prodromal features that predate the onset of bipolar disorder (BD) may enable the prevention of BD and aid early intervention. This review addresses two key questions: Is there a bipolar prodrome? And, if there is, what are its characteristic features? METHOD: A comprehensive search of databases (PubMed, Medline, EMBASE and PsycINFO) supplemented by hand searches was used to identify studies of symptoms preceding the onset of BD. RESULTS: Fifty-nine studies were identified, of which 14 met inclusion criteria. Symptoms can predate the onset of BD by months to years and can be categorized as attenuated forms of BD symptoms, general symptoms common to a range of mental disorders, and personality traits, particularly cyclothymia. Two studies provided sufficient data to enable sensitivity and specificity to be calculated. Specificity of several of the features was high (>90%) but sensitivity was generally low (all <60%). We propose a model based on the findings in the studies reviewed to illustrate the potential trajectory to BD and the points at which it may be possible to intervene. CONCLUSIONS: Clinical features preceding the onset of BD can be identified. However, conclusions about whether there is a distinct prodrome to BD are restricted by the limitations of current evidence. The high specificity of some features suggests they may be useful in clinical practice. Large-scale longitudinal studies are needed to validate these features and characterize their specificity and sensitivity in independent samples.

Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of human labor.

In most mammals, labor is heralded by progesterone withdrawal, which is believed to be related to the activation of multiple pathways leading to parturition. In humans, despite no decrease in placental progesterone production, activation of similar pathways preceding labor suggests the presence of an endogenous antiprogestin, which we reasoned might be cortisol, whose secretion from the fetal adrenal rises markedly at the end of human gestation. We report that in primary cultures of human placenta, cortisol is able to compete with the action of progesterone in the regulation of the corticotropin-releasing hormone (CRH) gene. CRH is a peptide highly expressed in human placenta at the end of gestation, which has been suggested to be involved in regulating the timing of parturition. These findings provide a model for functional progesterone withdrawal at the end of human pregnancy, which may be involved in the initiation of labor.