Small cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but ...the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast with the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53-deleted system led to nonmetastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3K pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test the phosphoinositide 3-kinase (PI3K) pathway inhibitors as targeted therapy for subsets of patients with SCLC.
The ability of PTEN inactivation to accelerate SCLC in a genetic mouse model suggests that targeting the PTEN pathway is a therapeutic option for a subset of human patients with SCLC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/28/1541-7786.MCR-13-0554/F1.large.jpg.
We examined the myogenic response to infarction in neonatal and adult mice to determine the role of c-kit ⁺ cardiovascular precursor cells (CPC) that are known to be present in early heart ...development. Infarction of postnatal day 1–3 c-kit ᴮᴬC-EGFP mouse hearts induced the localized expansion of (c-kit)EGFP ⁺ cells within the infarct, expression of the c-kit and Nkx2.5 mRNA, myogenesis, and partial regeneration of the infarction, with (c-kit)EGFP ⁺ cells adopting myogenic and vascular fates. Conversely, infarction of adult mice resulted in a modest induction of (c-kit)EGFP ⁺ cells within the infarct, which did not express Nkx2.5 or undergo myogenic differentiation, but adopted a vascular fate within the infarction, indicating a lack of authentic CPC. Explantation of infarcted neonatal and adult heart tissue to scid mice, and adoptive transfer of labeled bone marrow, confirmed the cardiac source of myogenic (neonate) and angiogenic (neonate and adult) cells. FACS-purified (c-kit)EGFP ⁺/(αMHC)mCherry ⁻ (noncardiac) cells from microdissected infarcts within 6 h of infarction underwent cardiac differentiation, forming spontaneously beating myocytes in vitro; cre/LoxP fate mapping identified a noncardiac population of (c-kit)EGFP ⁺ myocytes within infarctions, indicating that the induction of undifferentiated precursors contributes to localized myogenesis. Thus, adult postinfarct myogenic failure is likely not due to a context-dependent restriction of precursor differentiation, and c-kit induction following injury of the adult heart does not define precursor status.
The main challenges for industrial companies today are to improve the competitiveness of their products and to adapt and respond quickly to changes in the external environment. Ensuring the effective ...functioning of an industrial enterprise is largely determined by its procurement activities, including the reliability and consistency of the procurement process. Relevance of the topic is conditioned by the fact that procurement is one of the main components in increasing of competitiveness and efficiency of the enterprise, as the major part of costs in the cost price of the finished products is concentrated exactly in procurement. Reducing costs in procurement is one of the ways to improve the efficiency of the enterprise. This advantage can be achieved through the introduction of modern information technologies, namely automation of the process of selecting suppliers on an electronic trading platform. For this purpose, an information system for selecting suppliers on the electronic trading platform has been developed, which enables a more transparent, fast, profitable and less costly selection of the cheapest and most suitable goods for the operation of energy supplying enterprises. Procurement activities are aimed at ensuring that the energy-supplying undertaking receives the right quantity and quality of raw materials, materials, goods and services at the right time, in the right place, from a reliable and trustworthy supplier with good service and at a favourable price. Automating the supplier selection process on an electronic platform is essential in today's market environment.
MET, a receptor protein tyrosine kinase activated by hepatocyte growth factor (HGF), is a crucial determinant of metastatic progression. Recently, we have identified p53 as an important regulator of ...MET-dependent cell motility and invasion. This regulation occurs via feedforward loop suppressing MET expression by miR-34-dependent and -independent mechanisms. Here, by using Dicer conditional knockout, we provide further evidence for microRNA-independent MET regulation by p53. Furthermore, we show that while MET levels increase immediately after p53 inactivation, mutant cells do not contain active phosphorylated MET and remain non-invasive for a long latency period at contrary to cell culture observations. Evaluation of mouse models of ovarian and prostate carcinogenesis indicates that formation of desmoplastic stroma, associated production of HGF by stromal cells and coinciding MET phosphorylation precede cancer invasion. Thus, initiation mutation of p53 is sufficient for preprogramming motile and invasive properties of epithelial cells, but the stromal reaction may represent a critical step for their manifestation during cancer progression.
Progress in biomedical imaging depends on the development of probes that combine low toxicity with high sensitivity, resolution, and stability. Toward that end, a new class of highly fluorescent ...core-shell silica nanoparticles with narrow size distributions and enhanced photostability, known as C dots, provide an appealing alternative to quantum dots. Here, C dots are evaluated with a particular emphasis on
applications in cancer biology. It is established that C dots are nontoxic at biologically relevant concentrations, and can be used in a broad range of imaging applications including intravital visualization of capillaries and macrophages, sentinel lymph node mapping, and peptide-mediated multicolor cell labeling for real-time imaging of tumor metastasis and tracking of injected bone marrow cells in mice. These results demonstrate that fluorescent core-shell silica nanoparticles represent a powerful novel imaging tool within the emerging field of nanomedicine.
The Dynamics of Contact Interaction during the Cutting Process Vasilkov, Dmitriy V.; Nikitin, Alexander V.; Tarikov, Igor Y.
International journal of mathematical, engineering and management sciences,
10/2019, Letnik:
4, Številka:
5
Journal Article
Recenzirano
Odprti dostop
At parts manufacturing using metal-cutting machine tools, the process conditions eliminating high vibration levels are among the most important factors ensuring safe operation of the said ...metal-cutting machine tools. To solve the task, specific features typical for creation of the dynamic model of mechanical processing in the space of condition variables at contact interaction in the cutting zone based on the piecewise linear approximation were discussed. The contact interaction process was considered as the double-phase one envisaging sequence of retention at adhesion and sliding at adhesion bonds rupture. The cutting tool’ and the workpiece’ contact interactions are presented in the form of rheological models. Conditions of retention and sliding phases sequence are formed by the system itself that is the self-excited one. The set of research performed allowed considering contact interaction of the machined surface with the rear surface of the tool and the of the moving chip with the anterior surface of the tool with the anterior surface of the tool as factors largely defining the conditions of self-sustained oscillations. The contact interaction’ double-phase nature ensures self-organised dosing and selectiveness of the dynamic contours at interaction in the autonomous dynamic process system.
An analytical solution for the well-known fatigue criterion proposed by Papadopoulos was obtained. An arbitrary shift of phases was taken into account. Comparison between analytical, numerical ...solutions with experimental data was made. Computation results based on FEM were compared with assessments by the mentioned above criterion.
Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell ...motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: (i) transactivation of MET-targeting miR-34, and (ii) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network.
The role of cells of the diffuse neuroendocrine system in development and maintenance of individual organs and tissues remains poorly understood. Here we identify a regulatory region sufficient for ...accurate in vivo expression of synaptophysin (SYP), a common marker of neuroendocrine differentiation, and report generation of Tg(Syp-EGFP(loxP)-DTA)147(Ayn) (SypELDTA) mice suitable for flexible organ-specific ablation of neuroendocrine cells. These mice express EGFP and diphtheria toxin fragment A (DTA) in SYP positive cells before and after Cre-loxP mediated recombination, respectively. As a proof of principle, we have crossed SypELDTA mice with EIIA-Cre and PB-Cre4 mice. EIIA-Cre mice express Cre recombinase in a broad range of tissues, while PB-Cre4 mice specifically express Cre recombinase in the prostate epithelium. Double transgenic EIIA-Cre; SypELDTA embryos exhibited massive cell death in SYP positive cells. At the same time, PB-Cre4; SypELDTA mice showed a substantial decrease in the number of neuroendocrine cells and associated prostate hypotrophy. As no increase in cell death and/or Cre-loxP mediated recombination was observed in non-neuroendocrine epithelium cells, these results suggest that neuroendocrine cells play an important role in prostate development. High cell type specificity of Syp locus-based cassette and versatility of generated mouse model should assure applicability of these resources to studies of neuroendocrine cell functions in various tissues and organs.
In this work, the nanostructure of oxide dispersion-strengthened steels was studied by small-angle neutron scattering (SANS), transmission electron microscopy (TEM), and atom probe tomography (APT). ...The steels under study have different alloying systems differing in their contents of Cr, V, Ti, Al, and Zr. The methods of local analysis of TEM and APT revealed a significant number of nanosized oxide particles and clusters. Their sizes, number densities, and compositions were determined. A calculation of hardness from SANS data collected without an external magnetic field, or under a 1.1 T field, showed good agreement with the microhardness of the materials. The importance of taking into account two types of inclusions (oxides and clusters) and both nuclear and magnetic scattering was shown by the analysis of the scattering data.
PDF
