| 1. |
- Lindmark, Gudrun, et al.
(author)
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qRT-PCR analysis of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN in colon cancer lymph nodes : An improved method for assessment of tumor stage and prognosis
- 2024
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 154:3, s. 573-584
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Journal article (peer-reviewed)abstract
- One fourth of colorectal cancer patients having curative surgery will relapse of which the majority will die. Lymph node (LN) metastasis is the single most important prognostic factor and a key factor when deciding on postoperative treatment. Presently, LN metastases are identified by histopathological examination, a subjective method analyzing only a small LN volume and giving no information on tumor aggressiveness. To better identify patients at risk of relapse we constructed a qRT-PCR test, ColoNode, that determines levels of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN mRNAs. Combined these biomarkers estimate the tumor cell load and aggressiveness allocating patients to risk categories with low (0, −1), medium (1), high (2) and very high (3) risk of recurrence. Here we present result of a prospective, national multicenter study including 196 colon cancer patients from 8 hospitals. On average, 21 LNs/patient, totally 4698 LNs, were examined by both histopathology and ColoNode. At 3-year follow-up, 36 patients had died from colon cancer or lived with recurrence. ColoNode identified all patients that were identified by histopathology and in addition 9 patients who were undetected by histopathology. Thus, 25% of the patients who recurred were identified by ColoNode only. Multivariate Cox regression analysis proved ColoNode (1, 2, 3 vs 0, −1) as a highly significant risk factor with HR 4.24 [95% confidence interval, 1.42-12.69, P =.01], while pTN-stage (III vs I/II) lost its univariate significance. In conclusion, ColoNode surpassed histopathology by identifying a significantly larger number of patients with future relapse and will be a valuable tool for decisions on postoperative treatment.
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| 2. |
- Brydsten, Anna, 1984-
(author)
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Yesterday once more? Unemployment and health inequalities across the life course in northern Sweden
- 2017
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Doctoral thesis (other academic/artistic)abstract
- AbstractBackground. It is relatively well established in previous research that unemployment has direct health consequences in terms of mental and physical ill health. Recently, knowledge has emerged indicating that unemployment can lead to economic consequences that remain long after re-establishment in the labour market. However, few empirical studies have been able to apply a life course perspective asking whether there are also long-term health consequences of unemployment, and, when and in which context unemployment may affect the individual health status across the life course. The aim of this thesis was to analyse the relationship between unemployment and illness across the life course, and how it relates to individual and structural factors in the geographical setting of northern Sweden. In particular, three main areas have been explored: youth unemployment and illness in adulthood (Paper I and Paper II), contextual unemployment of national unemployment rate and neighbourhood unemployment (Paper II and Paper III) and lastly, social determinants of health inequality between employment statuses (Paper IV).Methods. This thesis is positioned in Sweden between the early 1980s and the mid-2010s, following two comparable cohorts sampled from northern Sweden (26 and 19 years follow-up time respectively from youth to midlife) and a cross-sectional sample from 2014 of the four northernmost counties in Sweden. The two longitudinal cohorts comprised the Northern Swedish Cohort and the Younger Northern Swedish Cohort, consisting of all pupils in the 9th grade of compulsory school in Luleå municipality in 1981 and 1989. The participants responded to an extensive questionnaire on socioeconomic factors, work and health, in 5 and 2 waves respectively of data collections. Neighbourhood register data from Statistics Sweden was also collected for all participants in the Northern Sweden Cohort. At the latest data collection, 94.3% (n=1010) participated in the Northern Sweden Cohort and 85.6% (n=686) in the Younger Northern Sweden Cohort. The cross-sectional study Health on Equal Terms is a national study, administered by the Public Health Agency together with Statistics Sweden and county councils with the aim of mapping public health and living conditions in the country over time. In this thesis, material from 2014 has been used for northern Sweden with a response rate of around 50% (effective sample n=12769). The statistical analyses used were linear regression, multilevel analysis and difference-in-difference analysis to estimate the concurrent and long-term health consequences of unemployment, and a decomposition analysis to disentangle the inequality in health between different labour market positions. The health outcomes in focus were functional somatic symptoms (the occurrence of relatively common physical illnesses such as head, muscle and stomach ache, insomnia and palpitation) and psychological distress.Results. Among men only, as little as one month of youth unemployment was related to increased levels of functional somatic symptoms in midlife, regardless of previous ill health or unemployment later in life, although only during relatively low national unemployment (pre-recession) when comparing with youth unemployment during high national unemployment (recession). This was explained by the health promoting effect of more time spent in higher education during the recession period. Furthermore, the health impact of neighbourhood unemployment highlights the importance of the contextual setting for individuals’ health both across the life course and at specific periods of life. Lastly, employment-related mental health inequalities exist for both men and women in all life phases (youth, adulthood and midlife). Economic and social deprivation related to unemployment and illness varied across different phases in life and across genders.Conclusion. The key findings of this thesis paint a rather pessimistic vision of the future: one’s own and others’ unemployment may cause not only ill health today but also ill health later in life. Importantly, the responsibility of unemployment and the associated ill health should not be placed on the already marginalised individuals and communities. Instead, the responsibility should be directed towards the structural aspects of society and the political choices that shape these. In other words, health inequality manifested by the position in the labour market is socially produced, unfair and changeable through political decisions. The results of this study therefore cannot contribute to any simple or concrete solutions to the concurrent or long-term health consequences of individual or contextual unemployment, as the solution is beyond the areas of responsibility and abilities of research. However, if there are long-term health consequences of one’s own and other people’s unemployment, labour market and public health policies should be initiated from a young age and continue throughout the life course to reduce individual suffering and future costs of social insurance, sick-leave and unemployment benefits.
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| 3. |
- Brydsten, Anna, 1984-, et al.
(author)
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Youth unemployment and functional somatic symptoms in adulthood : Results from the Northern Swedish cohort
- 2015
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In: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 25:5, s. 796-800
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Journal article (peer-reviewed)abstract
- Background: Little is known about the possible long-term health consequences of youth unemployment. Research indicates that unemployment may lead to socioeconomic downward mobility and mental health problems, but we still lack knowledge of the long-term health consequences of youth unemployment. This article examines the potential long-term association between youth unemployment and functional somatic symptoms in adulthood. Methods: The ‘Northern Swedish cohort’ was used with data from five data collections, from 1981 (age 16) until 2007 (age 42). Youth unemployment was measured as months in unemployment between age 16 and 21, and health outcome as functional somatic symptoms (an index of 10 items of self-reported symptoms). Linear regression was used to analyse the relationship between months in youth unemployment and functional somatic symptoms at age 21 and age 42, stratified for women and men and adjusted for potential confounders, such as time spent in education at age 21 and later unemployment between age 21 and 42. Results: Youth unemployment was significantly related to functional somatic symptoms at age 21 for men after controlling for confounders, but not for women. Among men, the association remained for functional somatic symptoms at age 42, after controlling for confounders. Conclusions: Adolescence seems to be a sensitive period during which unemployment could have remaining health effects in adulthood, at least for men, though assumptions of causality are tentative and more research is needed.
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| 4. |
- Brännlund, Annica, 1963-, et al.
(author)
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Education and health-lifestyle among men and women in Sweden : a 27-year prospective cohort study
- 2013
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In: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 41:3, s. 284-292
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Journal article (peer-reviewed)abstract
- Background: Previous research has found a positive association between health-behaviour and health. Only a few longitudinalstudies have been performed, and as far as we found, none have followed a cohort for 27 years. Methods: This study used acohort study, the “Northern Swedish Cohort”, which consisted of all graduates, n = 1080, from a compulsory school in aSwedish town. Data were collected with a comprehensive questionnaire; response rate 96.4%. Health-behaviour was analysedwith binary logistic regression, with health-behaviour at age 21, 30 and 43 years as dependent variable. Besides baselinehealth-behaviour, gender, somatic and psychological health and socioeconomic background, the analyses were adjustedfor work situation and social network. Results: The main findings were that education reduces the probability of unhealthybehaviour over the life course, which held after controlling for early life health-behaviour and possible confounders. Thegeneral education effect on health-behaviour was stronger among men than among women. Conclusions: Higher educationreduces the probability of unhealthy behavior. Thus, investments in higher education should be an important public goal.
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| 5. |
- de Miranda, Noel F. C. C., et al.
(author)
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DNA repair genes are selectively mutated in diffuse large B cell lymphomas
- 2013
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 210:9, s. 1729-1742
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Journal article (peer-reviewed)abstract
- DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.
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| 6. |
- Du, Likun, et al.
(author)
-
Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis
- 2012
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 209:2, s. 291-305
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Journal article (peer-reviewed)abstract
- Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
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| 7. |
- Elwér, Sofia, et al.
(author)
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Life course models of economic stress and poor mental health in mid-adulthood : Results from the prospective Northern Swedish Cohort
- 2015
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In: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 43:8, s. 833-840
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Journal article (peer-reviewed)abstract
- Aim: The aim was to analyse the association between economic stress during youth and adulthood, and poor mental health through life course models of (1) accumulation of risk and (2) sensitive period. Methods: The study was based on the Northern Sweden Cohort, a 26-year prospective cohort (N = 1010 in 2007; 94% of those participating in 1981 still alive) ranging from adolescence to middle age. Economic stress was measured at age 16, 21, 30 and 42 years. Two life course models of accumulation of risk and sensitive period were analysed using ordinal regression with internalized symptoms of mental health as outcome. Results: Exposure of economic stress at several life course periods was associated with higher odds of internalized mental health symptoms for both women and men, which supports the accumulated risk model. No support for a sensitive period was found for the whole sample. For men, however, adolescence appears to be a sensitive period during which the exposure to economic stress has negative mental health consequences later in life independently of economic stress at other ages. Conclusion: This study confirms that the duration of economic stress between adolescence and middle age is important for mental health. In addition, the results give some indication of a sensitive period of exposure to economic stress during adolescence for men, although more research is needed to confirm possible gender differences.
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| 8. |
- Eriksson, Mikael, et al.
(author)
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Low-Dose Tamoxifen for Mammographic Density Reduction : A Randomized Controlled Trial
- 2021
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In: Journal of Clinical Oncology. - 0732-183X. ; 39:17, s. 1899-
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Journal article (peer-reviewed)abstract
- PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms.PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis.RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.
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| 9. |
- Fortage, Jerome, et al.
(author)
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Charge-Transfer State and Large First Hyperpolarizability Constant in a Highly Electronically Coupled Zinc and Gold Porphyrin Dyad
- 2009
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 15:36, s. 9058-9067
-
Research review (peer-reviewed)abstract
- We report the synthesis and the characterizations of a novel dyad composed of a zinc porphyrin (ZnP) linked to a gold porphyrin (AuP) through an ethynyl spacer. The UV/Vis absorption spectrum and the electrochemical properties clearly reveal that this dyad exhibits a strong electronic coupling in the ground state as evidenced by shifted redox potentials and the appearance of an intense charge-transfer band localized at lambda = 739 nm in dichloromethane. A spectroelectrochemical study of the dyad along with the parent homometallic system (i.e., ZnP-ZnP and AuP-AuP) was undertaken to determine the spectra of the reduced and oxidized porphyrin units. Femtosecond transient absorption spectroscopic analysis showed that the photoexcitation of the heterometallic dyad leads to an ultrafast formation of a charge-separated state (+ZnP-AuP center dot) that displays a particularly long lifetime (tau=4 ns in toluene) for such a short separation distance. The molecular orbitals of the dyad were determined by DFT quantum-chemical calculations. This theoretical study confirms that the observed intense band at lambda = 739 nm corresponds to an interporphyrin charge-transfer transition from the HOMO orbital localized on the zinc porphyrin to LUMO orbitals localized on the gold porphyrin. Finally, a Hyper-Rayleigh scattering study shows that the dyad possesses a large first molecular hyperpolarizability coefficient (beta = 2100 x 10(-30) esu at lambda = 1064 nm), thus highlighting the valuable nonlinear optical properties of this new type of push-pull porphyrin system.
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| 10. |
- Fortage, Jerome, et al.
(author)
-
Charge transfer state and large first hyperpolarizability in a highly electronically coupled zinc and gold porphyrin dyad
- 2009
-
In: Chemistry - A European Journal. - 1521-3765 .- 0947-6539. ; 15:36, s. 9058-9067
-
Journal article (peer-reviewed)abstract
- We report the synthesis and the characterizations of a novel dyad composed of a zinc porphyrin (ZnP) linked to a gold porphyrin (AuP) through an ethynyl spacer. The UV/Vis absorption spectrum and the electrochemical properties clearly reveal that this dyad exhibits a strong electronic coupling in the ground state as evidenced by shifted redox potentials and the appearance of an intense charge-transfer band localized at lambda = 739 nm in dichloromethane. A spectroelectrochemical study of the dyad along with the parent homometallic system (i.e., ZnP-ZnP and AuP-AuP) was undertaken to determine the spectra of the reduced and oxidized porphyrin units. Femtosecond transient absorption spectroscopic analysis showed that the photoexcitation of the heterometallic dyad leads to an ultrafast formation of a charge-separated state (+ZnP-AuP center dot) that displays a particularly long lifetime (tau=4 ns in toluene) for such a short separation distance. The molecular orbitals of the dyad were determined by DFT quantum-chemical calculations. This theoretical study confirms that the observed intense band at lambda = 739 nm corresponds to an interporphyrin charge-transfer transition from the HOMO orbital localized on the zinc porphyrin to LUMO orbitals localized on the gold porphyrin. Finally, a Hyper-Rayleigh scattering study shows that the dyad possesses a large first molecular hyperpolarizability coefficient (beta = 2100 x 10(-30) esu at lambda = 1064 nm), thus highlighting the valuable nonlinear optical properties of this new type of push-pull porphyrin system.
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