Lymph node tissue kallikrein-related peptidase 6 mRNA: a progression marker for colorectal cancer

BACKGROUND: A most important characteristic feature for poor prognosis in colorectal cancer (CRC) is the presence of lymph node metastasis. Determination of carcinoembryonic antigen (CEA) mRNA levels in lymph nodes has proven powerful for quantification of disseminated tumour cells. Here, we investigate the utility of human tissue kallikrein-related peptidase 6 (KLK6) mRNA as a progression biomarker to complement CEA mRNA, for improved selection of patients in need of adjuvant therapy and intensified follow-up after surgery. METHODS: Lymph nodes of pTNM stage I-IV CRC-(166 patients/503 lymph nodes) and control (23/108) patients were collected at surgery and analysed by quantitative RT-PCR. RESULTS: Lymph node KLK6 positivity was an indicator of poor outcome (hazard ratio 3.7). Risk of recurrence and cancer death increased with KLK6 lymph node levels. Patients with KLK6 lymph node levels above the 90th percentile had a hazard ratio of 6.5 and 76 months shorter average survival time compared to patients with KLK6 negative nodes. The KLK6 positivity in lymph nodes with few tumour cells, that is, low CEA mRNA levels, also indicated poor prognosis (hazard ratio 2.8). CONCLUSION: In CRC patients, lymph node KLK6 positivity indicated presence of aggressive tumour cells associated with poor prognosis and high risk of tumour recurrence. British Journal of Cancer (2012) 107, 150-157. doi: 10.1038/bjc.2012.220 www.bjcancer.com Published online 14 June 2012 (C) 2012 Cancer Research U

Biomarker selection for detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT–PCR

Accurate identification of lymph node involvement is critical for successful treatment of patients with colorectal carcinoma (CRC). Real-time quantitative RT–PCR with a specific probe and RNA copy standard for biomarker mRNA has proven very powerful for detection of disseminated tumour cells. Which properties of biomarker mRNAs are important for identification of disseminated CRC cells? Seven biomarker candidates, CEA, CEACAM1-S/L, CEACAM6, CEACAM7-1/2, MUC2, MMP7 and CK20, were compared in a test-set of lymph nodes from 51 CRC patients (Dukes' A–D) and 10 controls. Normal colon epithelial cells, primary tumours, and different immune cells were also analysed. The biomarkers were ranked according to: (1) detection of haematoxylin/eosin positive nodes, (2) detection of Dukes' A and B patients, who developed metastases during a 54 months follow-up period and (3) identification of patients with Dukes' C and D tumours using the highest value of control nodes as cutoff. The following properties appear to be of importance; (a) no expression in immune cells, (b) relatively high and constant expression in tumour tissue irrespective of Dukes' stage and (c) no or weak downregulation in tumours compared to normal tissue. CEA fulfilled these criteria best, followed by CK20 and MUC2

Inequalities of quality of life in unemployed young adults: A population-based questionnaire study

BACKGROUND: It is well known that unemployment is a great problem both to the exposed individual and to the whole society. Unemployment is reported as more common among young people compared to the general level of unemployment. Inequity in health status and life-satisfaction is related to unemployment. The purpose of this population-based study was to describe QOL among unemployed young people compared to those who are not unemployed, and to analyse variables related to QOL for the respective groups. METHODS: The sample consisted of 264 young unemployed individuals and 528 working or studying individuals as a reference group. They all received a questionnaire about civil status, educational level, immigration, employment status, self-reported health, self-esteem, social support, social network, spare time, dwelling, economy and personal characteristics. The response rate was 72%. The significance of differences between proportions was tested by Fisher's exact test or by χ(2 )test. Multivariate analysis was carried out by means of a logistic regression model. RESULTS: Our results balance the predominant picture of youth unemployment as a principally negative experience. Although the unemployed reported lower levels of QOL than the reference group, a majority of unemployed young adults reported good QOL, and 24% even experienced higher QOL after being unemployed. Positive QOL related not only to good health, but also to high self-esteem, satisfaction with spare time and broad latitude for decision-making. CONCLUSION: Even if QOL is good among a majority of unemployed young adults, inequalities in QOL were demonstrated. To create more equity in health, individuals who report reduced subjective health, especially anxiety need extra attention and support. Efforts should aim at empowering unemployed young adults by identifying their concerns and resources, and by creating individual programmes in relation not only to education and work, but also to personal development

NF kappa B induces overexpression of bovine FcRn: a novel mechanism that further contributes to the enhanced immune response in genetically modified animals carrying extra copies of FcRn

Among the many functions of the neonatal Fc receptor (FcRn) for IgG, it binds to IgG-opsonized antigen complexes and propagates their traffic into lysosomes where antigen processing occurs. We previously reported that transgenic (Tg) mice and rabbits that carry multiple copies and overexpress FcRn have augmented humoral immune responses. Nuclear factor-kappa B (NFκB) is a critical molecule in the signaling cascade in the immune response. NFκB induces human FcRn expression and our previous in silico analysis suggested NFκB binding sites in the promoter region of the bovine (b) FcRn α-chain gene (FCGRT). Here, we report the identification of three NFκB transcription binding sites in the promoter region of this gene using luciferase reporter gene technology, electromobility shift assay and supershift analysis. Stimulation of primary bovine endothelial cells with the Toll like receptor-4 ligand lipopolysaccharide (LPS), which mediates its effect via NFκB, resulted in rapid upregulation of the bFcRn expression and a control gene, bovine E-selectin. This rapid bFcRn gene induction was also observed in the spleen of bFcRn Tg mice treated with intraperitoneally injected LPS, analyzed by northern blot analysis. Finally, NFκB- mediated bFcRn upregulation was confirmed at the protein level in macrophages isolated from the bFcRn Tg mice using flow cytometry with a newly developed FcRn specific monoclonal antibody that does not cross-react with the mouse FcRn. We conclude that NFκB regulates bFcRn expression and thus optimizes its functions, e.g., in the professional antigen presenting cells, and contributes to the much augmented humoral immune response in the bFcRn Tg mice

Time-Resolved IR Spectroscopy Reveals a Mechanism with TiO2 as a Reversible Electron Acceptor in a TiO2 - Re Catalyst CO2 Photoreduction System

Attaching the phosphonated molecular catalyst [Re$^{I}$Br(bpy)(CO)₃]⁰ to the wide-band gap semiconductor TiO₂ strongly enhances the rate of visible-light driven reduction of CO₂ to CO in dimethyl formamide (DMF) with triethanolamine (TEOA) as sacrificial electron donor. Herein, we show by transient mid-IR spectroscopy that the mechanism of catalyst photoreduction is initiated by ultrafast electron injection into TiO₂, followed by rapid (ps-ns) and sequential two-electron oxidation of TEOA that is coordinated to the Re center. The injected electrons can be stored in the conduction band (CB) of TiO₂ on a ms-s time scale, and we propose they lead to further reduction of the Re-catalyst and completion of the catalytic cycle. Thus, the excited Re catalyst gives away one electron and would eventually get three electrons back. The function of an electron reservoir would represent a role for TiO₂ in photo-catalytic CO₂ reduction that has previously not been considered. We propose that the increase in photocatalytic activity upon heterogenisation of the catalyst to TiO₂ is due to the slow charge recombination and the high oxidative power of the ReII species after electron injection, as compared to the excited MLCT state of the unbound Re catalyst or when immobilized on ZrO₂, which results in a more efficient reaction with TEOA.Knut and Alice Wallenberg Foundation, Swedish Energy Agency, Swedish Research Council, Austrian Christian Doppler Research Association, OMV Grou

Модернізація стоматологічної установки УС- 30

Background: The novel chemokine CXCL17 acts as chemoattractant for monocytes, macrophages and dendritic cells. CXCL17 also has a role in angiogenesis of importance for tumour development. Methods: Expression of CXCL17, CXCL10, CXCL9 and CCL2 was assessed in primary colon cancer tumours, colon carcinoma cell lines and normal colon tissue at mRNA and protein levels by real-time qRT-PCR, immunohistochemistry, two-colour immunofluorescence and immunomorphometry. Results: CXCL17 mRNA was expressed at 8000 times higher levels in primary tumours than in normal colon (P<0.0001). CXCL17 protein was seen in 17.2% of cells in tumours as compared with 0.07% in normal colon (P = 0.0002). CXCL10, CXCL9 and CCL2 mRNAs were elevated in tumours but did not reach the levels of CXCL17. CXCL17 and CCL2 mRNA levels were significantly correlated in tumours. Concordant with the mRNA results, CXCL10-and CXCL9-positive cells were detected in tumour tissue, but at significantly lower numbers than CXCL17. Two-colour immunofluorescence and single-colour staining of consecutive sections for CXCL17 and the epithelial cell markers carcinoembryonic antigen and BerEP4 demonstrated that colon carcinoma tumour cells indeed expressed CXCL17. Conclusions: CXCL17 is ectopically expressed in primary colon cancer tumours. As CXCL17 enhances angiogenesis and attracts immune cells, its expression could be informative for prognosis in colon cancer patients

Relative Health Effects of Education, Socioeconomic Status and Domestic Gender Inequity in Sweden: A Cohort Study

Introduction: Limited existing research on gender inequities suggests that for men workplace atmosphere shapes wellbeing while women are less susceptible to socioeconomic or work status but vulnerable to home inequities. Methods: Using the 2007 Northern Swedish Cohort (n = 773) we identified relative contributions of perceived gender inequities in relationships, financial strain, and education to self-reported health to determine whether controlling for sex, examining interactions between sex and other social variables, or sex-disaggregating data yielded most information about sex differences. Results and Discussion: Men had lower education but also less financial strain, and experienced less gender inequity. Overall, low education and financial strain detracted from health. However, sex-disaggregated data showed this to be true for women, whereas for men only gender inequity at home affected health. In the relatively egalitarian Swedish environment where women more readily enter all work arenas and men often provide parenting, traditional primacy of the home environment (for women) and the work environment (for men) in shaping health is reversing such that perceived domestic gender inequity has a significant health impact on men, while for women only education and financial strain are contributory. These outcomes were identified only when data were sex-disaggregated

GRAZ, Hauptplatz

Hauptplatz mit Erzherzog-Johann-Brunnendenkma

Expanding clinical phenotype and novel insights into the pathogenesis of ICOS deficiency

Background: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)–like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte–associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. Methods: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. Results: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. Conclusions: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation