Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1α

<p>Abstract</p> <p>Background</p> <p>Searching for novel molecular markers that dependably predict or indicate responses of human cancer cells to epidermal growth factor receptor (EGFR)-targeted therapy is strongly warranted. The purpose of the current study was to evaluate hypoxia-inducible factor-1α (HIF-1α) as a novel response marker compared with previously explored markers following treatment with an EGFR-blocking monoclonal antibody (cetuximab) and a small-molecule EGFR tyrosine kinase inhibitor (gefitinib) in a group of cancer cell lines containing wild-type or tyrosine kinase domain-mutated EGFR.</p> <p>Results</p> <p>We found that, compared with previously studied response markers, including EGFR <it>per se </it>and three EGFR downstream signal molecules (ERK, Akt, and STAT3), which showed variable post-treatment changes in levels of phosphorylation and no consistent link of the changes to therapeutic responses, HIF-1α showed a selective decrease in protein levels only in responsive cell lines. To demonstrate a critical role of HIF-1α downregulation by EGFR-targeted treatment, we introduced a constitutively expressed HIF-1α mutant (HIF-1α/ΔODD) that is resistant to cetuximab-induced downregulation in a cetuximab-responsive cell line (A431); we found that the HIF-1α/ΔODD-transfected cells remained sensitive to cetuximab-induced inhibition of Akt and ERK phosphorylation but were remarkably less responsive to cetuximab-induced growth inhibition compared with corresponding control cells.</p> <p>Conclusion</p> <p>Our data indicates that downregulation of HIF-1α is associated with positive therapeutic responses of cancer cells to EGFR-targeted therapy and suggest further investigation using HIF-1α as an indicator of tumor response to EGFR-targeted therapy in preclinical studies and in the clinical setting.</p

Formation Control with Unknown Directions and General Coupling Coefficients

Generally, the normal displacement-based formation control has a sensing mode that requires the agent not only to have certain knowledge of its direction, but also to gather its local information characterized by nonnegative coupling coefficients. However, the direction may be unknown in the sensing processes, and the coupling coefficients may also involve negative ones due to some circumstances. This paper introduces these phenomena into a class of displacement-based formation control problem. Then, a geometric approach have been employed to overcome the difficulty of analysis on the introduced phenomena. The purpose of this approach is to construct some convex polytopes for containing the effects caused by the unknown direction, and to analyze the non-convexity by admitting the negative coupling coefficients in a certain range. Under the actions of these phenomena, the constructed polytopes are shown to be invariant in view of the contractive set method. It means that the convergence of formation shape can be guaranteed. Subsequently, an example is given to examine the applicability of derived result

“Reporting or Interpreting?”—A Discoursal Study of Broadcasts on NBA Games in China

From the perspective of empirical discourse analysis, this paper identifies the site broadcasters’ roles and cognitive blending process in NBA (National Basketball Association) broadcasts in China. The authors find that NBA broadcasters chiefly interpret the information they have obtained from sports sites and interviews with the coaches and players, employing various interpreting strategies, such as commentary, amplification, supplementation and restructure. Cognitively, the language that NBA broadcasters applied reveals their cognitive blending process of interpreting techniques, strategies, sports knowledge and attitudes towards the games, of who take up different roles to fulfill different communicating purposes, all of which project various cognitions on NBA games. Despite the fact that one role might make certain linguistic behaviors prevail over the others, especially their interpreting role, NBA site broadcasters coordinate it with other roles properly through which they present different levels of translational and constructional schematicity, thus yielding a coherent and constructional working mode of NBA broadcasting practice in China

Transverse Mode Revival of a Light-Compensated Quantum Memory

A long-lived quantum memory was developed based on light-compensated cold $^{87}$Rb atoms in a dipole trap. The lifetime of the quantum memory was improved by 40 folds, from 0.67 ms to 28 ms with the help of a compensation laser beam. Oscillations of the memory efficiency due to the transverse mode breathing of the singly-excited spin wave have been clearly observed and clarified with a Monte-Carlo simulation procedure. With detailed analysis of the decoherence processes of the spin wave in cold atomic ensembles, this experiment provides a benchmark for the further development of high-quality quantum memories.Comment: 4 pages, 4 figure

Metastable state of gas hydrate during decomposition: a novel phenomenon

Natural gas hydrates are solid compounds with cage-like structures formed by gas and water. An intriguing phenomenon that gas hydrates can dissociate at a low rate below the ice freezing point has been viewed as the metastability of hydrate. The mechanisms of hydrate metastability have been widely studied, and many mechanisms were proposed involving the self-preservation effect, supercooled water-gas-hydrate metastable equilibrium, and supersaturated liquid–gas-hydrate system etc. The metastable state of hydrate could be of crucial significance in the kinetics of hydrate formation and decomposition, heat and mass transfer during gas production processes, and the application of hydrate-based technique involving desalination, energy storage and transportation, and gas separation and sequestration. Few researches have systematically considered this phenomenon, and its mechanism remains unclear. In this work, various mechanisms and hypothesis explaining the metastable state of gas hydrates were introduced and discussed. Further studies are still required to reveal the intrinsic nature of this metastable state of gas hydrate, and this work could give some implications on the existing theory and current status of relevant efforts

Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors

Abstract Background Reprogramming of cancers into normal-like tissues is an innovative strategy for cancer treatment. Recent reports demonstrate that defined factors can reprogram cancer cells into pluripotent stem cells. Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor. Therefore, developing novel therapeutic strategy is a critical requirement. Methods We have developed a novel reprogramming method that uses a conceptually unique strategy for GBM treatment. We screened a kinase inhibitor library to find which candidate inhibitors under reprogramming condition can reprogram GBM cells into neurons. The induced neurons are identified whether functional and loss of tumorigenicity. Results We have found that mTOR and ROCK kinase inhibitors are sufficient to reprogram GBM cells into neural-like cells and “normal” neurons. The induced neurons expressed neuron-specific proteins, generated action potentials and neurotransmitter receptor-mediated currents. Genome-wide transcriptional analysis showed that the induced neurons had a profile different from GBM cells and were similar to that of control neurons induced by established methods. In vitro and in vivo tumorigenesis assays showed that induced neurons lost their proliferation ability and tumorigenicity. Moreover, reprogramming treatment with ROCK-mTOR inhibitors prevented GBM local recurrence in mice. Conclusion This study indicates that ROCK and mTOR inhibitors-based reprogramming treatment prevents GBM local recurrence. Currently ROCK-mTOR inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials