Combining the receptor tyrosine kinase inhibitor AEE788 and the mammalian target of rapamycin (mTOR) inhibitor RAD001 strongly inhibits adhesion and growth of renal cell carcinoma cells

Background Treatment options for metastatic renal cell carcinoma (RCC) are limited due to resistance to chemo- and radiotherapy. The development of small-molecule multikinase inhibitors have now opened novel treatment options. The influence of the receptor tyrosine kinase inhibitor AEE788, applied alone or combined with the mammalian target of rapamycin (mTOR) inhibitor RAD001, on RCC cell adhesion and proliferation in vitro has been evaluated. Methods RCC cell lines Caki-1, KTC-26 or A498 were treated with various concentrations of RAD001 or AEE788 and tumor cell proliferation, tumor cell adhesion to vascular endothelial cells or to immobilized extracellular matrix proteins (laminin, collagen, fibronectin) evaluated. The anti-tumoral potential of RAD001 combined with AEE788 was also investigated. Both, asynchronous and synchronized cell cultures were used to subsequently analyze drug induced cell cycle manipulation. Analysis of cell cycle regulating proteins was done by western blotting. Results RAD001 or AEE788 reduced adhesion of RCC cell lines to vascular endothelium and diminished RCC cell binding to immobilized laminin or collagen. Both drugs blocked RCC cell growth, impaired cell cycle progression and altered the expression level of the cell cycle regulating proteins cdk2, cdk4, cyclin D1, cyclin E and p27. The combination of AEE788 and RAD001 resulted in more pronounced RCC growth inhibition, greater rates of G0/G1 cells and lower rates of S-phase cells than either agent alone. Cell cycle proteins were much more strongly altered when both drugs were used in combination than with single drug application. The synergistic effects were observed in an asynchronous cell culture model, but were more pronounced in synchronous RCC cell cultures. Conclusions Potent anti-tumoral activitites of the multikinase inhibitors AEE788 or RAD001 have been demonstrated. Most importantly, the simultaneous use of both AEE788 and RAD001 offered a distinct combinatorial benefit and thus may provide a therapeutic advantage over either agent employed as a monotherapy for RCC treatment

Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium

Drug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). In pursuit of alternative treatments for chemoresistant tumour cells, we tested the response of multidrug-resistant SKNSH and of vincristine (VCR)-, doxorubicin (DOX)-, or cisplatin (CDDP)-resistant UKF-NB-2, UKF-NB-3 or UKF-NB-6 NB tumour cell lines to valproic acid (VPA), a differentiation inducer currently in clinical trials. Drug resistance caused elevated NB adhesion (UKF-NB-2VCR, UKF-NB-2DOX, UKF-NB-2CDDP, UKF-NB-3VCR, UKF-NB-3CDDP, UKF-NB-6VCR, UKF-NB-6CDDP) to an endothelial cell monolayer, accompanied by downregulation of the adhesion receptor neural cell adhesion molecule (NCAM). Based on the UKF-NB-3 model, N-myc proteins were enhanced in UKF-NB-3VCR and UKF-NB-3CDDP, compared to the drug naïve controls. p73 was diminished, whereas the p73 isoform deltaNp73 was upregulated in UKF-NB-3VCR and UKF-NB-3CDDP. Valproic acid blocked adhesion of UKF-NB-3VCR and UKF-NB-3CDDP, but not of UKF-NB-3DOX, and induced the upregulation of NCAM surface expression, NCAM protein content and NCAM coding mRNA. Valproic acid diminished N-myc and enhanced p73 protein level, coupled with downregulation of deltaNp73 in UKF-NB-3VCR and UKF-NB-3CDDP. Valproic acid also reverted enhanced adhesion properties of drug-resistant UKF-NB-2, UKF-NB-6 and SKNSH cells, and therefore may provide an alternative approach to the treatment of drug-resistant NB by blocking invasive processes

Learning from Negative Feedback in Patients with Major Depressive Disorder is Attenuated by SSRI Antidepressants

One barrier to interpreting past studies of cognition and Major Depressive Disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of Selective Serotonin Reuptake Inhibitors (SSRI) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine and healthy control subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) versus learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject’s relative sensitivity to positive versus negative feedback showed that both the medicated MDD and healthy control groups conform to Kahneman and Tversky’s (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not ‘normal’ when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the ...(rest is in manuscript

Inhibition of <i>Acinetobacter baumannii</i> Biofilm Formation Using Different Treatments of Silica Nanoparticles

There exists a multitude of pathogens that pose a threat to human and public healthcare, collectively referred to as ESKAPE pathogens. These pathogens are capable of producing biofilm, which proves to be quite resistant to elimination. Strains of A. baumannii, identified by the “A” in the acronym ESKAPE, exhibit significant resistance to amoxicillin in vivo due to their ability to form biofilm. This study aims to inhibit bacterial biofilm formation, evaluate novel silica nanoparticles’ effectiveness in inhibiting biofilm, and compare their effectiveness. Amoxicillin was utilized as a positive control, with a concentration exceeding twice that when combined with silica NPs. Treatments included pure silica NPs, silica NPs modified with copper oxide (CuO.SiO2), sodium hydroxide (NaOH.SiO2), and phosphoric acid (H3PO4.SiO2). The characterization of NPs was conducted using scanning electron microscopy (SEM), while safety testing against normal fibroblast cells was employed by MTT assay. The microtiter plate biofilm formation assay was utilized to construct biofilm, with evaluations conducted using three broth media types: brain heart infusion (BHI) with 2% glucose and 2% sucrose, Loria broth (LB) with and without glucose and sucrose, and Dulbecco’s modified eagle medium/nutrient (DMEN/M). Concentrations ranging from 1.0 mg/mL to 0.06 µg/mL were tested using a microdilution assay. Results from SEM showed that pure silica NPs were mesoporous, but in the amorphous shape of the CuO and NaOH treatments, these pores were disrupted, while H3PO4 was composed of sheets. Silica NPs were able to target Acinetobacter biofilms without harming normal cells, with viability rates ranging from 61–73%. The best biofilm formation was achieved using a BHI medium with sugar supplementation, with an absorbance value of 0.35. Biofilms treated with 5.0 mg/mL of amoxicillin as a positive control alongside 1.0 mg/mL of each of the four silica treatments in isolation, resulting in the inhibition of absorbance values of 0.04, 0.13, 0.07, 0.09, and 0.08, for SiO2, CuO.SiO2, NaOH.SiO2 and H3PO4.SiO2, respectively. When amoxicillin was combined, inhibition increased from 0.3 to 0.04; NaOH with amoxicillin resulted in the lowest minimum biofilm inhibitory concentration (MBIC), 0.25 µg/mL, compared to all treatments and amoxicillin, whereas pure silica and composite had the highest MBIC, even when combined with amoxicillin, compared to all treatments, but performed better than that of the amoxicillin alone which gave the MBIC at 625 µg/mL. The absorbance values of MBIC of each treatment showed no significant differences in relation to amoxicillin absorbance value and relation to each other. Our study showed that smaller amoxicillin doses combined with the novel silica nanoparticles may reduce toxic side effects and inhibit biofilm formation, making them viable alternatives to high-concentration dosages. Further investigation is needed to evaluate in vivo activity

Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants

One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject’s relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky’s (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not “normal” when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naïve state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs

Depression impairs learning, whereas the selective serotonin reuptake inhibitor, paroxetine, impairs generalization in patients with major depressive disorder

To better understand how medication status and task demands affect cognition in major depressive disorder (MDD), we evaluated medication-naive patients with MDD, medicated patients with MDD receiving the selective serotonin reuptake inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naive MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampal-dependent generalization of past learning to novel contexts, not otherwise seen in the medication-naive MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures is critical for generalization

Metrology for industrial quantum communications: The MIQC project

The 'Metrology for Industrial Quantum Communication Technologies' project (MIQC) is a metrology framework that fosters development and market take-up of quantum communication technologies and is aimed at achieving maximum impact for the European industry in this area. MIQC is focused on quantum key distribution (QKD) technologies, the most advanced quantum-based technology towards practical application. QKD is a way of sending cryptographic keys with absolute security. It does this by exploiting the ability to encode in a photon's degree of freedom specific quantum states that are noticeably disturbed if an eavesdropper trying to decode it is present in the communication channel. The MIQC project has started the development of independent measurement standards and definitions for the optical components of QKD system, since one of the perceived barriers to QKD market success is the lack of standardization and quality assurance