Molecular Mechanisms of Chemoresistance Induced by Cisplatin in NSCLC Cancer Therapy

Cancer cells utilise several mechanisms to increase their survival and progression as well as their resistance to anticancer therapy: deregulation of growth regulatory pathways by acquiring grow factor independence, immune system suppression, reducing the expression of antigens activating T lymphocyte cells (mimicry), induction of anti-apoptotic signals to counter the action of drugs, activation of several DNA repair mechanisms and driving the active efflux of drugs from the cell cytoplasm, and epigenetic regulation by microRNAs (miRNAs). Because it is commonly diagnosed late, lung cancer remains a major malignancy with a low five-year survival rate; when diagnosed, the cancer is often highly advanced, and the cancer cells may have acquired drug resistance. This review summarises the main mechanisms involved in cisplatin resistance and interactions between cisplatin-resistant cancer cells and the tumour microenvironment. It also analyses changes in the gene expression profile of cisplatin sensitive vs. cisplatin-resistant non-small cell lung cancer (NSCLC) cellular model using the {"type":"entrez-geo","attrs":{"text":"GSE108214","term_id":"108214"}}GSE108214 Gene Expression Omnibus database. It describes a protein-protein interaction network that indicates highly dysregulated TP53, MDM2, and CDKN1A genes as they encode the top networking proteins that may be involved in cisplatin tolerance, these all being upregulated in cisplatin-resistant cells. Furthermore, it illustrates the multifactorial nature of cisplatin resistance by examining the diversity of dysregulated pathways present in cisplatin-resistant NSCLC cells based on KEGG pathway analysis.     

Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics

Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans → all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.     

The effect of reduced atmospheric deposition on soil and soil solution chemistry at a site subjected to long-term acidification, Nacetín, Czech Republic

During the 1990s the emissions of SO(2) fell dramatically by about 90% in the Czech Republic; the measured throughfall deposition of sulphur to a spruce forest at Nacetín in the Ore Mts. decreased from almost 50 kg ha(-1) in 1994 to 15 kg ha(-1) in 2005. The throughfall flux of Ca decreased from 17 kg ha(-1) in 1994 to 9 kg ha(-1) in 2005; no change was observed for Mg. The deposition of nitrogen ranged between 15 and 30 kg ha(-1) with no statistically significant trend in the period 1994-2005. The desorption of previously stored sulphur and the decrease of Ca deposition are the main factors controlling the recovery of soil solution. The pH of the soil solution at a depth of 30 cm remains unchanged, and the Al concentration decreased from 320 micromol l(-1) in 1997 to 140 micromol l(-1) in 2005. The enhanced leaching of base cations relative to no acidified conditions has continued, although the Ca concentration decreased from 110 microeq l(-1) in 1997 to 25 microeq l(-1) in 2005 in the mineral soil solution at 30 cm depth. This dramatic change was not observed for Mg concentration in soil solution, because its deposition remained stable during the observed period. Similar patterns were observed in the deeper soil solution at 90 cm. The reduction in Ca availability resulted in lower uptake by tree assimilatory tissues, measured as concentration in needles. Since 2005, the leaching of nitrate observed in soil solution at 30 cm depth has disappeared. By 2003 a similar situation occurred at 90 cm. Higher incorporation into the trees after 1997 could be an important factor. With respect to the formerly high sulphur deposition and consequently released aluminium, which could have negatively influenced the biotic immobilization driven by microbes and fungi, the recovery may have positively impacted and therefore improved retention in the ecosystem during recent years. The delay in the successful retention of nitrogen in the ecosystem was probably caused by the high mineralization of organic matter after improvement of chemical parameters in the organic horizon (increase in pH and decrease in Al concentration). It seems that high mineralization of stored organic matter after decades of high acidic deposition could be an important factor affecting the high losses of nitrogen in spruce forest ecosystems.     

COMPARISON OF CHARACTERIZATION TECHNIQUES IN P-ON-N HgCdTe LWIR PHOTODIODES TECHNOLOGY 

IntroductionAt present Hg Cd Te is the most widely used variable-gap semiconductor for infrared( IR) photodetectors.Over the years it has successfully fought off majorchallenges from extrinsic silicon and lead- tin telluridedevices despite that it has more competitors todaythan ever before.These include Schottky barriers onsilicon,Si Ge heterojunctions,Al Ga As multiplequantum wells,Ga In Sb strained layer superlattices,high temperature superconductors and especially twotypes of thermal …     

Simulation of cerebrospinal fluid transport

The pulsatile nature of the CSF movement is a result of the cardiac-related pulsations in blood volume in cranial region. According to Monro–Kellie Doctrine, the net inflow of arterial blood during systole is compensated by an equal outflow of venous blood and by caudal displacement of the CSF. Knowledge of the distribution of physical properties (compliance, resistance) along the craniospinal system is crucial for understanding of the CSF hydrodynamics. The synthesis of both invasively and non-invasively obtained data is needed. The aim of our project was to develop a lumped-parameter compartment model of the craniospinal system and, in relation to the cardiac-related blood-volume pulsations, to describe its basic hydrodynamic properties. The model consists of six compartments representing major parts of the craniospinal system. Each compartment has its own set of physical properties which describe its behavior. The pressure transmission from head arteries to the brain compartment serves as a source of pulsations. The simulation tightly mimics pressure waves of the CSF and thus the flow characteristics and magnitudes. The fitted compliance of the spinal compartment in our model was two orders higher (9 × 10⁻¹⁰ m³/Pa) then the cranial compartment (5.2 × 10⁻¹² m³/Pa): only in this adjustment pulsations were present. It makes 99.5% of compliance related to the spinal canal and 0.5% to the intracranial structures. Our fitting showed that this model might be used in medical education as well as in medical practice.     

The switch mechanism of the cell death mode from apoptosis to necrosis in menadione-treated human osteosarcoma cell line 143B cells

Time-dependent changes in the cell death mode from apoptosis to necrosis were studied in cultured 143B cells treated with menadione, an anti-cancerous drug, excluding a possible involvement of "secondary necrosis." The population of apoptotic cells judged by FITC-Annexin V and propidium iodide (PI) double staining reached its maximum at 6 hours after 100 microM menadione treatment followed by an abrupt decrease thereafter, while that of necrotic cells continuously increased reaching 90% at 24 hours. Electron microscopically, cells attached to the culture dish at 6 hours after the treatment consisted of two different types of cells: cells with typical apoptotic features occupying the major population and those with condensed nuclei and swollen cytoplasm. Cells attached to the culture dish at 8 hours after the treatment consisted exclusively of those with condensed nuclei and swollen cytoplasm. Mitochondria in these cells showed various structural changes: those swollen to various degrees with deposition of flocculent densities, or those with highly condensed matrix. Distinct decreases both in intracellular levels of ATP and caspase-3-like activities and remarkable elevations of intracellular levels of superoxide, which were partly suppressed by NAD(P)H oxidase inhibitors, occurred at 6 hours after the treatment. These results may suggest that distinct increases of the intracellular level of superoxide derived from plasma membrane NAD(P)H oxidase besides that from mitochondria have triggered the transition of cell death mode from apoptosis to necrosis. Transition of highly condensed mitochondria to extremely swollen ones may reflect necrotic processes in menadione-treated cells. The present study strongly suggests that time-dependent study is essential using the electron microscopic technique to analyze detailed processes in the changes of the cell death mode.     

Ultrastructural basis for the transition of cell death mode from apoptosis to necrosis in menadione-treated osteosarcoma 143B cells

Time-dependent ultrastructural changes of menadione-treated human osteosarcoma 143B cells were correlated with those in their stainability to Annexin V and propidium iodide (PI). Populations of both apoptotic (Annexin V(+)/PI(-)) and necrotic (Annexin V(+)/PI(+)) cells, judged by flow cytometry, began to increase at 2 h after menadione treatment. The former reached a maximum at 6 h followed by abrupt decreases thereafter, while the latter continued to increase. Electron microscopically, cells obtained at 6 h after the menadione treatment consisted of mixed populations of cells with typical apoptotic features and those with a mixture of apoptotic and necrotic features, while cells obtained at 8-24 h consisted exclusively of cells with a mixture of apoptotic and necrotic features. Thus, necrotic cells, as judged by flow cytometry, were in a transitional state of cell death mode from apoptosis to necrosis and are thus designated as 'intermediate cells'. Lack of apoptotic bodies, judged by flow cytometric analysis on sub-G1 nuclei and by electron microscopy in menadione-treated cells, suggested that the transition of cell death mode from apoptosis to necrosis occurred before the apoptotic processes were completed. Effects of N-acetylcysteine and Z-VAD-fmk on menadione-induced ultrastructural changes were also studied.     

β-Actin Peptide-Based Inhibitors of Histidine Methyltransferase SETD3

SETD3 was recently identified as the histidine methyltransferase responsible for N³-methylation of His73 of β-actin in humans. Overexpression of SETD3 is associated with several diseases, including breast cancer. Here, we report a development of actin-based peptidomimetics as inhibitors of recombinantly expressed human SETD3. Substitution of His73 by simple natural and unnatural amino acids led to selected β-actin peptides with high potency against SETD3 in MALDI-TOF MS assays. The selenomethionine-containing β-actin peptide was found to be the most potent SETD3 inhibitor (IC₅₀=161 nM). Supporting our inhibition assays, a combination of computational docking and molecular dynamics simulations revealed that the His73 binding pocket for β-actin in SETD3 is rigid and accommodates the inhibitor peptides with similar binding modes. Collectively, our work demonstrates that actin-based peptidomimetics can act as potent SETD3 inhibitors and provide a basis for further development of highly potent and selective inhibitors of SETD3.     

Novel Approach to Tooth Chemistry: Quantification of Human Enamel Apatite in Context for New Biomaterials and Nanomaterials Development

A series of linear profiles of the elements of the enamel in human molar teeth were made with the use of an electron microprobe and a Raman microscope. It is postulated that the enamel can be treated as the superposition of variable “overbuilt” enamel on the stable “core” enamel at the macro-, micro- and nanoscale level. The excessive values characterize the “overbuilt enamel”. All the profiles of excessive parameters along the enamel thickness from the enamel surface to the dentin enamel junction (DEJ) can be approximated very precisely with the use of exponential functions, where Ca, P, Cl and F spatial profiles are decaying while Mg, Na, K and CO₃²⁻ ones are growing distributions. The “overbuilt” apatite formed on the boundary with DEJ, enriched in Na, Mg, OH and carbonates, reacts continuously with Ca, Cl and F, passing into an acid-resistant form of the “overbuilt” enamel. The apparent phases arriving in boundary regions of the “overbuilt enamel” were proposed. Microdiffraction measurements reveal relative variation of energy levels during enamel transformations. Our investigations are the milestones for a further new class of biomaterial and nanomaterial development for biomedical applications.     

Optical Pliers: Micrometer-Scale,Light-Driven Tools Grown on Optical Fibers

The ability to grip and handle small objects, from sub-millimeter electronic components to single-micrometer living cells, is vital for numerous ever-shrinking technologies. Mechanical grippers, powered by electric, pneumatic, hydraulic or piezoelectric servos, are well suited for the job at larger scales, but their complexity and need for force transmission prevent their miniaturization and remote control in tight spaces. Using liquid crystal elastomer microstructures that can change shape quickly and reversibly in response to light, a light-powered gripping tool—optical pliers—is built by growing two bending jaws on the tips of optical fibers. By delivering UV light to trigger polymerization via a micrometer-size fiber core, structures of similar size can be made without resorting to any microfabrication technology, such as laser photolithography. The tool is operated using visible light energy supplied through the fibers, with no force transmission. The elastomer growth technique readily offers micrometer-scale, remotely controlled functional structures with different modes of actuation as building blocks for the microtoolbox.