Gelatin‐coated Gold Nanoparticles as Carriers of FLT3 Inhibitors for Acute Myeloid Leukemia Treatment

This study presents the design of a gold nanoparticle (AuNPs)—drug system with improved efficiency for the treatment of acute myeloid leukemia. The system is based on four different FLT3 inhibitors, namely midostaurin, sorafenib, lestaurtinib, and quizartinib, which were independently loaded onto gelatin‐coated gold nanoparticles. Detailed investigation of the physicochemical properties of the formed complexes lead to the selection of quizartinib—loaded AuNPs for the in vitro evaluation of the biological effects of the formed complex against OCI‐AML3 acute myeloid leukemia cells. Viability tests by MTT demonstrated that the proposed drug complex has improved efficacy when compared with the drug alone. The obtained results constitute a premise for further in vivo investigation of such drug vehicles based on AuNPs. To the best of our knowledge, this is the first study that investigates the delivery of the above‐mentioned FLT3 inhibitors via gelatin‐coated gold nanoparticles.     

Stimulus-focused attention speeds up auditory processing

Stimulus-focused attention enhances the processing of auditory stimuli, which is indicated by enhanced neural activity. In situations where fast responses are required, attention may not only serve as a means to gain more information about the relevant stimulus, but it may provide a processing speed gain as well. In two experiments we investigated whether attentional focusing decreased the latency of the auditory N1 event related potential. In Experiment 1 slowly emerging, soft (20dB sensation level) sounds were presented in two conditions, in which participants performed a sound-detection task or watched a silent movie and ignored the sounds. N1 latency was shorter in the sound-detection task in comparison to the ignore condition. In Experiment 2 we investigated whether the attentional N1 latency-decrease was caused by a frequency-specific attentional preparation or not. To this end, tone sequences were presented with a single tone frequency or with four different frequencies. N1 latency was shorter in the sound-detection task in comparison to the ignore condition regardless the number of frequencies. These results suggest that stimulus-focused attention increases stimulus processing speed by generally increasing sensory gain.     

Mucin glycosylation and sulphation in airway epithelial cells is not influenced by cystic fibrosis transmembrane conductance regulator expression

Abnormalities in mucus properties and clearance make a major contribution to the pathology of cystic fibrosis (CF). Our aim was to test the hypothesis that the defects in CF mucus are a direct result of mutations in the CF transmembrane conductance regulator (CFTR) protein. We evaluated a single mucin molecule MUC1F/5ACTR that carries tandem repeat sequence from MUC5AC, a major secreted airway mucin, in a MUC1 mucin vector. To establish whether the presence of mutant or normal CFTR directly influences the O-glycosylation and sulphation of mucins in airway epithelial cells, we used the CFT1-LC3 (DeltaF508 CFTR mutant) and CFT1-LCFSN (wild-type CFTR corrected) human airway epithelial cell lines. MUC1F/5ACTR mucin was immunoprecipitated, centricon purified, and O-glycosylation was evaluated by Matrix-assisted laser desorption ionization and electrospray tandem mass spectrometry to determine the composition of different carbohydrate structures. Mass spectrometry data showed the same O-glycans in both CFTR mutant and wild-type CFTR corrected cells. Metabolic labeling assays were performed to evaluate gross glycosylation and sulphation of the mucins and showed no significant difference in mucin synthesized in six independent clones of these cell lines. Our results show that the absence of functional CFTR protein causes neither an abnormality in mucin O-glycosylation nor an increase in mucin sulphation.     

The decidua—the maternal bed embracing the embryo—maintains the pregnancy

The decidua has been known as maternal uterine tissue, which plays essential roles in protecting the embryo from being attacked by maternal immune cells and provides nutritional support for the developing embryo prior to placenta formation. However, there are questions that still remain to be answered: (1) How does the decidua supply nutrition and provide a physical scaffold for the growing embryo, before placental vascular connection is established? (2) How is the balance between preventing an anti-embryo immune response and protecting both embryo and mother from infections established? To understand basic personas in decidual tissues, we review the structure of the decidua composed of terminally differentiated uterine stromal cells, blood vessels, and a number of repertoire of uterine local immune cells, including the well-known uterine natural killer (uNK) cells and recently discovered innate lymphoid cells (ILCs). Decidual macrophages and uterine dendritic cells (DCs) are supposed to modulate adaptive immunity via balancing cytokines and promoting generation of regulatory T (T_reg) cells. During decidualization, vascular and tissue remodeling in the uterus provide nutritional and physical support for the developing embryo. Secretion of various cytokines and chemokines from both the embryo and the decidual cells activates multiple signaling network between the mother and the embryo upon implantation. Defects in the decidual development during early pregnancy result in loss of pregnancy or complications in later gestational stage.     

Drawing your way out: Imagery rehearsal based art therapy (IR-AT) for post-traumatic nightmares in borderline personality disorder

Posttraumatic nightmares (PTN) are a frequent symptom after a traumatic event and often play part in the psychopathology of patients with borderline personality disorder (BPD). Imagery rehearsal therapy (IRT) currently offers the best evidence for an effective treatment to reduce PTNs, although high drop-out rates are common. Art therapy in IRT may counteract this, by its indirect, nonverbal, and often playful approach that helps to break through avoidance. This case study focusses on the perception of a patient with BPD in an art therapy based IRT treatment for patients with PTNs. It tells the story of Aurelia, a 40-year-old woman who, within this treatment, processes traumatic contents of her childhood like physical and sexual violence, but also current interactional problems that manifest themselves in her nightmares. Following the IR-AT treatment for PTNs Aurelia noticed a reduction in her nightmares, was less afraid of them and felt calmer towards her trauma. She expressed herself in the art medium and by this developed more self-efficacy. Her process resulted in an integration of the trauma and a perceived decrease in borderline symptoms. Future research can build on this basis to further explore the mechanisms and effects of IR-AT for PTNs.     

Alterations of glucocorticoid receptor expression during glucocorticoid hormone therapy in renal transplant patients

Previous studies have demonstrated that glucocorticoid resistance develops in some patients during glucocorticoid therapy due to the down-regulation of glucocorticoid receptor (GCR) expression. A new flow cytometric method has been used for monitoring the intracellular GCR level in peripheral blood mononuclear cells (PBMCs). GCR expression by different lymphocyte subpopulations (bearing surface CD4+ CD8+ or CD19+) in steroid-treated (ST) and non-treated (NT) renal transplant patients was also compared. High, decreasing-dose steroid treatment caused a reduced GCR expression in 50% of the renal transplant patients. Long-lasting, low-dose steroid therapy caused a fall in GCR level in only 11% of patients. CD4+ T lymphocytes showed both the lowest GCR level and its alteration due to steroid therapy, while CD8+ T cells and CD19+ B lymphocytes expressed higher GCR levels and were more sensitive to steroid treatment. Detection of GCR expression in lymphocytes may provide useful information about the changes of glucocorticoid sensitivity during the therapy.     

Effect of the chalcone analog E,E-bis(2-hydroxybenzylidene) acetone on the 7,12-dimethylbenz[a]anthracene-induced Ha-ras gene activity in vivo

The chalcone analog E,E-bis(2-hydroxybenzylidene)acetone (HBA) was found to display strong NAD(P)H:quinone reductase (NQO1) inducer potency in Hepa 1c1c7 cells. In order to determine whether this promising chemopreventive activity would extend to anticarcinogenic properties, the effect of HBA on the 7,12-dimethylbenz[a]anthracene (DMBA)-induced expression of the Ha-ras gene in isolated RNA from liver, lung, kidney, spleen, thymus, lymph nodes and bone marrow of CBA/Ca inbred mice was investigated. DMBA is a well-known chemical carcinogen, which can act as initiator by causing point mutations in certain oncogenes and tumor suppressor genes. According to the previous results, elevated Ha-ras expression has been noted even 24 h after DMBA treatment. Administration of HBA simultaneously with DMBA resulted in a decrease of the DMBA-induced Ha-ras gene expression in all the investigated tissues. This observation suggests metabolic interaction of HBA and DMBA. Administration of HBA 24 h prior to the DMBA treatment reduced the Ha-ras gene expression in all the tissues but the liver, where a slight elevation could be detected. This latter effect could be the result of a possible CYPIA inducer and pro-oxidant effects of HBA. The pro-oxidant effect of HBA can be taken into consideration based on its previously demonstrated GSH-reactivity and the present results obtained by investigation of the time-course of Fenton reaction-initiated degradation of 2-deoxyribose in the presence of HBA.     

Extracellular matrix molecules and their possible roles in the regeneration of frog nervous system

Recent biochemical and histochemical analyses explored different components of the extracellular matrix (ECM) in the nervous system, and either permissive or non-permissive roles in neuronal development and regeneration were suggested. The aim of this study was to detect the distribution pattern of a few of these molecules in the nervous system of intact frogs and during nerve regeneration. The hyaluronan (HA) and tenascin C reactions were negative in the peripheral nerves, but appeared in their entry zones. In the CNS, different populations of neurons were surrounded with HA and tenascin C-positive material, forming a perineuronal net (PN). The phosphacan reaction was weakly positive in the PNS, and a moderate intensity was detected in the entry zone and in the PN. Laminin and fibronectin immunoreactivity was strong in the PNS, but laminin could not be detected in the CNS. In animals with cut and regenerating vestibulocochlear nerve, the distribution of the ECM molecules in the CNS and PNS characteristically changed from that of the normal pattern. Our results showed a non-homogenous distribution of ECM components in the frog nervous system that could be associated with their different roles in physiological and pathological processes.     

Effect of polycyclic aromatic hydrocarbons on erythrocyte membranes by DSC and EPR

Differential scanning calorimetry (DSC) and electron paramagnetic resonance spectroscopy (EPR) experiments were performed on human erythrocyte membranes and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) model systems in order to study the effect the polycyclic aromatic hydrocarbons on lipid structure and dynamics. Eight different compounds among others naphthalene and pyrene were compared, which occur in significant concentrations in dust collected from the air in large cities.

Experiments using spin label technique showed that the compounds induced mobility changes in the lipid region in the environment of the fatty acid probe molecules incorporated into the membranes. The effects depended on the structure and concentration of the different compounds. Similarly to EPR observations, DSC measurements reported decrease of transition temperature in comparison to control DPPC vesicles. These results suggest that polycyclic aromatic hydrocarbons were able to modify the internal dynamics of erythrocyte membranes which might lead to damage of the biological functions.