S100A9 in inflammatory disease: a potential target for amelioration

The quinoline-3-carboxamides (Q compounds) are a family of small molecules with immunomodulatory functions that have shown efficacy in various murine models of inflammatory diseases. One such compound has demonstrated antitumor effects in murine models. Q compounds bind to S100A9, thereby preventing its ligation to TLR4 and RAGE. S100A9 is a small molecule which has shown to have a role in the establishment of tumors.In the first part of this thesis (paper I and II), effects of Q compounds during inflammation and cancer, with the focus on myeloid cells has been investigated. While, the focus of the second part (paper III and IV) was on the molecule S100A9. Given the important role of S100A9 during tumorigenesis, the aim was to evaluate the induction and expression of this molecule in vivo in the context of cancer.In paper I, the effect of the Q compound tasquinimod was evaluated on myeloid cells in a mouse mammary carcinoma tumor. Short-term treatment reduced the accumulation of inflammatory monocytes in the tumors. Depletion of this cell population using an anti-Gr1 antibody resulted in the comparable anti-tumor effect as treatment with tasquinimod during the first few days of tumor growth. Furthermore, long-term tasquinimod treatment reduced myeloid cell expansion in the spleen and made the frequency of precursor cells in the spleen of tumor-bearing mice resemble the naïve state.In paper II, the effect of the Q compound paquinimod was studied in the spontaneous mouse model of type 1 diabetes (NOD mouse). Paquinimod was given to the NOD mice in drinking water in two different protocols: short-term and longterm treatment and disease development were monitored weekly. Paquinimod induced a dose-dependent reduction in the incidence of diabetes and delayed the onset of disease in both treatment strategies. Interestingly, the treated mice showed less destructed islets in their pancreas. Moreover, the treatment reduced number of splenic inflammatory monocytes and macrophages.In paper III, the formation of S100A9 homodimer under inflammatory conditions and cancer was investigated. The cellular source of S100A9 homodimer was shown to be CD11b+ Gr1+ cells. Given the fact that in order to act as a DAMP, S100A9 should reach extracellular space, the presence of S100A9 homodimer in the extracellular milieu was shown. The presence of cells expressing only S100A9, and not both S100A8 and S100A9 was shown in spleens of tumor-bearing animals.In paper IV, the conditions that lead to de novo expression of S100A9 were studied. It was shown that in vivo environment induces S100A9 expression, and this induction is so dependent to this milieu that it was rapidly downregulated after removal of the cells from in vivo. Hypoxia in tumor microenvironment promotes tumor progression and survival and do so mainly by the activity of HIF-1 transcription factor which regulates the expression of many genes involved in the process of tumorigenesis. However, providing hypoxic condition was not sufficient for the induction of S100A9 expression in vitro. Combination of HIF-1α (one component of the transcription factor HIF-1) stabilizer and cytokines did not induce S100A9 expression either.In summary, in the first part of this thesis, we showed that treatment with Q compounds can reduce recruitment of monocytes to the site of inflammation. Given the important role of these cells in promoting the development of inflammatory diseases and cancer, this observation may partially explain the ameliorating effects of the Q compounds in a broad range of disease models. Furthermore, the second part of the thesis shows the induction of formation of S100A9 homodimer in vivo under inflammatory conditions and cancer, which may create a positive feedback loop for the propagation of inflammatory cascades. Our results also suggest that there is a requirement for a complex interplay of different factors in vivo for induction of S100A9 expression

Operating regime and stability of mode-locking in 10GHz quantum dot laser diodes around 1.5µm

In this paper we investigate and explore the stability and operating regime of modelocking (ML) in 4mm long Fabry-Perot type lasers, corresponding to a roundtrip frequency of 10GHz. The devices are fabricated on InAs/InP quantum dot material, operating at wavelengths around 1.5um, and are HR-coated at the absorber side. In order to find the stable ML region of operation in these devices, we have performed sweep-scans on the injection current of the gain section, and the reverse bias voltage on the absorber section. We will present the optical and electrical spectrum of devices with different absorber length. These results will be compared with the performance of earlier devices without HR coating

Frequency comb generation by CW laser injection into a quantum-dot mode-locked laser

100 GHz) RF generation and telecommunication applications. (C) 2012 Optical Society of Americ

Observation and modeling of long-wavelength InAs/InP (100) quantum dot amplifier small signal gain spectra

Measured gain spectra from InAs/InP (100) quantum-dot amplifiers have been analyzed with a quantum-dot rate-equation model. The amplifiers are fabricated to have a peak gain wavelength around 1700nm. Our comparison between measured and simulated gain spectra shows that two effects in the quantum-dot material introduce the 65 nm blue shift and change in shape that have been observed in the measured gain spectrum with an increase in injection current density from 1000A/cm2 to 3000A/cm2. The first effect is the shift from GS to ES, and the second effect the dot size dependent filling due to the dot size dependent escape rates

A monolithic 20GHz integrated extended cavity mode-locked quantum well ring laser at 1.58µm fabricated in the JEPPIX platform

We report on a passively modelocked InP/InGaAsP quantum well semiconductor ring laser which operates at 20GHz repetition rate and at 1.58µm output wavelength. A number of devices with varying relative positions of the absorbers and amplifiers have been realized using active-passive integration technology in the JEPPIX fabrication platform. The 4mm-long laser ring cavity incorporates a 750µm-long optical amplifier section, a separate 40µm-long saturable absorber section, passive waveguide sections and a passive MMI-type 50% output coupler. We investigate operation regimes of the laser and explore conditions for single mode lasing and mode-locked operation

Monolithically Integrated InP-based Optical Pulse Shaper

Spectral phase control of optical pulses is often required to generate short pulses, and an important application of a pulse shaper is spectral chirp/dispersion (pre-) compensation. In this paper, we present the pulse shaping/compression capability of a monolithically integrated optical pulse shaper. Chip fabrication has been carried out in a standardized generic photonic integration platform which is available in the framework of European FP7 project EuroPIC. A key capability of this platform is the active-passive integration scheme which allows direct integration of active components such as semiconductor optical amplifiers (SOAs) with passive elements such as arrayed waveguide gratings (AWGs) and phase modulators (PMs) on a single photonic chip