Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better?

The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit.

Towards Low Cost and Low Temperature Capacitive CO Sensors Based on Amine Functionalized Silica Nanoparticles.

Hybrid materials based on inorganic particles and an organic polymer were developed and used as an efficient sensing material for carbon dioxide (CO). The sensing material consists of fumed silica that is functionalized with an organic polymer, polyethylenimine, by means of the impregnation method. The organic polymer is effectively immobilized around the silica nanoparticles and confirmed by infrared spectroscopy.

Dynamical ion transfer between coupled Coulomb crystals in a double-well potential.

We investigate the nonequilibrium dynamics of coupled Coulomb crystals of different sizes trapped in a double well potential. The dynamics is induced by an instantaneous quench of the potential barrier separating the two crystals. Due to the intra- and intercrystal Coulomb interactions and the asymmetric population of the potential wells, we observe a complex reordering of ions within the two crystals as well as ion transfer processes from one well to the other.

Effects of elevated CO2 concentrations and fly ash amended soils on trace element accumulation and translocation among roots, stems and seeds of Glycine max (L.) Merr.

The carbon dioxide (CO(2)) levels of the global atmosphere and the emissions of heavy metals have risen in recent decades, and these increases are expected to produce an impact on crops and thereby affect yield and food safety. In this study, the effects of elevated CO(2) and fly ash amended soils on trace element accumulation and translocation in the root, stem and seed compartments in soybean [Glycine max (L.) Merr.

Accumulation of polycyclic aromatic hydrocarbons and trace elements in the bioindicator plants Tillandsia capillaris and Lolium multiflorum exposed at PM10 monitoring stations in Stuttgart (Germany).

The accumulation of polycyclic aromatic hydrocarbons (PAHs) in Tillandsia capillaris Ruiz and Pav. form capillaris and trace elements in T. capillaris and Lolium multiflorum (LAM) cv.

Validation of the normal, freely moving Göttingen minipig for pharmacological safety testing.

Introduction: The objective of this study was to use a newly established cardiovascular model using freely moving minipigs to document the hemodynamic and electrocardiographic effects of known pharmacological agents. The data generated are to serve as the basis of pharmacological drug safety evaluations using this new model.

Methods: 6 Göttingen minipigs were equipped with a radiotelemetry system (ITS).

Evaluation of cardiovascular and ECG parameters in the normal, freely moving Göttingen Minipig.

Introduction: The objective of this study was to evaluate the normal cardiovascular and ECG parameters in freely moving minipigs and to use these data as the basis of pharmacological drug safety evaluation.

Methods: 7 Göttingen Minipigs were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body temperature were continuously monitored.

The value added by measuring myocardial contractility 'in vivo' in safety pharmacological profiling of drug candidates.

Introduction: The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation.

Methods: Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored.

Steps taken to protect and rescue cryopreserved embryos during Hurricane Katrina.

Hurricane Katrina was a devastating storm that brought lessons in emergency preparedness. All IVF programs should have a plan to protect fresh and cryopreserved embryos in case of natural or human-made disaster.

Optimizing the experimental environment for dog telemetry studies.

Introduction: The objective of this study was to test the influence of housing conditions on hemodynamics during cardiovascular general pharmacological studies. Our goal was to optimize both the quality of the data through an optimization of the physiological conditions, as well as to ensure the dog's well-being in general pharmacological studies.

Methods: Two groups of four dogs were equipped with radiotelemetry transmitters and continuously monitored in two different housing models.

Environmental monitoring of fluoride emissions using precipitation, dust, plant and soil samples.

A pollution gradient was observed in precipitation, plants and soils sampled at different locations around a fluoride producing chemical plant in Germany. In all samples the influence of emissions was discernible up to a distance of 500 m from the plant. However, fluoride concentrations in plant bioindicators (leaves of birch and black berry) and in bulk precipitation showed a more pronounced relationship with the distance from the source than fluoride concentrations in soil.

Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies.

Arsenic contaminates ground water worldwide. Methylation is an important reaction in the biotransformation of arsenic. We set out to study the pharmacogenetics of human arsenic methyltransferase (AS3MT, previously CYT19).

O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells.

Temozolomide (TMZ) is a methylating agent which prolongs survival when administered during and after radiotherapy in the first-line treatment of glioblastoma and which also has significant activity in recurrent disease. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme attributed a role in cancer cell resistance to O6-alkylating agent-based chemotherapy. Using a panel of 12 human glioma cell lines, we here defined the sensitivity to TMZ in acute cytotoxicity and clonogenic survival assays in relation to MGMT, mismatch repair and p53 status and its modulation by dexamethasone, irradiation and BCL-X(L).

Tradescantia micronucleus test indicates genotoxic potential of traffic emissions in European cities.

Urban atmospheres contain complex mixtures of air pollutants including mutagenic and carcinogenic substances such as benzene, diesel soot, heavy metals and polycyclic aromatic hydrocarbons. In the frame of a European network for the assessment of air quality by the use of bioindicator plants, the Tradescantia micronucleus (Trad-MCN) test was applied to examine the genotoxicity of urban air pollution. Cuttings of Tradescantia clone #4430 were exposed to ambient air at 65 monitoring sites in 10 conurbations employing a standardised methodology.

Collaborative inhibition is due to the product, not the process, of recalling in groups.

When people remember together, they recall less than if they remembered separately. This is called collaborative inhibition. We examine whether this is due to the product of group recall or the process of recalling in groups.

Hypoxia sensitizes human malignant glioma cells towards CD95L-induced cell death.

Death ligands such as CD95 ligand (CD95L) have limited activity against glioma cells under normoxic conditions. Hypoxia is a critical aspect of the microenvironment of gliomas in vivo. We investigated the effect of co-exposure to acute hypoxia and CD95 ligand in three human malignant glioma cell lines with different susceptibility to CD95L under normoxic conditions.

Influence of climatic conditions on the mutations in pollen mother cells of Tradescantia clone 4430 and implications for the Trad-MCN bioassay protocol.

The present was study aimed at investigating the influence of relative humidity and temperature on spontaneous and pollution-induced mutation rates during exposure and recovery periods in the Trad-MCN test. Cuttings of Tradescantia clone 4430 were exposed to a negative control, to 4 mM maleic hydrazide (MH), and to a polluted water sample under varying conditions of air temperature and humidity in climatic chamber experiments. The relative humidity did not affect the spontaneous mutation rate in the clone investigated, but was negatively correlated with the frequency of pollution-induced mutations.

A novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogs.

Introduction: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device.

Methods: Labrador dogs (male or female) were used that had transducers implanted for the measurement of left ventricular and descending aortic blood pressures and an ECG for use together with a telemetry system.

Co-inhibition of epidermal growth factor receptor and type 1 insulin-like growth factor receptor synergistically sensitizes human malignant glioma cells to CD95L-induced apoptosis.

Inhibition of epidermal growth factor receptor (EGFR) signaling sensitizes human malignant glioma cells to death ligand-induced apoptosis. However, tumor cells may compensate the loss of EGFR signaling by activation of the type 1 insulin-like growth factor receptor (IGF-1R). We here report that antagonism of the IGF-1R with the small-molecule inhibitor AG1024 in combination with inhibitors of the EGFR synergistically sensitizes human malignant glioma cells to CD95L-induced apoptosis.

Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death.

Epidermal growth factor receptor (EGFR) signaling has become an important target for drug development because EGFR signaling enhances tumor cell proliferation, migration, and invasion and inhibits apoptosis. However, the results of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing. Here, we report a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hypoxia, which contrasts with their proapoptotic effects under normoxia.

Bioindication of air pollution effects near a copper smelter in Brazil using mango trees and soil microbiological properties.

A field study near the copper smelter of a large industrial complex examined air pollution effects on vegetation and soil parameters in Camaçari (northeast Brazil). Close to the smelter, soil pH-value was lower and total acidity as well as organic carbon contents were higher compared with a site far from the source and two reference sites. The acidification of top soil particularly and the drastically enhanced plant-available copper concentrations were caused by atmospheric deposition.

Hypoxia-induced cell death in human malignant glioma cells: energy deprivation promotes decoupling of mitochondrial cytochrome c release from caspase processing and necrotic cell death.

Hypoxia induces apoptosis in primary and transformed cells and in various tumor cell lines in vitro. In contrast, there is little apoptosis and predominant necrosis despite extensive hypoxia in human glioblastomas in vivo. We here characterize ultrastructural and biochemical features of cell death in LN-229, LN-18 and U87MG malignant glioma cells in a paradigm of hypoxia with partial glucose deprivation in vitro.

Tropical fruit trees as bioindicators of industrial air pollution in southeast Brazil.

Psidium guajava L., Psidium cattleyanum Sabine and Mangifera indica L. were tested under field conditions as possible tropical bioindicators of industrial air pollution.

EuroBionet: a pan-European biomonitoring network for urban air quality assessment.

EuroBionet, the 'European Network for the Assessment of Air Quality by the Use of Bioindicator Plants', is an EU-funded cooperative project currently consisting of public authorities and scientific institutes from 12 cities in 8 countries. In 2000, the bioindicator plants tobacco (Nicotiana tabacum Bel W3), poplar (Populus nigra 'Brandaris'), spiderwort (Tradescantia sp. clone 4430), Italian rye grass (Lolium multiflorum italicum) and curly kale (Brassica oleracea acephala) were exposed to ambient air at 90 monitoring sites according to standardised methods.