| 1. |
- Duell, Eric J, et al.
(författare)
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Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort
- 2013
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Ingår i: Genes & Nutrition. - : Springer Berlin/Heidelberg. - 1555-8932 .- 1865-3499. ; 8:6, s. 549-560
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.
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| 2. |
- Feng, Xiaoshuang, et al.
(författare)
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Evaluation of pre-diagnostic blood protein measurements for predicting survival after lung cancer diagnosis
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Tidskriftsartikel (refereegranskat)abstract
- Background: To evaluate whether circulating proteins are associated with survival after lung cancer diagnosis, and whether they can improve prediction of prognosis.Methods: We measured up to 1159 proteins in blood samples from 708 participants in 6 cohorts. Samples were collected within 3 years prior to lung cancer diagnosis. We used Cox proportional hazards models to identify proteins associated with overall mortality after lung cancer diagnosis. To evaluate model performance, we used a round-robin approach in which models were fit in 5 cohorts and evaluated in the 6th cohort. Specifically, we fit a model including 5 proteins and clinical parameters and compared its performance with clinical parameters only.Findings: There were 86 proteins nominally associated with mortality (p < 0.05), but only CDCP1 remained statistically significant after accounting for multiple testing (hazard ratio per standard deviation: 1.19, 95% CI: 1.10–1.30, unadjusted p = 0.00004). The external C-index for the protein-based model was 0.63 (95% CI: 0.61–0.66), compared with 0.62 (95% CI: 0.59–0.64) for the model with clinical parameters only. Inclusion of proteins did not provide a statistically significant improvement in discrimination (C-index difference: 0.015, 95% CI: −0.003 to 0.035).Interpretation: Blood proteins measured within 3 years prior to lung cancer diagnosis were not strongly associated with lung cancer survival, nor did they importantly improve prediction of prognosis beyond clinical information.
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| 3. |
- Feng, Xiaoshuang, et al.
(författare)
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Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools
- 2023
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 115:9, s. 1050-1059
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test.METHODS: We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided.RESULTS: The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference = .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model.CONCLUSION: Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung.
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| 4. |
- Henriksson, Roger, et al.
(författare)
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Brain Tumors - Prognostic and Predictive Markers
- 2009
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Ingår i: Histological and Serological Tumor Markers and Gene Expression and Their Clinical Usefulness in Cancers. - Hauppauge : Nova Science Publishers, Inc.. - 9781607413820 ; , s. 53-75
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Bokkapitel (refereegranskat)abstract
- This review summarizes the status of prognostic and predictive markers in brain tumors with a focus on the most frequent tumors, gliomas. Brain tumors are a heterogeneous group of different tumors with a huge variation in outcome. Although the most common tumor, high-grade malignant glioma, still has a dismal prognosis, the last years have seen a significant improvement in the management in this tumor as well as in most other brain tumors. Age, tumor grade and KPS are still the most reliable prognostic and predictive variables available for patients with brain tumors. Although chromosome 1p/19q co-deletion and methylation status of the promoter of the MGMT gene (encoding O6-methylguanine-DNA methyl transferase) have been identified as the most promising potential predictors of response to chemotherapy in malignant gliomas, there are as yet no reliable biomarkers for tumour grading or tumour monitoring in the clinical setting.
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| 5. |
- Johansson, David, et al.
(författare)
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Adenylate cyclase toxin from Bordetella pertussis enhances cisplatin-induced apoptosis to lung cancer cells in vitro.
- 2006
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Ingår i: Oncology Research. - 0965-0407 .- 1555-3906. ; 15:9, s. 423-430
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Tidskriftsartikel (refereegranskat)abstract
- The present study examined the possibility to enhance lung cancer cell cytotoxicity and apoptosis of the anticancer drug cisplatin by exposure with adenylate cyclase (AC) toxin from Bordetella pertussis. A malignant mesothelioma cell line (P31) and a small-cell lung cancer cell line (U1690) were exposed to increasing concentrations of cisplatin and AC toxin, alone or in combination. Cytotoxicity was determined by a fluorescein-based assay and apoptosis by flow cytometry quantification of annexin V binding. Caspase-3, -8, and -9 activities were measured by enzyme activity assays. The cytotoxicity of AC toxin was time and dose dependent with an LD50 value at 72 h of 3 and 7 mg/L for P31 cells and U1690 cells, respectively. Cisplatin showed a similar time- and dose-dependent cytotoxicity, which was increased in the presence of a low toxic concentration (1 mg/L) of AC toxin. Furthermore, cisplatin caused a dose-dependent increase of annexin V binding cells of both cell lines after 24-h incubation, which was also enhanced in combination with AC toxin. AC toxin (1 mg/L) increased cisplatin-induced caspase-3, -8, and -9 activities in U1690 cells. Only minor increases of caspase-8 and -9 were noted for P31 cells. The present results, together with the knowledge that bacterial toxins decrease side effects of traditional cancer treatment, suggest a possibility to use them to enhance the therapeutic effect of cancer chemotherapy with reduced clinical adverse effects.
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| 6. |
- Johansson, David, 1979-
(författare)
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Bacterial toxins for cancer treatment
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Even though anti‐cancer chemotherapy has been continuously improved during the last decades. problems with adverse effects and drug resistance still constitutes a considerable obstacle and sets a demand for new effective treatment options. Tissue homeostasis in multi‐cellular organisms is maintained through intrinsic cell death, apoptosis, which removes unwanted or damaged cells. Disrupted apoptosis is an important factor in tumorgenesis and drug resistance, therefore induction or restoration of apoptotic pathways is also important for the treatment of cancer. Several naturally occurring bacterial toxins have the ability to induce apoptosis and could thus be candidates to complement or improve the therapeutic effect of other anticancer drugs. The bacterial toxins, adenylate cyclase (AC) toxin from Bordetella pertussis, α‐toxin from Staphylococcus aureus and verotoxin‐1 (VT‐1) from Escherichia coli were investigated for their ability to induce apoptosis in different tumor cell lines. Toxin induction of cell death was investigated by cell viability assays, end‐stage apoptosis induction by DNA‐fregmentation (TUNEL) assay. Toxin receptor expression and signal transduction pathways to apoptosis were investigated by flow cytometry, caspase enzyme activity assays and western blot. Immunohistochemistry was used for identification of toxin receptor expression in tumor tissue samples. AC‐toxin was cytotoxic and induced apoptosis in cultured malignant plural mesothelioma (MPM) and small‐cell lung cancer (SCLC) cells. Low‐toxic concentrations of AC‐toxin enhanced cisplatin cytotoxicity and apoptosis in both cell lines. MPM‐cells with acquired cisplatin resistance were more sensitive to α‐toxin than the less resistant parental MPM cell line. A low‐toxic concentration of α‐toxin re‐sensitized resistant MPM cells to cisplatin cytotoxicity by apoptosis induced through the mitochondrial pathway without detectable activation of common up‐stream apoptosis signalling proteins. VT‐1 was highly cytotoxic and induced apoptosis in globotriosylceramide (Gb3) ‐expressing glioma, breast cancer and non‐small‐cell lung cancer (NSCLC) cells but was not cytotoxic to non‐Gb3‐expressing cells. PPMP, an inhibitor of glucosylceramide synthesis which makes exposed cells unable to synthesize Gb3 rendered Gb3‐expressing cells resistant to VT‐1. MPM cells with acquired‐cisplatin resistance expressed Gb3 in contrast to the absent of expression in the less resistant parental cell line. Gb3, could however be up‐regulated by cisplatin in Gb3‐negative MPM‐cells. Presence of a low‐toxic concentration of VT‐1 potentiated cisplatin‐induced cytotoxicity and apoptosis in the cisplatin‐resistance MPM cell line. VT‐1 was a potent inducer of apoptosis, probably via stress‐induced Mitogen‐activated protein kinase (MAPK)‐signaling involving c‐Jun N‐terminal kinase (JNK) and p38, leading to disruption of the mitochondrial membrane integrety, activation of caspase‐9 and ‐3, and ultimately DNA fragmentation and cell death. Gb3 expression was demonstrated in clinical specimens of glioblastoma and breast cancer making these tumor types interesting for further VT‐1 studies. We conclude that bacterial toxins may be used to induce apoptosis in several types of cancer cells. Low concentrations of verotoxin‐1 and α‐toxin may potentially be used to overcome acquired cisplatin‐resistance in cancer patients.
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| 7. |
- Johansson, David, et al.
(författare)
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Verotoxin-1 Induction of Apoptosis in Gb3-Expressing Human Glioma Cell Lines
- 2006
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Ingår i: Cancer Biology & Therapy. - 1538-4047 .- 1555-8576. ; 5:9, s. 1211-1217
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine the cytotoxicity and mechanism of apoptosis induction of verotoxin-1 (VT-1) in human glioma cell lines. VT-1 is a member of the shiga-toxin family expressed by some serotypes of Escherichia coli and Shigella dysenteriae. Shiga-toxins have been shown to induce apoptosis by binding to its membrane receptor Gb3. The human glioma cell lines SF-767, U-343 MG, and U-251 MG were studied together with BT4C, a rat glioma cell line. Cells were first screened for Gb3 expression by flow cytometry. Fluorescein diacetate was used to determine cell viability after VT-1 and irradiation exposure and apoptosis was studied by TUNEL staining, a mitochondrial membrane potential assay, and caspase activity assays. SF-767 and U-343 MG cells were found to express Gb3 and were also sensitive to VT-1-induced cytotoxicity, whereas nonGb3-expressing U-251 MG and BT4C glioma cells were not. VT-1 depolarized the mitochondrial membrane and activated caspase-9 and -3 of SF-767 and U-343 MG cells. VT-1 exposure for 72 h resulted in approx. 60 and 90% TUNEL-stained cells, respectively. D, L-Threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) an inhibitor of glucosylceramide synthesis was used to block Gb3 synthesis. Two mumol/L PPMP for 72 h abolished SF-767 and U-343 MG expression of Gb3 and made the cells completely resistant to VT-1 induced apoptosis. Key components of MAP kinase signalling pathways that control BAX and mitochondrial function were investigated. VT-1 induced JNK phosphorylation in both cell lines, suggesting that survival signal pathways were overruled by VT-1-induced JNK activation leading to mitochondrial depolarization, caspase-9 activation and apoptosis. Immunohistochemistry of cryostat section from glioma biopsies demonstrated expression of Gb3 was in the vascular endothelial cells as well as tumor cells, but not in astrocytes. The high specificity and apoptosis inducing properties of verotoxin-1 indicates that the toxin may be a potential anti-neoplastic agent for Gb3-expressing gliomas.
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| 8. |
- Johansson, Gun-Britt, 1956-
(författare)
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Synderskan och lagen: Barnamord i tre Norrlandslän 1830-1870
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACTMany studies have been conducted on infanticide and child homicide. Researchers have approached the subject with different theoretical frameworks and explored it from different dimensions, geographical areas, and time periods. As much as the questions have varied so have the answers. This study contributes to greater clarity on the causes of infanticide. Despite numerous studies on the subject, there is still no consensus its causes. My aim has been to combine different strategies for understanding the subject. I have used material both from an aggregated level and from an individual level. The main question I sought to answer was whether social causes rather than individual factors force or trigger women to kill their newborn child? Court material also provides for an in-depth understanding of our history. The social sciences have frequently drawn sketches of the social world with big lines. These lines have been necessary and useful to point at large-scale transformations of civilisation and modernisation but, in terms of understanding real life, they can provide us with a foggy and even mistaken picture. When social scientists enter the historical archives and similar sources, we often blunder in its richness and variation. Society may, in any case, have always been complicated and the every day life for each person as well.My findings show that infanticide signals low tolerance. In general, the women did not want to kill their own children. Moreover, my findings, like the results of other studies before mine, demonstrate that women who carry out infanticide represent normal women. To my knowledge, there isn’t one study on infanticide that claims the women were not normal. Women who committed infanticide did so out of fear: fear of losing their social bonds. They killed their children if the existence of the bonds was endangered or threatened. Often social bonds were related to their work situation as maids in farming households. If they couldn’t stay in the household after having the baby, many women had no where else to go. Their parents – poor, elderly or deceased – were unable to help. Sometimes the social bonds were threatened by other factors, often related to the child’s father. If he was already married or had a close relation with the woman’s family, their relationship could in fact, break her bonds to her own family and other relatives. Some women already had an illegitimate child. With a child out of wedlock, they had a difficult time getting work and housing. If they got pregnant again and the father to the new child refused to marry her or to support the child, she could in fact lack any resources for handling the situation.Finally: the findings talk about honour and infanticide. It was always shameful to get a child out of wedlock. But demographic research from North of Sweden has shown that these children had almost the same chances of survival during their first year as legitimate children. Sexuality outside marriage was not respected but much discussion around honour was more related to how the women would manage with the child. In my findings, shame seems to be related to having no support. Extramarital relations were not accepted but people probably didn’t care to much about it as far as they managed on their own. Being rejected, helpless, not able to work and not able to take care of the child that was what shame was about.Keywords: Infanticide, child homicide, illegitimacy, social bonds, shame
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| 9. |
- Marushchak, Denys, et al.
(författare)
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Fluorescence Depolarisation Studies of Filamentous Actin Analysed with a Genetic Algorithm
- 2007
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Ingår i: Biophysical Journal. - : CellPress. - 0006-3495 .- 1542-0086. ; 93:9, s. 3291-3299
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Tidskriftsartikel (refereegranskat)abstract
- A new method, in which a genetic algorithm was combined with Brownian dynamics and Monte Carlo simulations, was developed to analyze fluorescence depolarization data collected by the time-correlated single photon-counting technique. It was applied to studies of BODIPY-labeled filamentous actin (F-actin). The technique registered the local order and reorienting motions of the fluorophores, which were covalently coupled to cysteine 374 (C374) in actin and interacted by electronic energy migration within the actin polymers. Analyses of F-actin samples composed of different fractions of labeled actin molecules revealed the known helical organization of F-actin, demonstrating the usefulness of this technique for structure determination of complex protein polymers. The distance from the filament axis to the fluorophore was found to be considerably less than expected from the proposed position of C374 at a high filament radius. In addition, polymerization experiments with BODIPY-actin suggest a 25-fold more efficient signal for filament formation than pyrene-actin.
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| 10. |
- Muller, David C., et al.
(författare)
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Circulating high sensitivity C reactive protein concentrations and risk of lung cancer : nested case-control study within Lung Cancer Cohort Consortium
- 2019
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Ingår i: The BMJ. - : BMJ Publishing Group Ltd. - 1756-1833 .- 0959-8138. ; 364
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.Design Nested case-control study.Setting 20 population based cohort studies in Asia, Europe, Australia, and the United States.Participants 5299 patients with incident lung cancer, with individually incidence density matched controls.Exposure Circulating hsCRP concentrations in prediagnostic serum or plasma samples.Main outcome measure Incident lung cancer diagnosis.Results A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.Conclusions Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.
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