Focal adhesion kinase regulates collagen I-induced airway smooth muscle phenotype switching

Increased extracellular matrix (ECM) deposition and airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma. Recently, we demonstrated that the ECM protein collagen I, which is increased surrounding asthmatic ASM, induces a proliferative, hypocontractile ASM phenotype. Little is known, however, about the signaling pathways involved. Using bovine tracheal smooth muscle, we investigated the role of focal adhesion kinase (FAK) and downstream signaling pathways in collagen I-induced ASM phenotype modulation. Phosphorylation of FAK was increased during adhesion to both uncoated and collagen I-coated culture dishes, without differences between these matrices. Nor were any differences found in cellular adhesion. Inhibition of FAK activity by overexpression of the FAK deletion mutants FAT (focal adhesion targeting domain) and FRNK (FAK-related nonkinase) attenuated adhesion. After attachment, FAK phosphorylation increased in a time-dependent manner in cells cultured on collagen I, whereas no activation was found on an uncoated plastic matrix. In addition, collagen I increased in a time- and concentration-dependent manner the cell proliferation, which was fully inhibited by FAT and FRNK. Similarly, the specific pharmacologic FAK inhibitor PF-573228 [6-((4-((3-(methanesulfonyl)benzyl)amino)-5-trifluoromethylpyrimidin-2-yl) amino)-3,4-dihydro-1H-quinolin-2-one] as well as specific inhibitors of p38 mitogen-activated protein kinase (MAPK) and Src also fully inhibited collagen I-induced proliferation, whereas partial inhibition was observed by inhibition of phosphatidylinositol-3-kinase (PI3-kinase) and mitogen-activated protein kinase kinase (MEK). The inhibition of cell proliferation by these inhibitors was associated with attenuation of the collagen I-induced hypocontractility. Collectively, the results indicate that induction of a proliferative, hypocontractile ASM phenotype by collagen I is mediated by FAK and downstream signaling pathways

Balloon-Borne Superconducting Integrated Receiver for Atmospheric Research

A Superconducting Integrated Receiver (SIR) was proposed more than 10 years ago and has since then been developed up to the point of practical applications.We have demonstrated for the first time the capabilities of the SIR technology for heterodyne spectroscopy both in the laboratory and at remote operation under harsh environmental conditions for atmospheric research. Within a SIR the main components needed for a superconducting heterodyne receiver such as an SIS-mixer with quasi-optical antenna, a Flux-Flow oscillator (FFO) as the local oscillator, and a harmonic mixer to phase-lock the FFO are integrated on a single chip. Light weight and low power consumption combined with broadband operation and nearly quantum limited sensitivity make the SIR a perfect candidate for future airborne and space-borne missions. The noise temperature of the SIR was measured to be as low as 85 K, with an intermediate frequency band of 4–8 GHz in double sideband operation; the spectral resolution is well below 1 MHz. The SIR was implemented in the three-channel balloon-borne instrument TELIS (TErahertz and submillimeter LImb Sounder) that detects spectral emission lines of stratospheric trace gases (like ClO and BrO). These gases even in small quantities can have a significant impact on the atmosphere because they speed up certain chemical processes, such as ozone depletion

TELIS SIR channel performance analysis

The TELIS (Terahertz and sub-millimeter limb sounder) instrument is a three-channel heterodyne receiver developed for atmospheric research. TELIS is mounted together with the MIPAS-B2 instrument on a balloon platform of the Institute for Meteorology and Climate Research of the Karlsruhe Institute of Technology. TELIS can observe both in the sub-millimeter range (480-650 GHz) and at 1.8 THz, while MIPAS-B2 observes trace-gases in the thermal infrared window. Results are used to refine and constrain numerical chemical transport models. The SRON contribution to TELIS is the 480-650 GHz Superconducting Integrated Receiver (SIR) channel. This is a unique superconducting on-chip heterodyne receiver, consisting of a double dipole antenna, a SIS mixer, a flux-flow Local Oscillator, and a superconducting harmonic mixer used for phase locking of the LO-signal. The lowest noise temperature of the receiver is 120 K DSB, measured over the full IF bandwidth (2 GHz). The first successful flight campaign with TELIS/MIPAS was in March 2009 from Kiruna (Sweden). The SIR channel was operating well during the 11 hour flight. Many hundreds of limb scan data have been taken at different frequency settings. This has shown the stable remote operation of the SIR receiver in harsh environmental conditions. The data is currently further analyzed and in order to get reliable level 2 data processing we have further characterized the channel properties after return of the instrument to the laboratory. Especially the Side Band Ratio of the channel is of importance and we have performed detailed analysis of this with a high resolution Bruker Fourier Transform Spectrometer. A new flight with TELIS is scheduled for winter 2010, again from Kiruna. We will present data of the first flight, details of the channel characterization and possibly new results on the second flight of the instrument

Development and characterization of the superconducting integrated receiver channel of the TELIS atmospheric sounder

The balloon-borne instrument TELIS (TErahertz and submillimetre LImb Sounder) is a three-channel superconducting heterodyne spectrometer for atmospheric research use. It detects spectral emission lines of stratospheric trace gases that have their rotational transitions at THz frequencies. One of the channels is based on the superconducting integrated receiver (SIR) technology. We demonstrate for the first time the capabilities of the SIR technology for heterodyne spectroscopy in general, and atmospheric limb sounding in particular. We also show that the application of SIR technology is not limited to laboratory environments, but that it is well suited for remote operation under harsh environmental conditions. Within a SIR the main components needed for a superconducting heterodyne receiver such as a superconductor-insulator-superconductor (SIS) mixer with a quasi-optical antenna, a flux-flow oscillator (FFO) as the local oscillator, and a harmonic mixer to phase lock the FFO are integrated on a single chip. Light weight and low power consumption combined with broadband operation and nearly quantum limited sensitivity make the SIR a perfect candidate for use in future airborne and space-borne missions. The noise temperature of the SIR was measured to be as low as 120 K, with an intermediate frequency band of 4-8 GHz in double-sideband operation. The spectral resolution is well below 1 MHz, confirmed by our measurements. Remote control of the SIR under flight conditions has been demonstrated in a successful balloon flight in Kiruna, Sweden. The sensor and instrument design are presented, as well as the preliminary science results from the first flight

Integrated SubmmWave Receiver: Development and Applications

A superconducting integrated receiver (SIR) comprises in a single chip a planar antenna combined with a superconductor-insulator-superconductor (SIS) mixer, a superconducting Flux Flow Oscillator (FFO) acting as a Local Oscillator (LO) and a second SIS harmonic mixer (HM) for the FFO phase locking. In this report, an overview of the SIR and FFO developments and optimizations is presented. Improving on the fully Nb-based SIR we have developed and studied Nb–AlN–NbN circuits, which exhibit an extended operation frequency range. Continuous tuning of the phase locked frequency has been experimentally demonstrated at any frequency in the range 350–750GHz. The FFO free-running linewidth has been measured between 1 and 5MHz, which allows to phase lock up to 97% of the emitted FFO power. The output power of the FFO is sufficient to pump the matched SIS mixer. Therefore, it is concluded that the Nb–AlN–NbN FFOs are mature enough for practical applications. These achievements enabled the development of a 480–650GHz integrated receiver for the atmospheric-research instrument TErahertz and submillimeter LImb Sounder (TELIS). This balloon-borne instrument is a three-channel superconducting heterodyne spectrometer for the detection of spectral emission lines of stratospheric trace gases that have their rotational transitions at THz frequencies. One of the channels is based on the SIR technology. We demonstrate for the first time the capabilities of the SIR technology for heterodyne spectroscopy in general, and atmospheric limb sounding in particular. We also show that the application of SIR technology is not limited to laboratory environments, but that it is well suited for remote operation under harsh environmental conditions. Light weight and low power consumption combined with broadband operation and nearly quantum limited sensitivity make the SIR a perfect candidate for future airborne and space-borne missions. The noise temperature of the SIR was measured to be as low as 120K in double sideband operation, with an intermediate frequency band of 4–8GHz. The spectral resolution is well below 1MHz, confirmed by our measurements. Remote control of the SIR under flight conditions has been demonstrated in a successful balloon flight in Kiruna, Sweden. Capability of the SIR for high-resolution spectroscopy has been successfully proven also in a laboratory environment by gas cell measurements. The possibility to use SIR devices for the medical analysis of exhaled air will be discussed. Many medically relevant gases have spectral lines in the sub-terahertz range and can be detected by an SIR-based spectrometer. The SIR can be considered as an operational device, ready for many applications

Correlation of immunohistochemical staining p63 and TTF-1 with EGFR and K-ras mutational spectrum and diagnostic reproducibility in non small cell lung carcinoma

For treatment purposes, distinction between squamous cell carcinoma and adenocarcinoma is important. The aim of this study is to examine the diagnostic accuracy on lung cancer small biopsies for the distinction between adenocarcinoma and squamous cell carcinoma and relate these to immunohistochemical and KRAS and EGFR mutation analysis. An interobserver study was performed on 110 prospectively collected biopsies obtained by bronchoscopy or transthoracic needle biopsy of patients with non-small cell lung cancer. The diagnosis was correlated with immunohistochemical (IHC) analysis for markers of adeno- (TTF1 and/or mucin positivity) and squamous cell differentiation (P63 and CK5/6) as well as KRAS and EGFR mutation analysis. Eleven observers independently read H&E-stained slides of 110 cases, resulting in a kappa value of 0.55 ± 0.10. The diagnosis non-small cell lung cancer not otherwise specified was given on average on 29.5 % of the biopsies. A high concordance was observed between hematoxylin-eosin-based consensus diagnosis (≥8/11 readings concordant) and IHC markers. In all cases with EGFR (n = 1) and KRAS (n = 20) mutations, adenodifferentiation as determined by IHC was present and p63 staining was absent. In 2 of 25 cases with a consensus diagnosis of squamous cell carcinoma, additional stainings favored adenodifferentation, and a KRAS mutation was present. P63 is most useful for distinction between EGFR/KRAS mutation positive and negative patients. In the diagnostic work-up of non-small cell lung carcinoma the limited reproducibility on small biopsies is optimized with immunohistochemical analysis, resulting in reliable delineation for predictive analysis