A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma

Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Tyr-321 in all HNSCC cell lines. Inhibition of DYRK1A resulted in an increased apoptosis and decrease in invasion and colony formation ability of HNSCC cell lines. Further, administration of the small molecular inhibitor against DYRK1A in mice bearing HNSCC xenograft tumors induced regression of tumor growth. Immunohistochemical labeling of DYRK1A in primary tumor tissues using tissue microarrays revealed strong to moderate staining of DYRK1A in 97.5% (39/40) of HNSCC tissues analyzed. Taken together our results suggest that DYRK1A could be a novel therapeutic target in HNSCC

Simultaneous on-line vacuum single- and multi-photon ionization on an orthogonal acceleration time-of-flight mass spectrometer platform.

The development of orthogonal acceleration time-of-flight (oa-tof) technology is driven forward due to higher mass accuracy and resolving power than conventional linear/reflectron tof instruments. This is achieved with a more accurate definition of starting energies and coordinates of ions by spatial separation of ion generation and orthogonal ion extraction. Consequently, the ability to cover the whole mass spectral range without scanning is not given anymore. Therefore, continuous ion sources are favored for ensuring high duty cycles and thus high temporal resolution. For pulsed ion sources, high repetition rates are mandatory for covering large m/z ranges without losing their high temporal resolution. We have combined an oa-tof with deuterium lamp single-photon ionization (SPI) as a continuous ion source together with a pulsed 2000 Hz excimer (KrF) laser for resonance enhanced multi-photon ionization (REMPI). These two ionization techniques can be used simultaneously. To the best of our knowledge, this system is the first of its kind in combining a vacuum pulsed ionization source with an oa-tof instrument without any other ion storage hardware. The combination of a soft broadband ionization for organics (SPI) in combination with a very sensitive and selective soft ionization (REMPI) can be used for covering the whole mass range or in targeted on-line monitoring cases one or several smaller mass ranges. To demonstrate the simultaneous SPI/REMPI-oa-tof technique, two applicative areas are explored: on-line monitoring of coffee roast gas emissions and e-cigarette vapor. The complementary information from SPI and REMPI signals are combined in a way to exploit the advantages of both ionization types. In a further development step, a second data acquisition card is built into the system. This modification allows the independent storage of data from both ionization methods without mixing. For demonstration, a third example with a GC measurement is provided. The last example shows the possibility of modified sensitivities for different mass regions in REMPI data acquisition without affecting the SPI channel. The newly developed system shows high robustness in terms of measurements in real industrial environments. The simultaneous measurement technique provides a higher density of information in a single measurement, saving time and resources

Application of modeling techniques for ultrasonic austenitic weld inspection

After a brief discussion of the fundamental equations of elastic wave propagation in anisotropic (transversely isotropic) materials and their basic solutions in terms of plane waves and Green functions, we point out and demonstrate the usefulness of Huygen's principle in conjunction with the results obtained by the numerical Elastodynamic Finite Intergration Technique (EFIT)-code for an intuitive physical understanding of ultrasound propagation in austentic steel. EFIT is briefly explained and then validated against a weld transmission experiment; applications to pilse echo simulations for various and real-life geometries and structures with and without backwall entering notches are to follow. Further, we have been able to confirm the existence of the second qSV-wave, as predicted by plane wave theory, through EFIT-modeling as well as experiments

Puff-resolved analysis and selected quantification of chemicals in the gas phase of E-Cigarettes, Heat-not-Burn devices and conventional cigarettes using single photon ionization time-of-flight mass spectrometry (SPI-TOFMS): A comparative study.

INTRODUCTION: A wide array of alternative nicotine delivery devices (ANDD) has been developed and they are often described as less harmful than combustible cigarettes. This work compares the chemical emissions of three ANDD in comparison to cigarette smoke. All the tested ANDD are characterized by not involving combustion of tobacco. METHOD: Single photon ionization time-of-flight mass spectrometry (SPI-TOFMS) is coupled to a linear smoking machine, which allows a comprehensive, online analysis of the gaseous phase of the ANDD aerosol and the conventional cigarette smoke (CC). The following devices were investigated in this study: a tobacco cigarette with a glowing piece of coal as a heating source, an electric device for heating tobacco and a first-generation electronic cigarette. Data obtained from a standard 2R4F research cigarette are taken as a reference. RESULTS: The puff-by-puff profile of all products was recorded. The ANDD show a substantial reduction or complete absence of known harmful and potentially harmful substances compared to the CC. In addition, tar substances (i.e. semivolatile and low volatile aromatic and phenolic compounds) are formed to a much lower extent. Nicotine, however, is supplied in comparable amounts except for the investigated electronic cigarette. CONCLUSIONS: The data shows that consumers switching from CC to ANDD are exposed to lower concentrations of harmful and potentially harmful substances. However, toxicological and epidemiological studies must deliver conclusive results if these reduced exposures are beneficial for users. IMPLICATION: The comparison of puff-resolved profiles of emissions from different tobacco products, traditional and alternative, may help users switch to lower emission products. Puff-resolved comparison overcomes technical changes, use modes between products and may help in their regulation

On-line derivatization for resonance-enhanced multiphoton ionization time-of-flight mass spectrometry

On-line derivatization for resonance-enhanced multiphoton ionization time-of-flight mass spectrometry : detection of aliphatic aldehydes and amines via reactive coupling of aromatic photo ionization labels / R. Zimmermann ...- In: Analytical chemistry. 77. 2005. S. 1-1

On-line derivatization for resonance-enhanced multiphoton ionization time-of-flight mass spectrometry:Detection of aliphatic aldehydes and amines via reactive coupling of aromatic photo ionization labels.

Resonance-enhanced multiphoton ionization time-of-flight mass spectrometry (REMPI-TOFMS) is a powerful technique for the on-line analysis of aromatic compounds with unique features regarding selectivity and sensitivity. Aliphatic compounds, however, are difficult to address by REMPI due to their unfavorable photo ionization properties. This paper describes the proof of concept for an on-line derivatization approach for converting nonaromatic target analytes into specific, photoionizable aromatic derivatives that are readily detectable by REMPI-TOFMS. A multichannel silicone trap or poly(dimethylsiloxane) (PDMS) open tubular capillary was used as a reaction medium for the derivatization of volatile alkyl aldehydes and alkylamines with aromatic "photoionization labels"and to concentrate the resulting aromatic derivatives. The aldehydes formaldehyde, acetaldehyde, acrolein, and crotonal, which when underivatized are poorly detectable by REMPI, were converted into their easily photoionizable phenylhydrazone derivatives by the on-line reaction with phenylhydrazine as reagent. Similarly, the methyl-, ethyl-, propyl-, and butylamines were converted into their REMPI-ionizable benzaldehyde alkylimine derivatives by the on-line reaction with benzaldehyde as reagent. The derivatives were thermally desorbed from the PDMS matrix and transferred into the REMPI-TOFMS for detection. The REMPI-TOFMS detection limits obtained for acetaldehyde; acrolein; crotonal; and methyl-, ethyl-, propyl-, and butylamine using this photo ionization labeling method were in the sub-parts-per-million range and, thus, readily below the permissible exposure limits set by OSHA

Evolution of volatile flavor compounds during roasting of nut seeds by thermogravimetry coupled to fast cycling optical heating gas chromatography-mass spectrometry with electron- and photoionization.

Online multidimensional evolved gas analysis was conducted during the roasting of nuts using fast-cycling optical heating gas chromatography (OHGC) coupled to mass spectrometry with electron ionization and soft single photon ionization (OHGC-EI/SPI-MS). SPI is a semi-selective soft ionization method for organic compounds that produces mainly molecular ions, whereas EI is a hard ionization method that results in fragmentation. Ionization was either done exclusively by one of these methods or both were used alternately. Roasting of the nuts (almonds, Brazil nuts, cashews, peanuts, hazelnuts, pecans, pine nuts, and walnuts) was simulated in a thermal analysis (TA) device at a roasting temperature of 170 °C. The TA device was directly coupled to the OHGC-EI/SPI-MS for quasi-real-time analysis. Multidimensional analysis was possible with a temporal resolution of 1 min. Good chromatographic separation, constant sampling repetition rates, and constant retention times (RTs) were obtained. Peak assignment was performed using the molecular mass information obtained from SPI-MS, the characteristic fragmentation patterns from EI-MS, and the OHGC RTs. The gases that evolved during roasting of each type of nut were monitored online using the TA-OHGC-MS setup. Aldehydes, furans, and pyrazines were detected as flavor compounds. Changes in the compositions of the evolved gases during the roasting process were evaluated. The TA-OHGC-MS method could separate isobaric and isomeric compounds

Optically heated ultra-fast-cycling gas chromatography module for rapid separation of direct sampling and online monitoring applications.

This work describes an ultra-fast-cycling gas chromatography module (fast-GC module) for direct-sampling gas chromatography - mass spectrometry (GC-MS). The sample can be introduced into the fast-GC module using a common GC injector or any GC×GC modulator. The new fast-GC module offers the possibility to conduct a complete temperature cycle within 30 s. Its thermal mass is minimized by using a specially developed home-built fused silica capillary column stack and a halogen lamp for heat generation, both placed inside a gold-coated quartz glass cylinder. A high airflow blower enables rapid cooling. The new device is highly flexible concerning the used separation column, the applied temperature program and the integration into existing systems. An application of the fast-GC module is shown in this work by thermal analysis coupled to gas chromatography - mass spectrometry (TA-GC-MS). The continuously evolving gases of the TA are modulated by a liquid CO2 modulator. Due to the rapid cycling of the fast-GC module, it is possible to obtain the best separation while maintaining the online character of the TA. Restrictions in separation and retention time shifting, known from isothermal and normal ramped fast-GC systems, are overcome