Systemic and local immunosuppression in glioblastoma and its prognostic significance.

The effectiveness of tumor therapy, especially immunotherapy and oncolytic virotherapy, critically depends on the activity of the host immune cells. However, various local and systemic mechanisms of immunosuppression operate in cancer patients. Tumor-associated immunosuppression involves deregulation of many components of immunity, including a decrease in the number of T lymphocytes (lymphopenia), an increase in the levels or ratios of circulating and tumor-infiltrating immunosuppressive subsets [e.g., macrophages, microglia, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)], as well as defective functions of subsets of antigen-presenting, helper and effector immune cell due to altered expression of various soluble and membrane proteins (receptors, costimulatory molecules, and cytokines). In this review, we specifically focus on data from patients with glioblastoma/glioma before standard chemoradiotherapy. We discuss glioblastoma-related immunosuppression at baseline and the prognostic significance of different subsets of circulating and tumor-infiltrating immune cells (lymphocytes, CD4+ and CD8+ T cells, Tregs, natural killer (NK) cells, neutrophils, macrophages, MDSCs, and dendritic cells), including neutrophil-to-lymphocyte ratio (NLR), focus on the immune landscape and prognostic significance of isocitrate dehydrogenase (IDH)-mutant gliomas, proneural, classical and mesenchymal molecular subtypes, and highlight the features of immune surveillance in the brain. All attempts to identify a reliable prognostic immune marker in glioblastoma tissue have led to contradictory results, which can be explained, among other things, by the unprecedented level of spatial heterogeneity of the immune infiltrate and the significant phenotypic diversity and (dys)functional states of immune subpopulations. High NLR is one of the most repeatedly confirmed independent prognostic factors for shorter overall survival in patients with glioblastoma and carcinoma, and its combination with other markers of the immune response or systemic inflammation significantly improves the accuracy of prediction; however, more prospective studies are needed to confirm the prognostic/predictive power of NLR. We call for the inclusion of dynamic assessment of NLR and other blood inflammatory markers (e.g., absolute/total lymphocyte count, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, and systemic immune response index) in all neuro-oncology studies for rigorous evaluation and comparison of their individual and combinatorial prognostic/predictive significance and relative superiority.

Antibodies against N-Methyl D-Aspartate Receptor in Psychotic Disorders: A Systematic Review.

OBJECTIVE: The objective of this study was to provide comprehensive evidence synthesis including all available up-to-date data about the prevalence of N-methyl D-aspartate receptor (NMDAR) antibodies (ABs) in psychotic patients in order to evaluate the clinical relevance of ABs as well as to specify potential explanations of the heterogeneity of the findings and determine areas for further research. METHODS: A literature search was conducted using the PubMed/Medline, Web of Knowledge, and Scopus databases. RESULTS: Forty-seven studies and 4 systematic reviews (including 2 meta-analyses) were included in the present review. Studies that used cell-based assays (CBAs) provided heterogeneous results on AB prevalence, obviously depending on the type of detection assay and sample characteristics. Improvement of AB detection methods is necessary to determine the real prevalence of ABs across different groups of patients and healthy people. Live CBAs seem to have better sensitivity but probably poorer specificity than fixed CBAs. Moreover, some links between AB-positive status and acute symptoms are possible. A small amount of data on immunotherapy in AB-positive patients raises the possibility of its effectiveness but obviously require further research. CONCLUSIONS: NMDAR ABs are definitely present in a subset of psychotic patients. NMDAR ABs might shape psychosis and underlie some symptoms, and immunotherapy might be regarded as a treatment option for patients failing to respond to other therapies.

Plasma Neurotrophic Factor Levels are not Associated with the Severity of Depression: Prospective Pilot Study.

INTRODUCTION: Depression is one of the most common mental illnesses. Impaired neurogenesis is observed in depression. Biomarkers of impaired neurogenesis in depression can act as a useful objective and diagnostic and prognostic tool to determine the severity of depression. AIM: To study the concentration of biochemical indicators in the blood that may be involved in the pathogenesis of depression and their intercorrelations, and to determine any associations between the concentrations of biochemical indicators and severity of depressive symptoms. METHODS: We determined the plasma concentrations of serotonin, dopamine, and neurotrophic factors involved in neurogenesis (BDNF, CDNF and neuropeptide Y) using enzyme immunoassay and mass spectrometry in depressed patients (n=22) and healthy controls (n=16) matched by socio-demographic parameters. All participants were assessed using the Hamilton Depression Scale (HAMD), the Generalized Anxiety Disorder Questionnaire (GAD-7), and the Center for Epidemiologic Studies Depression Scale (CES-D) to enter the study. The standard cut-offs for the CES-D and GAD-7 scales were used to confirm the presence or absence of depression and anxiety. RESULTS: The concentrations of serotonin, dopamine, BDNF, CDNF, and neuropeptide Y in plasma did not differ between the groups and was not found to be associated with the scores on the scales. Positive correlations were found between the concentration of neuropeptide Y and serotonin, BDNF, and CDNF in blood plasma. CONCLUSIONS: Plasma concentrations of biomarkers related to the pathophysiology of depression did not correlate with the severity of its symptoms.

The role of extracellular inducer of matrix metalloproteinases in premature rupture of membranes.

OBJECTIVE: To investigate the role of matrix metalloproteinases (MMP-2, MMP-9) and their inducer (CD147) in premature rupture of membranes (PROM) at term labor. METHODS: In a cross-sectional study, 24 women aged 19-39, with 37-40-week pregnancy, and no clinical and histological signs of chorioamnionitis, were divided into two groups with and without PROM. The histological and immunohistochemical study of the fetal membranes was performed with polyclonal rabbit antibodies to MMP-2/MMP-9 and monoclonal rabbit antibodies to CD147. RESULTS: The analysis of MMP revealed the increase of MMP-9 expression in the amniotic epithelium during premature membrane rupture both in rupture area, and beyond it, and increased MMR-2 expression in the mesodermal cells. We also found high level of CD147 in the amniotic epithelium in PROM group. The above-mentioned changes were found in all areas of fetal membranes, regardless of the rupture localization. CONCLUSIONS: The study results demonstrate the increased expression of MMR-2 and MMR-9, which regulate the catabolism of fetal membrane extracellular matrix proteins, in amniotic membranes of women with PROM at term labor. The increased expression of CD147 may be one of the mechanisms triggering PROM in the absence of infection.

Genetic determinants of aggression and impulsivity in humans.

Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function.