Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking

Head and neck cancer (HNC) is a collective name for heterogeneous tumors located in the head and neck regions for which smoking, alcohol and human papillomavirus (HPV) are documented risk factors. The survival of HNC patients has only improved marginally during the last decade. The most important prognostic factors are tumor size, local spread and distant metastases, tumor node metastasis (TNM) staging. Prognostic biomarkers are needed as a complement to TNM staging. The aim for this thesis was to investigate rapid and low cost blood based biomarkers which could indicate the risk of HNC, recurrence of the disease or the survival of HNC patients. Furthermore, the aim was to examine how cigarette smoking influences the levels of biomarkers. In paper I, a possible role of plasma cytokines or proteins associated with immune response or inflammation, as biomarkers for the survival of HNC patients was investigated. Higher levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) were detected in plasma of the patients compared with the levels in the controls. The elevated levels of these two biomarkers detected in patients were associated with decreased survival. In paper II, the influence of 45 single nucleotide polymorphisms (SNPs) located in 41 genes associated with cell cycle progression, cell death, DNA repair or immune response on cancer risk, tumor recurrence and survival in HNC patients were investigated. SNPs in immune response genes were associated with risk for HNC, an elevated risk for recurrence and a decreased survival in HNC patients. In paper III, the influence of cigarette smoking on levels of inflammatory cells, proteins or cytokines/chemokines, microRNAs (miRNAs) and SNPs was analysed in healthy smokers and non-smokers. Higher levels of total white blood cells (WBCs), neutrophils, monocytes, lymphocytes, neutrophil to lymphocyte ratio (NLR), CRP, monocyte chemoattractant protein- 1 (MCP-1) and interferon gamma (IFN-γ) were detected in smokers compared to non-smokers and indicate an inflammatory response. Also, a lower level of oncomiRNA miR-21was detected in smokers. This alteration, in combination with the elevated levels of IFN-γ in smokers could be a protective response to cigarette smoke. The higher levels of IFN-γ in smokers compared to non-smokers were however only detected in individuals with SNP rs2069705 genotype AG/GG. This indicates a genetic association of the levels of IFN-γ. In paper IV, the separate effects of cigarette smoking and HNC on inflammatory or immune biomarkers and the impact of high risk human papillomavirus, age and gender were investigated. Comparisons of circulating levels of WBCs and its subpopulations, plasma proteins or cytokines/chemokines between smoking and non-smoking patients, smoking and non-smoking controls and between the patient and control groups were analysed. Smoking had highest impact on elevated levels of WBCs, IFN-γ and MCP-1, and HNC had highest impact on elevated levels of neutrophils, monocytes, NLR, CRP, macrophage inflammatory protein 1 beta and TNF-α. In conclusion, host immune response associated parameters could be suitable as biomarkers for the risk of HNC, risk of recurrence or in predicting survival of HNC patients. This thesis show that HNC are associated with systemic inflammatory response and upregulated CRP and TNF-α is related to shorter survival in HNC patients. Additionally, SNPs in immune response genes such as rs1800629 in the TNF-α gene indicates a risk for HNC or an elevated risk for recurrence and a decreased survival in HNC patients. These rapid and low cost blood based biomarkers could be used in combination or as a supplement to established biomarkers in the clinic for a more personalized treatment modality.Huvud- och halscancer (HH-cancer) innefattar tumörer belägna i huvud och halsområdet. Tobaksrökning ökar risken dramatiskt för olika sjukdomar. Knappt hälften av rökande patienter dör i de av rökning orsakade sjukdomarna. Cancer är orsaken till en tredjedel av de rökrelaterade dödsfallen av vilka HH-cancer är en. En andel av patienterna med HH-cancer dör på grund av att tumören varit för stor redan vid diagnos eller att tumören har spridit sig till övriga delar av kroppen. Men för många patienter är det mycket oklart vad som bestämmer behandlingsresultatet. Tumörerna är till synes lika och behandlingen standardiserad. Målet med denna doktorsavhandling var att undersöka billiga och lättillgängliga biologiska markörer som kan indikera risk för att drabbas av HH-cancer eller om dessa markörer kan förutspå behandlingsresultat och överlevnad hos de drabbade patienterna. Dessutom undersöktes hur cigarettrökning påverkade nivåerna av markörerna. I studie I, undersöktes om molekyler i blodet (biomarkörer), förknippade med immunförsvaret, kunde förutsäga överlevnaden hos HH-cancerpatienter. I jämförelse med friska individer sågs högre nivåer av molekylerna TNF-α och CRP hos patienterna och dessa förhöjningar var relaterade till förkortad överlevnad hos patienterna. I studie II, var målet att undersöka om variationer i gener, förknippade med immunförsvaret, celldelning, celldöd eller enzymer som reparerar skadat DNA, kunde påverka risk och prognos för HH-cancer. Resultatet visade framför allt att små ärftliga variationer i gener som reglerar immunförsvaret kunde påverkade risk för HH-cancer, risk för återfall i sjukdomen samt överlevnaden hos patienterna. I studie III, jämfördes inflammatoriska och immunförknippade biomarkörer som kunde påverkas av cigarettrökning mellan friska rökare och friska icke-rökare. Rökarna hade en högre inflammatorisk aktivitet med högre nivåer av totalt antal vita blodkroppar och tre av dess olika undergrupper (neutrofiler, monocyter och lymfocyter) samt av biomarköerna CRP, MCP-1 och IFN-γ. De funna lägre nivåerna av den cancerförknippade biomarkören miR-21 och högre nivåer av den förmodat skyddande biomarkören IFN-γ hos rökarna, kan vara ett uttryck för kroppens försvar mot den cancerframkallade cigarettröken. Ärftliga faktorer tycks kunna påverka de högre nivåerna av IFN-γ hos rökarna, eftersom ökningen endast fanns i en grupp individer med viss typ av genetisk uppsättning. Eftersom både rökning och HH-cancer ger upphov till inflammation, undersöktes i studie IV hur dessa var för sig påverkade nivåerna av inflammatoriska biomarkörer. Detta för en bättre förståelse hur immunförsvaret reagerar på rökning och HH-cancer. Jämförelser av inflammatoriska markörer från rökande och icke-rökande patienter, och rökande och ickerökande friska individer genomfördes. Rökning hade störst påverkan på de högre nivåerna av totalt antal vita blodkroppar och signalmolekylerna MCP-1 och IFN-γ. HH-cancer hade störst påverkan på högre nivåerna av neutrofiler, monocyter, kvoten mellan neutrofiler och lymfocyter, CRP, MIP-1b och TNF-α. Uppkomsten av HH-cancer, behandlingsresultat och överlevnad bland patienterna kan antas inte bara bero på tumörens egenskaper, utan även på värdfaktorer hos patienten. Dessa kan vara ärftliga, eller bero på reglering av gener eller tumörens omgivning av t.ex. immunceller och inflammatoriska molekyler och hur dessa samverkar med miljöfaktorer som tobaksrökning. I denna avhandling presenteras biomarkörer som kan bidra med information om risk och prognos för HH-cancer samt hur tobaksrökning påverkar dessa markörer

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Local lateral distribution of heat transfer on tube surface on membrane walls in CFB boilers

The wall to bed heat transfer was investigated in a 12 MWth CFB boiler at different locations in the combustion chamber and under various operating conditions. At high levels in the furnace the lateral distribution of heat flow to the tube and fin was found to be a result of radiation from the hot bed bulk, especially at low bulk densities. The local heat flow to the fin decreased considerably with decreasing height in contrast to the heat flow to the crest of the tube. This is due to the large down-flow of particles in the fin region and the growth of the boundary layer. The average heat transfer coefficient across the membrane wall was found to decrease with decreased bulk density, but at low bulk densities the decrease is very small since radiation dominates heat transfer

Experimental methods of estimating heat transfer in circulating fluidized bed boilers

Four different experimental methods have been used for the estimation of the bed-to-membrane wall heat transfer in a 12 MW,, circulating fluidized bed boiler. The methods are compared for a case of normal operating conditions and the measured heat transfer coefficients are presented. In the central part of the combustion chamber where most of the cooling surface is located, the cross-sectional average suspension density normally varies in the range of 10-20 kg m -’ and the heat transfer coefficient is around 130 W m ’ K-’ with a scatter of + 15% due to the different methods. The methods are critically analyzed and the heat transfer data are compared with relevant literature data

Coherent synchrotron radiation in the far infrared from a 1-mm electron bunch

The coherent generation of synchrotron radiation by an electron storage ring is predicted for wavelengths equal to or longer than the electron bunch length. With typical bunch lengths of approximately 1 cm, diffraction and chamber-screening effects have so far blocked observation of coherent radiation from a conventional radiation beamline. In the low-energy, second-generation light source MAX-I, the magnet lattice has been tuned to a small momentum compaction factor, allowing rms bunch lengths as short as 1 mm. Here we report the coherent far-infrared emission observed from such a bunch. The paper discusses the origin of coherent synchrotron radiation for Gaussian and non-Gaussian electron bunches, and the procedure used to generate such bunches. The emission was characterized using the infrared beamline at MAX-I, including an interferometer, a liquid-helium-cooled bolometer detector, waveguide high-pass filters, and a conductive-grid polarization filter. The intensity of the coherent radiation is greater by a factor of 2×103 to 6×103 than normal incoherent synchrotron radiation, and is seen between 8 and 22 cm-1

Observation of coherent synchrotron radiation from a 1 mm electron bunch at the MAX-I storage ring

The coherent generation of synchrotron radiation by an electron storage ring is predicted for wavelengths equal to or longer than the electron bunch length. With typical bunch lengths of approximately 1 cm, diffraction and chamber- screening effects have so-far blocked observation of coherent radiation from a conventional radiation beam line. In the low-energy, second-generation light source MAX-I, the magnet lattice has been tuned to a small momentum compaction factor, allowing rms bunch lengths as short as 1 mm. Here we report the coherent emission phenomena observed from such a bunch at the infrared beam line attached to the MAX-I ring.The coherent generation of synchrotron radiation by an electron storage ring is predicted for wavelengths equal to or longer than the electron bunch length. With typical bunch lengths of approximately 1 cm, diffraction and chamber- screening effects have so-far blocked observation of coherent radiation from a conventional radiation beam line. In the low-energy, second-generation light source MAX-I, the magnet lattice has been tuned to a small momentum compaction factor, allowing rms bunch lengths as short as 1 mm. Here we report the coherent emission phenomena observed from such a bunch at the infrared beam line attached to the MAX-I ring

Operational results from the 16 MW FBB at the Chalmers University

The 16 MW fluidised bed boiler was first started in 1982 and has since then run for 3325 hours. After only 1200 hours the material wastage on the in-bed heat transfer surfaces was so great that tubes had to be removed. Wear resistant coatings of various kinds have been tried but the result of their use is not quite clear. Measurements of elutriated solids and the corresponding combustion efficiency is discussed. Finally, in contrast to the problems of material wastage and low combustion efficiency, some positive operational characteristics such as start-up and load control are presented

Pressure distribution and particle concentration in bubbling fluidized beds

The expansion of and particle concentration in large-particle (>0.5 mm) bubbling beds, fluidized at high gas velocities (U-Umf>1 m/s) have been studied in a boiler with 10 m2 hot bed and in a cold two-dimensional bed. The significantly different behaviour of a freely bubbling versus a tube-filled bed at high gas velocity is demonstrated