Therapeutically engineered stem cells have shown promise for glioblastoma multiforme (GBM) therapy; however, key preclinical studies are urgently needed for their clinical translation. In this study, ...we investigated a new approach to GBM treatment using therapeutic stem cells encapsulated in biodegradable, synthetic extracellular matrix (sECM) in mouse models of human GBM resection. Using multimodal imaging, we first showed quantitative surgical debulking of human GBM tumors in mice, which resulted in increased survival. Next, sECM encapsulation of engineered stem cells increased their retention in the tumor resection cavity, permitted tumor-selective migration and release of diagnostic and therapeutic proteins in vivo. Simulating the clinical scenario of GBM treatment, the release of tumor-selective S-TRAIL (secretable tumor necrosis factor apoptosis inducing ligand) from sECM-encapsulated stem cells in the resection cavity eradicated residual tumor cells by inducing caspase-mediated apoptosis, delayed tumor regrowth and significantly increased survival of mice. This study demonstrates the efficacy of encapsulated therapeutic stem cells in mouse models of GBM resection and may have implications for developing effective therapies for GBM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objective: Rational therapeutic development in bipolar is hampered by a lack of pathophysiological model. However, there is a wealth of converging data on the role of dopamine in bipolar disorder. ...This paper therefore examines the possibility of a dopamine hypothesis for bipolar disorder.
Method: A literature search was conducted using standard search engines Embase, PyschLIT, PubMed and MEDLINE. In addition, papers and book chapters known to the authors were retrieved and examined for further relevant articles.
Results: Collectively, in excess of 100 articles were reviewed from which approximately 75% were relevant to the focus of this paper.
Conclusion: Pharmacological models suggest a role of increased dopaminergic drive in mania and the converse in depression. In Parkinson’s disease, administration of high‐dose dopamine precursors can produce a ‘maniform’ picture, which switches into a depressive analogue on withdrawal. It is possible that in bipolar disorder there is a cyclical process, where increased dopaminergic transmission in mania leads to a secondary down regulation of dopaminergic receptor sensitivity over time. This may lead to a period of decreased dopaminergic transmission, corresponding with the depressive phase, and the repetition of the cycle. This model, if verified, may have implications for rational drug development.
Objective
We examined the relationship between biological rhythms and severity of depressive symptoms in subjects with bipolar disorder and the effects of biological rhythms alterations on functional ...impairment.
Method
Bipolar patients (n = 260) and healthy controls (n = 191) were recruited from mood disorders programs in three sites (Spain, Brazil, and Canada). Parameters of biological rhythms were measured using the Biological Rhythms Assessment in Neuropsychiatry (BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity.
Results
Multivariate analyses of covariance showed significant intergroup differences after controlling for potential confounders (Pillai's F = 49.367; df = 2, P < 0.001). Depressed patients had the greatest biological rhythms disturbance, followed by patients with subsyndromal symptoms, euthymic patients, and healthy controls. Biological rhythms and HAMD scores were independent predictors of poor functioning (F = 12.841, df = 6, P < 0.001, R2 = 0.443).
Conclusion
Our study shows a dose‐dependent association between the severity of depressive symptoms and degree of biological rhythms disturbance. Biological rhythms disturbance was also an independent predictor of functional impairment. Although the directionality of this relationship remains unknown, our results suggest that stability of biological rhythms should be an important target of acute and long‐term management of bipolar disorder and may aid in the improvement of functioning.
Objective
We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for ...bipolar disorders are outlined.
Method
We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging.
Results
We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers.
Conclusion
Most studies to date indicate that globally defined late‐stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end‐stage medical disorders. We believe it is possible at this juncture to speak broadly of ‘early’‐ and ‘late’‐stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.
Objective
To assess the prevalence of childhood trauma and types of trauma on mood disorders among young adults in a population‐based sample. We further gathered data on family history of mood ...disorders to test the hypothesis that childhood trauma is a mediating factor for the association between family history of mood disorder and mood disorder in adulthood.
Method
This is a cross‐sectional study, including young adults with bipolar disorder, major depressive disorder, and matched controls without any mood disorder. Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). The Hicks and Tingley implementation was employed to assess whether trauma is a mediator of the effect of family history on diagnosis of any mood disorder.
Results
All types of trauma were associated with both major depression and bipolar disorder, with the exception of sexual abuse, which was only associated with bipolar disorder. Moreover, family history of psychiatric illness was also associated with mood disorder in adulthood and with childhood trauma. Using the presence of any mood disorder as the outcome, a third of the effect of having any family history of mood disorder was mediated via childhood trauma.
Conclusion
This investigation provides further support, in a population‐based sample of young adults, of the association between childhood trauma and mood disorders, with sexual abuse being specifically linked with bipolar disorder. The hypothesis that childhood trauma would function as a partial mediator of the association between family history of mood disorder and mood disorder in adulthood was also confirmed.
Objective
Immune activation in bipolar disorder (BD) has been frequently reported. Damage‐associated molecular patterns (DAMPs) are key players in the immune activation reaction. The aim of this ...study was to assess DAMP levels in drug‐free patients with BD during acute episodes.
Method
Serum levels of a predetermined set of DAMPs were assessed in drug‐free patients with BD (n = 20) during an acute mood episode. We also included two control groups: healthy subjects, used as a negative control (n = 20); and patients with sepsis, used as a positive control for severe immune activation (n = 20).
Results
Multivariate analysis using generalized linear mixed model indicated that all DAMPs differed as a function of group membership after controlling for age and addressing multiplicity (P < 0.0006 for all comparisons). Follow‐up analyses showed higher levels in BD subjects of circulating cell‐free (ccf) nuclear (n)DNA (P = 0.02), HSP70 (P = 0.03) and HSP90α (P = 0.02) as compared to healthy subjects. Also, patients with BD showed lower levels of ccf nDNA (P = 0.04), HSP60 (P = 0.03), HSP70 (P = 0.01), and HSP90α (P = 0.002) as compared to patients with sepsis and higher levels of ccf mitochondrial DNA (P < 0.0001).
Conclusion
The present findings may be linked to the inflammatory activity previously described among patients with BD and may help in the development of more targeted and personalized treatments for patients under acute episodes of BD.
We report a "hitchhiking mapping" study in D. melanogaster, which searches for genomic regions with reduced variability. The study's aim was to identify selective sweeps associated with the "out of ...Africa" habitat expansion. We scanned 103 microsatellites on chromosome 3 and 102 microsatellites on the X chromosome for reduced variability in non-African populations. When the chromosomes were analyzed separately, the number of loci with a significant reduction in variability only slightly exceeded the expectation under neutrality--six loci on the third chromosome and four loci on the X chromosome. However, non-African populations also have a more pronounced average loss in variability on the X chromosomes as compared to the third chromosome, which suggests the action of selection. Therefore, comparing the X chromosome to the autosome yields a higher number of significantly reduced loci. However, a more pronounced loss of variability on the X chromosome may be caused by demographic events rather than by natural selection. We therefore explored a range of demographic scenarios and found that some of these captured most, but not all aspects of our data. More theoretical work is needed to evaluate how demographic events might differentially affect X chromosomes and autosomes and to estimate the most likely scenario associated with the out of Africa expansion of D. melanogaster.
We present a portable four-channel atomic magnetometer array operating in the spin-exchange relaxation-free regime. The magnetometer array has several design features intended to maximize its ...suitability for biomagnetic measurement, specifically foetal magnetocardiography, such as a compact modular design and fibre-coupled lasers. The modular design allows the independent positioning and orientation of each magnetometer. Using this array in a magnetically shielded room, we acquire adult magnetocadiograms. These measurements were taken with a 6-11 fT Hz−1 2 single-channel baseline sensitivity that is consistent with the independently measured noise level of the magnetically shielded room.
Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a ...prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a large number of EWS-FLI1-anticorrelated genes including structural and regulatory cytoskeletal genes. Consistent with this finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of TEAD-binding motifs in these shared genomic binding regions and overlapping transcriptional footprints of MRTFB and TEAD factors led us to propose synergy between MRTFB and the YAP/TEAD complex in the regulation of EWS-FLI1-anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which directly affects the actin-autoregulatory feedback loop. As spontaneous fluctuations in EWS-FLI1 levels of Ewing sarcoma cells in vitro and in vivo, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non-proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells.
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