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

Does transition from an unstable labour market position to permanent employment protect mental health? Results from a 14-year follow-up of school-leavers

<p>Abstract</p> <p>Background</p> <p>Having secure employment, in contrast to being unemployed, is regarded as an important determinant of health. Research and theories about the negative health consequences of unemployment indicated that transition from unemployment to a paid job could lead to improved health. The objective of this study was to test the hypothesis that obtaining permanent employment after being in an unstable labour market position protects mental health.</p> <p>Methods</p> <p>A 14-year follow-up of all graduates from compulsory school in an industrial town in northern Sweden was performed at ages 16, 18, 21 and 30 years. Complete data on the cohort were collected for 1044 individuals with the aid of a comprehensive questionnaire. The response rate was 96.4%. The health measurement used in this study was the psychological symptoms analysed by multivariate logistic regression. Those who obtained permanent employment were the focus of the analysis. This group consisted of people who were in an unstable labour market position for a year or more between the ages of 25 and 29, and who had acquired a permanent job one year before and at the time of the investigation.</p> <p>Results</p> <p>After controlling for gender as well as for an indicator of health-related selection, possible confounders and mediators, an association was found between the lower probability of psychological symptoms and obtaining permanent employment (OR = 0.35, 95% CI 0.19–0.63) as well as having permanent employment (OR = 0.22, 95% CI 0.10–0.51).</p> <p>Conclusion</p> <p>Our findings suggest that transition from an unstable labour market position to permanent employment could be health-promoting, even after controlling for possible confounders and mediators, as well as for an indicator of health-related selection. However, as there are few studies in the field, there is a need for more longitudinal studies in order to further analyse the relationship and to examine possible explanations. The policy implication of our study is that the transformation of unstable labour market positions into permanent employment could contribute to better public health.</p

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

Mechanistic insights into the charge transfer dynamics of photocatalytic water oxidation at the lipid bilayer: water interface

Photosystem II, the natural water-oxidizing system, is a large protein complex embedded in a phospholipid membrane. A much simpler system for photocatalytic water oxidation consists of liposomes functionalized with amphiphilic ruthenium(II)-trisbipyridine photosensitizer (PS) and 6,6 '-dicarboxylato-2,2 '-bipyr-idine-ruthenium(II) catalysts (Cat) with a water-soluble sacrificial electron acceptor (Na2S2O8). However, the effect of embedding this photocatalytic system in liposome membranes on the mechanism of photocatalytic water oxidation was not well understood. Here, several phenomena have been identified by spectroscopic tools, which explain the drastically different kinetics of water photo oxidizing liposomes, compared with analogous homogeneous systems. First, the oxidative quenching of photoexcited PS* by S2O82- at the liposome surface occurs solely via static quenching, while dynamic quenching is observed for the homogeneous system. Moreover, the charge separation efficiency after the quenching reaction is much smaller than unity, in contrast to the quantitative generation of PS+ in homogeneous solution. In parallel, the high local concentration of the membrane-bound PS induces self quenching at 10:1-40:1 molar lipid-PS ratios. Finally, while the hole transfer from PS+ to catalyst is rather fast in homogeneous solution (kobs > 1 x 104 s-1 at [catalyst] > 50 mu M), in liposomes at pH = 4, the reaction is rather slow (kobs approximate to 17 s-1 for 5 mu M catalyst in 100 mu M DMPC lipid). Overall, the better understanding of these productive and unproductive pathways explains what limits the rate of photocatalytic water oxidation in liposomal vs homogeneous systems, which is required for future optimization of light-driven catalysis within self-assembled lipid interfaces.Horizon 2020(H2020)828838−SoFiAMetals in Catalysis, Biomimetics & Inorganic Material

Sound-meaning association biases evidenced across thousands of languages

It is widely assumed that one of the fundamental properties of spoken language is the arbitrary relation between sound and meaning. Some exceptions in the form of nonarbitrary associations have been documented in linguistics, cognitive science, and anthropology, but these studies only involved small subsets of the 6,000+ languages spoken in the world today. By analyzing word lists covering nearly two-thirds of the world's languages, we demonstrate that a considerable proportion of 100 basic vocabulary items carry strong associations with specific kinds of human speech sounds, occurring persistently across continents and linguistic lineages (linguistic families or isolates). Prominently among these relations, we find property words ("small" and i, "full" and p or b) and body part terms ("tongue" and l, "nose" and n). The areal and historical distribution of these associations suggests that they often emerge independently rather than being inherited or borrowed. Our results therefore have important implications for the language sciences, given that nonarbitrary associations have been proposed to play a critical role in the emergence of cross-modal mappings, the acquisition of language, and the evolution of our species' unique communication system

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

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

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