| 1. |
- Alexeyev, Oleg, et al.
(författare)
-
Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden)
- 2006
-
Ingår i: Cancer Causes and Control. - Dordrecht : Kluwer Academic Publishers. - 0957-5243 .- 1573-7225. ; 17:9, s. 1127-1133
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To study bacterial 16S RNA in archival prostate samples from 352 patients with benign prostate hyperplasia (BPH) and evaluate whether the presence of bacterial DNA was different in those who later developed prostate cancer (n = 171) and in the matched controls that did not progress to cancer (n = 181).Methods: 16S DNA PCR followed by cloning and sequencing the positive samples.Results: In 96/352 (27%) of the prostate tissue specimens 16S RNA were detected. Sequence analysis revealed Propionibacterium acnes as the predominant microorganism (23% of 16S RNA positive patients). The second most frequent isolate—Escherichia coli was found in 12 (12%) patients. The other isolates included Pseudomonas sp. (3 patients), Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2),Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P. acnes positive samples 62% exhibited severe histological inflammation versus 50% in the bacteria-negative group (p = 0.602). The presence of P. acnes in the prostate was associated with prostate cancer development (OR 2.17, 95% CI 0.77–6.95).Conclusions: This study has revealed P. acnes as the most common bacteria in the prostate in BPH. Further studies are needed to clarify its role in contributing to the development of prostatic inflammation and prostate cancer.
|
|
| 2. |
- Bergh, Johanna, et al.
(författare)
-
No link between viral findings in the prostate and subsequent cancer development
- 2007
-
Ingår i: British Journal of Cancer. - London : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 96:1, s. 137-139
-
Tidskriftsartikel (refereegranskat)abstract
- In an investigation of 201 prostate tissue samples from patients with benign prostate hyperplasia that later progressed to prostate cancer and 201 matched controls that did not, there were no differences in the prevalence of adenovirus, herpesvirus, papilloma virus, polyoma virus and Candida albicans DNA.
|
|
| 3. |
- Brown, David A, et al.
(författare)
-
Macrophage inhibitory cytokine 1 : a new prognostic marker in prostate cancer.
- 2009
-
Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 15:21, s. 6658-6664
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: High serum levels of macrophage inhibitory cytokine 1 (MIC-1) are strongly associated with metastatic prostate cancer, suggesting MIC-1 is a biomarker for prostate cancer prognosis. EXPERIMENTAL DESIGN: We conducted a prospective cohort study of 1,442 Swedish men with a pathologically verified diagnosis of prostate cancer between 2001 and 2003. Blood was drawn either pretreatment (n = 431) or posttreatment (n = 1,011) and cases were followed for a mean time of 4.9 years (range, 0.1-6.8 years). RESULTS: MIC-1 serum levels independently predicted poor cancer-specific survival with an almost 3-fold higher cancer death rate in patients with serum levels in the highest quartile compared with men with serum levels in the lowest quartile (adjusted hazard ratio, 2.98; 95% confidence interval, 1.82-4.68). Pretreatment MIC-1 levels revealed an even stronger association with disease outcome with an 8-fold higher death rate in the highest compared with the lowest category (adjusted hazard ratio, 7.98; 95% confidence interval, 1.73-36.86). Among patients considered to have localized disease, MIC-1 significantly increased the discriminative capacity between indolent and lethal prostate cancer compared with the established prognostic markers clinical stage, pathologic grade, and prostate-specific antigen level (P = 0.016). A sequence variant in the MIC-1 gene was associated with decreased MIC-1 serum levels (P = 0.002) and decreased prostate cancer mortality (P = 0.003), suggesting a causative role of MIC-1 in prostate cancer prognosis. CONCLUSIONS: Serum MIC-1 concentration is a novel biomarker capable of predicting prostate cancer prognosis.
|
|
| 4. |
- Lindberg, Johan, et al.
(författare)
-
The Mitochondrial and Autosomal Mutation Landscapes of Prostate Cancer
- 2013
-
Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 63:4, s. 702-708
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer (PCa) is the most common cancer in men. PCa is strongly age associated; low death rates in surveillance cohorts call into question the widespread use of surgery, which leads to overtreatment and a reduction in quality of life. There is a great need to increase the understanding of tumor characteristics in the context of disease progression. Objective: To perform the first multigenome investigation of PCa through analysis of both autosomal and mitochondrial DNA, and to integrate exome sequencing data, and RNA sequencing and copy-number alteration (CNA) data to investigate how various different tumor characteristics, commonly analyzed separately, are interconnected. Design, setting, and participants: Exome sequencing was applied to 64 tumor samples from 55 PCa patients with varying stage and grade. Integrated analysis was performed on a core set of 50 tumors from which exome sequencing, CNA, and RNA sequencing data were available. Outcome measurements and statistical analysis: Genes, mutated at a significantly higher rate relative to a genomic background, were identified. In addition, mitochondrial and autosomal mutation rates were correlated to CNAs and proliferation, assessed as a cell cycle gene expression signature. Results and limitations: Genes not previously reported to be significantly mutated in PCa, such as cell division cycle 27 homolog (Saccharomyces cerevisiae) (CDC27), myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3), lysine (K)-specific demethylase 6A (KDM6A), and kinesin family member 5A (KIF5A) were identified. The mutation rate in the mitochondrial genome was 55 times higher than that of the autosomes. Multilevel analysis demonstrated a tight correlation between high reactive-oxygen exposure, chromosomal damage, high proliferation, and in parallel, a transition from multiclonal indolent primary PCa to monoclonal aggressive disease. As we only performed targeted sequence analysis; copy-number neutral rearrangements recently described for PCa were not accounted for. Conclusions: The mitochondrial genome displays an elevated mutation rate compared to the autosomal chromosomes. By integrated analysis, we demonstrated that different tumor characteristics are interconnected, providing an increased understanding of PCa etiology. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Schwenk, Jochen M., et al.
(författare)
-
Toward Next Generation Plasma Profiling via Heat-induced Epitope Retrieval and Array-based Assays
- 2010
-
Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 9:11, s. 2497-2507
-
Tidskriftsartikel (refereegranskat)abstract
- There is a need for high throughput methods for screening patient samples in the quest for potential biomarkers for diagnostics and patient care. Here, we used a combination of undirected target selection, antibody suspension bead arrays, and heat-induced epitope retrieval to allow for protein profiling of human plasma in a novel and systematic manner. Several antibodies were found to reveal altered protein profiles upon epitope retrieval at elevated temperatures with limits of detection improving into lower ng/ml ranges. In a study based on prostate cancer patients, several proteins with differential profiles were discovered and subsequently validated in an independent cohort. For one of the potential biomarkers, the human carnosine dipeptidase 1 protein (CNDP1), the differences were determined to be related to the glycosylation status of the targeted protein. The study shows a path of pursuit for large scale screening of biobank repositories in a flexible and proteome-wide fashion by utilizing heat-induced epitope retrieval and using an antibody suspension bead array format. Molecular & Cellular Proteomics 9:2497-2507, 2010.
|
|
| 8. |
- Speliotes, Elizabeth K., et al.
(författare)
-
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
|
|
| 9. |
- Wiklund, Fredrik E, et al.
(författare)
-
Macrophage inhibitory cytokine-1 (MIC-1/GDF15) : a new marker of all-cause mortality
- 2010
-
Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 9:6, s. 1057-1064
-
Tidskriftsartikel (refereegranskat)abstract
- Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine whether serum MIC-1/GDF15 estimation is a predictor of all-cause mortality, we examined a cohort of 876 male subjects aged 35-80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) available. Patients were followed for up to 14 years and had cause-specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38-8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality.
|
|
| 10. |
- Adams, Charleen, et al.
(författare)
-
Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study
- 2019
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:1, s. 208-216
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
|
|
| 11. |
|
|
| 12. |
- Agarwal, Prasoon, et al.
(författare)
-
Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:6, s. 6809-6923
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.
|
|
| 13. |
- Agarwal, Prasoon, et al.
(författare)
-
The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.
|
|
| 14. |
- Alzrigat, Mohammad, et al.
(författare)
-
EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
- 2017
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:6, s. 10213-10224
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
|
|
| 15. |
- Alzrigat, Mohammad
(författare)
-
Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma : Implications for Biology and Therapy
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples. These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.
|
|
| 16. |
- Alzrigat, Mohammad, et al.
(författare)
-
The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
- 2017
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:61, s. 103731-103743
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
|
|
| 17. |
- Amundadottir, Laufey T., et al.
(författare)
-
A common variant associated with prostate cancer in European and African populations
- 2006
-
Ingår i: Nature Genetics. - DeCODE Genet, IS-101 Reykjavik, Iceland. Univ Iceland, Landspitali Hosp, Dept Pathol, IS-101 Reykjavik, Iceland. Univ Iceland, Landspitali Hosp, Dept Urol, IS-101 Reykjavik, Iceland. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Orebro Univ Hosp, Dept Urol & Clin Med, Orebro, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 38:6, s. 652-658
-
Tidskriftsartikel (refereegranskat)abstract
- With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.
|
|
| 18. |
- Andersson, Jonas, et al.
(författare)
-
Dysregulation of subcutaneous adipose tissue blood flow in overweight postmenopausal women
- 2010
-
Ingår i: Menopause. - : Ovid Technologies (Wolters Kluwer Health). - 1072-3714 .- 1530-0374. ; 17:2, s. 365-371
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: A putative link between abdominal obesity and metabolic-vascular complications after menopause may be due to a decreased adipose tissue blood flow (ATBF). The present work aimed to analyze possible changes in ATBF with being overweight and menopausal and its putative link to endothelial dysfunction and autonomic nervous system balance.METHODS: Forty-three healthy women were classified into four groups according to weight and menopause status. The ATBF was measured by xenon washout while fasting and after oral glucose intake. The nitric oxide synthase inhibitor asymmetric dimethylarginine was used as a marker of endothelial function and heart rate variability-estimated autonomic nervous system activity.RESULTS: Fasting ATBF was decreased in both overweight groups (P = 0.044 and P = 0.048) versus normal-weight premenopausal women. Normal-weight and overweight postmenopausal women exhibited lower maximum ATBF compared with normal-weight premenopausal women (P = 0.015 and P = 0.001, respectively), and overweight postmenopausal women exhibited lower maximum ATBF compared with normal-weight postmenopausal women (P = 0.003). A negative correlation was found between fasting ATBF and asymmetric dimethylarginine (P = 0.015), whereas maximum ATBF was negatively associated with sympathetic-parasympathetic nervous system balance (ratio of the power of the low frequency to the power of the high frequency; P = 0.002).CONCLUSIONS: Loss of ATBF flexibility in overweight postmenopausal women may contribute to the metabolic dysfunction seen in this group of women.
|
|
| 19. |
|
|
| 20. |
- Andersson, Ulrika, et al.
(författare)
-
A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk
- 2010
-
Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 12, s. 17-17
-
Tidskriftsartikel (refereegranskat)abstract
- Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.
|
|
| 21. |
|
|
| 22. |
- Atienza-Párraga, Alba, et al.
(författare)
-
Epigenomic re-configuration of primary multiple myeloma underlies the synergistic effect of combined DNMT and EZH2 inhibition.
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is characterized by an overexpression of EZH2 and a subsequent increase in H3K27me3-mediated silencing. However, the genome-wide redistribution of this mark in context with other epigenetic tags remains largely unexplored. Here, we show that EZH2 physically interacts with DNMT1 and that combined inhibition leads to a reduced G2/M arrest and increased apoptosis in MM. In addition, we present a catalogue of the genomic regulatory regions in normal plasma cells (NPC) as defined by their individual combination of histone marks. We used ChIP-seq and ATAC-seq data to generate whole-genome NPC chromatin annotations which we further analysed using DNA methylation arrays and RNA-seq. Comparison between NPC and MM demonstrated that, despite the global hypomethylation, enhancers show a tendency towards a higher DNA methylation levels in MM, whereas Polycomb and heterochromatic sites, highly methylated in NPC, show intermediate levels of the mark. Across all examined regulatory regions, 5-azacytidine treatment strongly reduced DNA methylation in MM. Furthermore, we find an extensive re-structuration of the global histone patterns in MM. We noticed a widespread increase in H3K27me3 except at active TSSs/promoters and enhancers, where we found a selective gain of the mark, suggestive of a directed silencing. In contrast, poised TSSs lose H3K27me3 and gain the activation mark H3K27ac, reflecting potential activation. Taken together, we present a comprehensive map of the epigenomic changes in MM as compared to NPC and provide insights into the interplay between EZH2 and DNMT1 in MM.
|
|
| 23. |
- Bailey-Wilson, Joan E, et al.
(författare)
-
Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families
- 2012
-
Ingår i: BMC Medical Genetics. - London : BioMed Central. - 1471-2350. ; 13, s. 46-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.Methods: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.Results: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.Conclusions: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
|
|
| 24. |
|
|
| 25. |
- Bankel, Johan, et al.
(författare)
-
The CDIO syllabus: a comparative study of expected student proficiency
- 2003
-
Ingår i: European Journal of Engineering Education. - : Taylor & Francis. - 0304-3797 .- 1469-5898. ; 28:3, s. 297-315
-
Tidskriftsartikel (refereegranskat)abstract
- Engineering students must graduate with command of a vast body of technical knowledge. They must possess personal, interpersonal and system-building skills to function in teams, and be prepared to produce products and systems. Their education must have been structured under a curriculum blending ability to combine technical expertise with ethical, innovative, philosophical and humanistic acumen. This paper describes a unique international collaboration among four universities to reform engineering education. The collaborators agreed to a statement of goals, which includes descriptions of knowledge, skills and attitudes vital to an effective education, and codifies proficiency levels expected of graduates. We developed and utilized unique stakeholder surveys both to validate our prototype and to determine desired proficiency levels. This collaboration resulted in The CDIO Syllabus, A Statement of Goals for Undergraduate Engineering Education. The syllabus is both a template and a process that can be used to customize the syllabus to others' programmes. It can define new educational initiatives/and be employed as the basis for rigorous assessment. This paper details how, with the input of industry, academia and others, we employed an engineering problem-solving paradigm to effect our redesign. It outlines the syllabus and the unique process employed to create it.
|
|
| 26. |
|
|
| 27. |
- Bergh, Jonas, et al.
(författare)
-
FACT : An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer
- 2012
-
Ingår i: Journal of Clinical Oncology. - Alexandria, VA : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:16, s. 1919-1925
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer. Patients and Methods: Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor– and/or progesterone receptor–positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP). Results: In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus standard arm, respectively (hazard ratio [HR] = 0.99; 95% CI, 0.81 to 1.20; P = .91); median overall survival was 37.8 and 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023). Death owing to AEs was reported in 11 (4.3%) and five patients (2.0%) in the experimental versus standard arm, respectively. Conclusion: Fulvestrant (250 mg + LD regimen) in combination with anastrozole offered no clinical efficacy advantage over anastrozole monotherapy in this population of individuals with a relatively high proportion of previous adjuvant antiestrogen exposure.
|
|
| 28. |
- Bergqvist, Michael, et al.
(författare)
-
Real world utilization of EGFR TKIs and prognostic factors for survival in NSCLC during 2010-2016 in Sweden : A nationwide observational study
- 2020
-
Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:9, s. 2510-2517
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of our study was to investigate time trends in treatment pattern and prognostic factors for overall survival (OS) in epidermal growth factor receptor (EGFR) targeting tyrosine kinase inhibitors (TKIs) treated nonsmall cell lung cancer (NSCLC) patients. Utilizing Swedish nationwide registers, we identified all Stage IIIB-IV NSCLC patients treated with EGFR TKIs and followed them from diagnosis (2010-2015) until death or end of observation (2016). Multivariable Cox regression analyses were performed to test associations of patient-, tumor-related factors with OS. Of 9,992 Stage IIIB-IV NSCLC patients, the 1,419 (14%) who initiated EGFR TKI treatment during observation were younger (median age 68 vs. 71 years), less >= 1 comorbidities (34% vs. 46%), more often female (59% vs. 47%), Stage IV (89% vs. 85%) and adenocarcinoma (85% vs. 66%) compared to non-TKI treated patients. After TKI initiation, 7% (n = 100) of the patients switched, 4% (n = 62) rechallenged a TKI treatment, 65% (n = 919) discontinued and 24% (n = 338) had died. A more recent diagnosis demonstrated shorter time to EGFR TKI initiation, prolonged treatment length and longer median OS (15.3 months 2010-2011; 14.4 months 2012-2013; 18.6 months 2014-2015). Prognostic factors for longer OS when treated with EGFR TKIs were younger age, adenocarcinoma, less advanced clinical stage and less comorbid disease. In conclusion, during the observation period, survival improved for EGFR TKI treated NSCLC patients, as did the accessibility for targeted therapies for these patients.
|
|
| 29. |
- Berndt, Sonja I, et al.
(författare)
-
Large-scale fine mapping of the HNF1B locus and prostate cancer risk
- 2011
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3322-3329
-
Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.
|
|
| 30. |
- Bolin, Sara, 1988-, et al.
(författare)
-
Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence
-
Tidskriftsartikel (refereegranskat)abstract
- Tumor recurrence is a slow biological process involving therapy resistance, immune escape, and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified a significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two-thirds of medulloblastoma. To follow relapse at the single-cell level we developed an inducible dual Tet model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells by doxycycline. SOX9 promoted immune es-cape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory, and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.
|
|
| 31. |
- Bonn, Stephanie E., et al.
(författare)
-
Body mass index and weight change in men with prostate cancer : progression and mortality
- 2014
-
Ingår i: Cancer Causes and Control. - : Springer Netherlands. - 0957-5243 .- 1573-7225. ; 25:8, s. 933-943
-
Tidskriftsartikel (refereegranskat)abstract
- Body mass index (BMI) is a modifiable lifestyle factor that has been associated with an increased risk of fatal prostate cancer and biochemical recurrence. The main purpose of the present study was to investigate the association between the exposure BMI at the time of a prostate cancer diagnosis and weight change after diagnosis, and the outcomes of prostate cancer progression and mortality in a large cohort study. Data from 4,376 men diagnosed with clinically localized prostate cancer between 1997 and 2002 were analyzed. BMI and weight change were self-reported in 2007. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated in complete-case analysis (n = 3,214) using Cox proportional hazards models. Progression was experienced among 639 (14.6 %) of the study participants, and in total, 450 (10.3 %) deaths of any cause and 134 (3.1 %) prostate cancer-specific deaths were recorded during follow-up. Obese men had a 47 % increased rate of overall mortality compared to normal weight men (HR 1.47, 95 % CI 1.03-2.10). No statistically significant associations were found for BMI and prostate cancer progression or prostate cancer-specific mortality. A weight loss > 5 % after diagnosis almost doubled the rate of overall mortality compared to maintaining a stable weight (HR 1.94, 95 % CI 1.41-2.66), while a weight gain > 5 % was associated with an almost doubled increased rate of prostate cancer-specific mortality (HR 1.93, 95 % CI 1.18-3.16). Being obese was associated with an increased rate of overall mortality, and gaining weight after a prostate cancer diagnosis was associated with an increased rate of prostate cancer-specific mortality.
|
|
| 32. |
- Bonn, Stephanie E., et al.
(författare)
-
Body mass index in relation to serum prostate-specific antigen levels and prostate cancer risk
- 2016
-
Ingår i: International Journal of Cancer. - : WILEY-BLACKWELL. - 0020-7136 .- 1097-0215. ; 139:1, s. 50-57
-
Tidskriftsartikel (refereegranskat)abstract
- High Body mass index (BMI) has been directly associated with risk of aggressive or fatal prostate cancer. One possible explanation may be an effect of BMI on serum levels of prostate-specific antigen (PSA). To study the association between BMI and serum PSA as well as prostate cancer risk, a large cohort of men without prostate cancer at baseline was followed prospectively for prostate cancer diagnoses until 2015. Serum PSA and BMI were assessed among 15,827 men at baseline in 2010-2012. During follow-up, 735 men were diagnosed with prostate cancer with 282 (38.4%) classified as high-grade cancers. Multivariable linear regression models and natural cubic linear regression splines were fitted for analyses of BMI and log-PSA. For risk analysis, Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) and natural cubic Cox regression splines producing standardized cancer-free probabilities were fitted. Results showed that baseline Serum PSA decreased by 1.6% (95% CI: -2.1 to -1.1) with every one unit increase in BMI. Statistically significant decreases of 3.7, 11.7 and 32.3% were seen for increasing BMI-categories of 25<30, 30<35 and 35 kg/m(2), respectively, compared to the reference (18.5<25 kg/m(2)). No statistically significant associations were seen between BMI and prostate cancer risk although results were indicative of a positive association to incidence rates of high-grade disease and an inverse association to incidence of low-grade disease. However, findings regarding risk are limited by the short follow-up time. In conclusion, BMI was inversely associated to PSA-levels. BMI should be taken into consideration when referring men to a prostate biopsy based on serum PSA-levels. What's new? High body mass index (BMI) has been associated with risk of aggressive or fatal prostate cancer. One possible explanation may be an effect on serum prostate-specific antigen (PSA) levels. Here, the authors assessed the association between BMI and serum PSA level and prostate cancer risk in a large prospective cohort study. While no statistically significant associations were found between BMI and overall risk of prostate cancer, increasing BMI was associated with decreased serum PSA levels among men with no previous prostate cancer diagnosis. BMI should be taken into consideration when referring men to a prostate biopsy based on PSA-test results.
|
|
| 33. |
- Bonn, Stephanie E., et al.
(författare)
-
Physical Activity and Survival among Men Diagnosed with Prostate Cancer
- 2015
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 24:1, s. 57-64
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Few studies have investigated the association between post-diagnosis physical activity and mortality among men diagnosed with prostate cancer. The aim of this study was to investigate the effect of physical activity after a prostate cancer diagnosis on both overall and prostate cancer-specific mortality in a large cohort. Methods: Data from 4,623 men diagnosed with localized prostate cancer 1997-2002 and followed-up until 2012 were analyzed. HRs with 95% confidence intervals (CI) were estimated using Cox proportional hazards models to examine the association between post-diagnosis recreational MET-h/d, time spent walking/bicycling, performing household work or exercising, and time to overall and prostate cancer-specific death. All models were adjusted for potential confounders. Results: During the follow-up, 561 deaths of any cause and 194 deaths from prostate cancer occurred. Statistically significantly lower overall mortality rates were found among men engaged in 5 recreationalMET-h/d (HR, 0.63; 95% CI, 0.52-0.77), walking/ bicycling 20 min/d (HR, 0.70; 95% CI, 0.57-0.86), performing householdwork > 1 h/d (HR, 0.71; 95% CI, 0.59-0.86), or exercising > 1 h/wk (HR, 0.74; 95% CI, 0.61-0.90), compared with less active men within each activity type. For prostate cancer-specific mortality, statistically significantly lower mortality rates were seen among men walking/bicycling >= 20 min/d (HR, 0.61; 95% CI, 0.43-0.87) or exercising 1 h/wk (HR, 0.68; 95% CI, 0.48-0.94). Conclusions: Higher levels of physical activity were associated with reduced rates of overall and prostate cancer-specific mortality. Impact: Our study further strengthens previous results indicating beneficial effects of physical activity on survival among men with prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 57-64.
|
|
| 34. |
- Borgenvik, Anna, 1987-, et al.
(författare)
-
Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
- 2022
-
Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603
-
Tidskriftsartikel (refereegranskat)abstract
- Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
|
|
| 35. |
- Brandão, Andreia, et al.
(författare)
-
The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor
- 2020
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:11
-
Tidskriftsartikel (refereegranskat)abstract
- The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
|
|
| 36. |
- Caspers, I. A., et al.
(författare)
-
Effect of preoperative chemotherapy on the histopathological classification of gastric cancer
- 2024
-
Ingår i: Gastric Cancer. - : Springer. - 1436-3291 .- 1436-3305. ; 27, s. 102-109
-
Tidskriftsartikel (refereegranskat)abstract
- Background: In the era of individualized gastric cancer (GC) treatment, accurate determination of histological subtype becomes increasingly relevant. As yet, it is unclear whether preoperative chemotherapy may affect the histological subtype. The aim of this study was to assess concordance in histological subtype between pretreatment biopsies and surgical resection specimens before and after the introduction of perioperative treatment.Methods: Histological subtype was centrally determined in paired GC biopsies and surgical resection specimens of patients treated with either surgery alone (SA) in the Dutch D1/D2 study or with preoperative chemotherapy (CT) in the CRITICS trial. The histological subtype as determined in the resection specimen was considered the gold standard. Concordance rates and sensitivity and specificity of intestinal, diffuse, mixed, and "other" subtypes of GC were analyzed.Results: In total, 105 and 515 pairs of GC biopsies and resection specimens of patients treated in the SA and CT cohorts, respectively, were included. Overall concordance in the histological subtype was 72% in the SA and 74% in the CT cohort and substantially higher in the diffuse subtype (83% and 86%) compared to the intestinal (70% and 74%), mixed (21% and 33%) and "other" subtypes (54% and 54%). In the SA cohort, sensitivities and specificities were 0.88 and 0.71 in the intestinal, 0.67 and 0.93 in the diffuse, 0.20 and 0.98 in the mixed, and 0.50 and 0.93 in the "other" subtypes, respectively.Conclusion: Our results suggest that accurate determination of histological subtype on gastric cancer biopsies is suboptimal but that the impact of preoperative chemotherapy on histological subtype is negligible.
|
|
| 37. |
- Caspers, Irene A., et al.
(författare)
-
The impact of sex on treatment and outcome in relation to histological subtype in patients with resectable gastric cancer : Results from the randomized CRITICS trial
- 2024
-
Ingår i: Journal of Surgical Oncology. - : John Wiley & Sons. - 0022-4790 .- 1096-9098. ; 129:4, s. 734-744
-
Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectiveThis study aims to investigate the impact of sex on outcome measures stratified by histological subtype in patients with resectable gastric cancer (GC).MethodsA post-hoc analysis of the CRITICS-trial, in which patients with resectable GC were treated with perioperative therapy, was performed. Histopathological characteristics and survival were evaluated for males and females stratified for histological subtype (intestinal/diffuse). Additionally, therapy-related toxicity and compliance were compared.ResultsData from 781 patients (523 males) were available for analyses. Female sex was associated with a distal tumor localization in intestinal (p = 0.014) and diffuse tumors (p < 0.001), and younger age in diffuse GC (p = 0.035). In diffuse GC, tumor-positive resection margins were also more common in females than males (21% vs. 10%; p = 0.020), specifically at the duodenal margin. During preoperative chemotherapy, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p = 0.015). Notwithstanding this, relative dose intensities were not significantly different between sexes.ConclusionsPositive distal margin rates were higher in females with diffuse GC, predominantly at the duodenal site. Females also experience more toxicity, but this neither impacts dose intensities nor surgical resection rates. Clinicians should be aware of these different surgical outcomes when treating males and females with GC.
|
|
| 38. |
|
|
| 39. |
- Cederquist, Kristina, et al.
(författare)
-
Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.
- 2005
-
Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 68:6, s. 533-541
-
Tidskriftsartikel (refereegranskat)abstract
- Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.
|
|
| 40. |
- Christensen, G Bryce, et al.
(författare)
-
Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.
- 2010
-
Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 70, s. 735-744
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS: We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS: Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS: Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate (c) 2010 Wiley-Liss, Inc.
|
|
| 41. |
- Conti, David, V, et al.
(författare)
-
Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
-
Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
-
Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
|
|
| 42. |
- Dahlström, Lisen Arnheim, et al.
(författare)
-
Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer
- 2011
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 20:12, s. 2541-2550
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects. Methods: Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI. Results: Exposure to HPV16 was the strongest risk factor for cervical cancer [ OR = 2.4; 95% confidence interval (CI), 2.0-3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2-3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3-4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9-1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8-1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5-2.3). Conclusions: A large prospective study has assessed the role of different STIs in cervical cancer. Impact: Prospective evidence supports cofactor role of some STI in cervical cancer. Cancer Epidemiol Biomarkers Prev; 20(12); 2541-50. (C) 2011 AACR.
|
|
| 43. |
- Danielsson, Mattias, et al.
(författare)
-
Association between cerebrospinal fluid biomarkers of neuronal injury or amyloidosis and cognitive decline after major surgery.
- 2021
-
Ingår i: British journal of anaesthesia. - : Elsevier BV. - 1471-6771 .- 0007-0912. ; 126:2, s. 467-76
-
Tidskriftsartikel (refereegranskat)abstract
- Postoperative neurocognitive decline is a frequent complication in adult patients undergoing major surgery with increased risk for morbidity and mortality. The mechanisms behind cognitive decline after anaesthesia and surgery are not known. We studied the association between CSF and blood biomarkers of neuronal injury or brain amyloidosis and long-term changes in neurocognitive function.In patients undergoing major orthopaedic surgery (knee or hip replacement), blood and CSF samples were obtained before surgery and then at 4, 8, 24, 32, and 48 h after skin incision through an indwelling spinal catheter. CSF and blood concentrations of total tau (T-tau), neurofilament light, neurone-specific enolase and amyloid β (Aβ1-42) were measured. Neurocognitive function was assessed using the International Study of Postoperative Cognitive Dysfunction (ISPOCD) test battery 1-2 weeks before surgery, at discharge from the hospital (2-5 days after surgery), and at 3 months after surgery.CSF and blood concentrations of T-tau, neurone-specific enolase, and Aβ1-42 increased after surgery. A similar increase in serum neurofilament light was seen with no overall changes in CSF concentrations. There were no differences between patients having a poor or good late postoperative neurocognitive outcome with respect to these biomarkers of neuronal injury and Aβ1-42.The findings of the present explorative study showed that major orthopaedic surgery causes a release of CSF markers of neural injury and brain amyloidosis, suggesting neuronal damage or stress. We were unable to detect an association between the magnitude of biomarker changes and long-term postoperative neurocognitive dysfunction.
|
|
| 44. |
- Dimberg, Lina, et al.
(författare)
-
Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells.
- 2005
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020.
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is an as yet incurable B cell malignancy. Increased survival in vitro is a hallmark of MM cells, implying that a therapeutic potential may lie in circumventing anti-apoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis (1). In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL and Fas were identified as IFN-targets. Sensitization to Fas-mediated apoptosis by IFNs was not affected by blocking Apo2L/TRAIL, suggesting that Apo2L/TRAIL is not a key mediator in this process. In contrast, we found that an elevated Fas expression was functionally linked to increased susceptibility to Fas-mediated apoptosis. This was further supported by the finding that IFN-treatment enhanced Fas-mediated caspase-8 activation, one of the earliest signaling events down-stream receptor activation. In addition, IFN treatment attenuated the IL-6 dependent activation of Stat3, interfering with a known survival-pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis. Taken together, our results show that IFN-induced up-regulation of Fas sensitizes MM cells to Fas-mediated apoptosis and suggest that attenuation of Stat3 activation may be a potentially important event in this process.
|
|
| 45. |
|
|
| 46. |
- Dimberg, Lina Y., et al.
(författare)
-
Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma
- 2012
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12, s. 318-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. Methods: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS). Results: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. Conclusion: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
- Eriksson, Henrik, 1973, et al.
(författare)
-
Effects of In-Company Quality Awards on Organizational Performance
- 2003
-
Ingår i: Total quality management (Print). - : Informa UK Limited. - 0954-4127 .- 1360-0613. ; 14:2, s. 235-242
-
Tidskriftsartikel (refereegranskat)abstract
- The relationship between total quality management (TQM) practices and improved performance has been frequently discussed in the literature. In this paper, the costs and the effects of in-company quality awards on performance are discussed and analysed. The paper covers a survey of Swedish companies that use or have used in-company quality awards to stimulate TQM efforts and thereby to improve performance. The study cannot show any strong evidence of improved performance for units that applied for the in-company quality award. However, in contrast to units that have not applied, some units that have applied for the in-company quality award considered that the results related to performance have improved greatly. One large positive effect perceived by the participating units was increased customer orientation while the largest costs were put on the description of activities and the improvement work itself.
|
|
| 50. |
- Felsberg, Michael, 1974-, et al.
(författare)
-
Online Learning of Correspondences between Images
- 2013
-
Ingår i: IEEE Transactions on Pattern Analysis and Machine Intelligence. - : IEEE Computer Society. - 0162-8828 .- 1939-3539. ; 35:1, s. 118-129
-
Tidskriftsartikel (refereegranskat)abstract
- We propose a novel method for iterative learning of point correspondences between image sequences. Points moving on surfaces in 3D space are projected into two images. Given a point in either view, the considered problem is to determine the corresponding location in the other view. The geometry and distortions of the projections are unknown as is the shape of the surface. Given several pairs of point-sets but no access to the 3D scene, correspondence mappings can be found by excessive global optimization or by the fundamental matrix if a perspective projective model is assumed. However, an iterative solution on sequences of point-set pairs with general imaging geometry is preferable. We derive such a method that optimizes the mapping based on Neyman's chi-square divergence between the densities representing the uncertainties of the estimated and the actual locations. The densities are represented as channel vectors computed with a basis function approach. The mapping between these vectors is updated with each new pair of images such that fast convergence and high accuracy are achieved. The resulting algorithm runs in real-time and is superior to state-of-the-art methods in terms of convergence and accuracy in a number of experiments.
|
|
