Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells

Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment-Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA-KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation

Morphodynamics of the exit of a cutoff meander: experimental findings from field and laboratory studies

The morphological evolution of the entrances and exits of abandoned river channels governs their hydrological connectivity. The study focusses on flow and sediment dynamics in the exit of a cut-off meander where the downstream entrance is still connected to the main channel, but the upstream entrance is closed. Two similar field and laboratory cases were investigated using innovative velocimetry techniques (acoustic Doppler profiling, image analysis). Laboratory experiments were conducted with a mobile-bed physical model of the Morava river (Slovakia). Field measurements were performed in the exit of the Port-Galland cut-off meander, Ain river (France). Both cases yielded consistent and complementary results from which a generic scheme for flow patterns and morphological evolution was derived. A simple analogy with flows in rectangular side cavities was used to explain the recirculating flow patterns which developed in the exit. A decelerating inflow deposits bedload in the downstream part of the cavity, while the upstream part is eroded by an accelerating outflow, leading to the retreat of the upstream bank. In the field, strong secondary currents were observed, especially in the inflow, which may enhance the scouring of the downstream corner of the cavity. Also, fine sediment deposits constituted a silt layer in a transitional zone, located between the mouth of the abandoned channel and the oxbow-lake within the cut-off meander. Attempts at morphological prediction should consider not only the flow and sediment conditions in the cavity, but also the dynamics of the main channel

Highly preferential association of NonF508del CF mutations with the M470 allele

AbstractBackgroundOn the basis of previous findings on random individuals, we hypothesized a preferential association of CF causing mutations with the M allele of the M470V polymorphic site of the CFTR gene.MethodsWe have determined the M/V-CF mutation haplotype in a series of 201 North East Italian and 73 Czech CF patients who were not F508del homozygotes, as F508del was already known to be fully associated with the M allele.ResultsOut of 358 not F508del CF genes, 84 carried the V allele and 274 the less common M allele. In the N-E Italian population, MM subjects have a risk of carrying a CF causing mutation 6.9× greater than VV subjects when F508del is excluded and 15.4× when F508del is included. In the Czech population a similar, although less pronounced, association is observed.ConclusionsBesides the possible biological significance of this association, the possibility of exploiting it for a pilot screening program has been explored in a local North East Italian population for which CF patients were characterized for their CF mutation. General M470V genotyping followed by common CF mutation screening limited to couples in which each partner carries at least one M allele would need testing only 39% of the couples, which contribute 89% of the total risk, with a cost benefit

Role of liraglutide in Alzheimer's disease pathology

Background The described relationship between Alzheimer's disease (AD) and type 2 diabetes (T2D) and the fact that AD has no succesful treatment has led to the study of antidiabetic drugs that may limit or slow down AD pathology. Main body Although T2D treatment has evident limitations, options are increasing including glucagon-like peptide 1 analogs. Among these, liraglutide (LRGT) is commonly used by T2D patients to improve beta cell function and suppress glucagon to restore normoglycaemia. Interestingly, LRGT also counterbalances altered brain metabolism and has anti-inflammatory properties. Previous studies have reported its capacity to reduce AD pathology, including amyloid production and deposition, tau hyperphosphorylation, or neuronal and synaptic loss in animal models of AD, accompanied by cognitive improvement. Given the beneficial effects of LRGT at central level, studies in patients have been carried out, showing modest beneficial effects. At present, the ELAD trial (Evaluating Liraglutide in Alzheimer's Disease NCT01843075) is an ongoing phase IIb study in patients with mild AD. In this minireview, we resume the outcomes of LRGT treatment in preclinical models of AD as well as the available results in patients up to date. Conclusion The effects of LRGT on animal models show significant benefits in AD pathology and cognitive impairment. While studies in patients are limited, ongoing clinical trials will probably provide more definitive conclusions on the role of LRGT in AD patients

Self-stigma and quality of life in patients with depressive disorder: a cross-sectional study

Michaela Holubova,1,2 Jan Prasko,1 Marie Ociskova,1 Marketa Marackova,1 Ales Grambal,1 Milos Slepecky3 1Department of Psychiatry, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, Olomouc, 2Department of Psychiatry, Hospital Liberec, Liberec, Czech Republic; 3Department of Psychology Sciences, Faculty of Social Science and Health Care, Constantine the Philosopher University, Nitra, Slovak Republic Background: Self-stigma is a maladaptive psychosocial phenomenon that can affect many areas of patients’ lives and have a negative impact on their quality of life (QoL). This study explored the association between self-stigma, QoL, demographic data, and the severity of symptoms in patients with depressive disorder. Patients and methods: Patients who met the International Classification of Diseases, 10th revision, research criteria for depressive disorder were enrolled in this cross-sectional study. All outpatients completed the following measurements: the Quality of Life Enjoyment and Satisfaction Questionnaire, the Internalized Stigma of Mental Illness Scale, demographic questionnaire, and the objective and subjective Clinical Global Impression-Severity scales that measure the severity of disorder. A total of 81 depressive disorder patients (with persistent affective disorder – dysthymia, major depressive disorder, or recurrent depressive disorder) and 43 healthy controls participated in this study. Results: Compared with the healthy control group, a lower QoL was observed in patients with depressive disorder. The level of self-stigma correlated positively with total symptom severity score and negatively with QoL. Multiple regression analysis revealed that the overall rating of objective symptom severity and score of self-stigma were significantly associated with QoL. Conclusion: This study suggests a lower QoL in patients with depressive disorder in comparison with healthy controls and a negative impact of self-stigma level on QoL in patients suffering from depressive disorders. Keywords: self-stigma, quality of life, depressive disorde

Role of Polymorphisms of NKG2D Receptor and Its Ligands in Acute Myeloid Leukemia and Human Stem Cell Transplantation

Natural killer cells possess key regulatory function in various malignant diseases, including acute myeloid leukemia. NK cell activity is driven by signals received through ligands binding activating or inhibitory receptors. Their activity towards elimination of transformed or virally infected cells can be mediated through MICA, MICB and ULBP ligands binding the activating receptor NKG2D. Given the efficiency of NK cells, potential target cells developed multiple protecting mechanisms to overcome NK cells killing on various levels of biogenesis of NKG2D ligands. Targeted cells can degrade ligand transcripts via microRNAs or modify them at protein level to prevent their presence at cell surface via shedding, with added benefit of shed ligands to desensitize NKG2D receptor and avert the threat of destruction via NK cells. NK cells and their activity are also indispensable during hematopoietic stem cell transplantation, crucial treatment option for patients with malignant disease, including acute myeloid leukemia. Function of both NKG2D and its ligands is strongly affected by polymorphisms and particular allelic variants, as different alleles can play variable roles in ligand-receptor interaction, influencing NK cell function and HSCT outcome differently. For example, role of amino acid exchange at position 129 in MICA or at position 98 in MICB, as well as the role of other polymorphisms leading to different shedding of ligands, was described. Finally, match or mismatch between patient and donor in NKG2D ligands affect HSCT outcome. Having the information beyond standard HLA typing prior HSCT could be instrumental to find the best donor for the patient and to optimize effects of treatment by more precise patient-donor match. Here, we review recent research on the NKG2D/NKG2D ligand biology, their regulation, description of their polymorphisms across the populations of patients with AML and the influence of particular polymorphisms on HSCT outcome

Quality of life, self-stigma, and coping strategies in patients with neurotic spectrum disorders: a cross-sectional study

Michaela Holubova,1–3 Jan Prasko,1,2,4 Marie Ociskova,1,2 Kryštof Kantor,1,2 Jakub Vanek,1,2 Milos Slepecky,4 Kristyna Vrbova1,2 1Department of Psychiatry, University Hospital Olomouc, Olomouc, Czech Republic; 2Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic; 3Department of Psychiatry, Hospital Liberec, Liberec, Czech Republic; 4Department of Psychology Sciences, Faculty of Social Science and Health Care, Constantine the Philosopher University in Nitra, Nitra, Slovakia Background: Modern psychiatry focuses on self-stigma, coping strategies, and quality of life (QoL). This study looked at relationships among severity of symptoms, self-stigma, demographics, coping strategies, and QoL in patients with neurotic spectrum disorders. Methods: A total of 153 clinically stable participants who met criteria for generalized anxiety disorder, social phobia, panic disorder, agoraphobia, mixed anxiety–depressive disorder, adjustment disorders, somatoform disorders, or obsessive–compulsive disorder were included in a cross-sectional study. Psychiatrists examined patients during regular psychiatric checkups. Patients completed the Quality of Life Satisfaction and Enjoyment Questionnaire (Q-LES-Q), Internalized Stigma of Mental Illness Scale (ISMI), a sociodemographic questionnaire, the Stress Coping Style Questionnaire (Strategie Zvládání Stresu [SVF] 78), and the Clinical Global Impression (CGI) scale. Results: The diagnostic subgroups differed significantly in age and use of negative coping strategies, but not in other measured clinical or psychological variables. The findings showed that neither sex nor partnership played a role in perceived QoL. All Q-LES-Q domains correlated negatively with all ISMI domains, except school/study. Unemployed and employed groups of patients differed in QoL. Each of the coping strategies, except the need for social support, was related to self-stigma. The findings showed that sex, partnership, education, and employment played no role in self-stigma. No differences between sexes in positive coping strategies, severity of disorder, self-stigma, or QoL were found. QoL correlated significantly with all coping strategies, except for guilt denial. Multiple regression showed the most important factors to be positive coping, employment, and overall self-stigma rating, explaining 32.9% of QoL. Mediation analysis showed self-stigma level and negative coping strategies to be the most influential. The most substantial factors associated with self-stigma, as indicated by regression analysis, were Q-LES-Q total, subjective CGI, and positive coping strategies, which clarified 44.5% of the ISMI. Conclusion: The study confirmed associations among self-stigma, quality of life, disorder severity, and coping strategies of outpatients with neurotic spectrum disorders. Keywords: self-stigma, quality of life, coping strategies, neurotic spectrum disorder

Glasses of stoichiometric (As2Se3)​100-​x(Sb2Se3)​x system

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