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| 3. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 4. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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- Kyle, R. A., et al.
(författare)
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Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management
- 2010
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 24:6, s. 1121-1127
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Forskningsöversikt (refereegranskat)abstract
- Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein < 15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months. Leukemia (2010) 24, 1121-1127; doi:10.1038/leu.2010.60; published online 22 April 2010
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| 8. |
- Landgren, Annelie M., et al.
(författare)
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Autoimmune Disease and Subsequent Risk of Developing Alimentary Tract Cancers Among 4.5 Million US Male Veterans
- 2011
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 117:6, s. 1163-1171
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Autoimmunity is clearly linked with hematologic malignancies, but less is known about autoimmunity and alimentary tract cancer risk, despite the specific targeting of alimentary organs and tissues by several autoimmune diseases. The authors therefore conducted the first systematic evaluation of a broad range of specific autoimmune diseases and risk for subsequent alimentary tract cancer. METHODS: On the basis of 4,501,578 US male veterans, the authors identified 96,277 men who developed alimentary tract cancer during up to 26.2 years of follow-up. By using Poisson regression methods, the authors calculated relative risks (RRs) and 95% confidence intervals. RESULTS: A history of autoimmune disease with localized alimentary tract effects generally increased cancer risks in the organ(s) affected by the autoimmune disease, such as primary biliary cirrhosis and liver cancer (RR, 6.01; 95% confidence interval [Cl], 4.76-7.57); pernicious anemia and stomach cancer (RR, 3.17; 95% Cl, 2.47-4.07); and ulcerative colitis and small intestine, colon, and rectal cancers (RR, 2.53; 95% Cl, 1.05-6.11; RR, 2.06; 95% Cl, 1.70-2.48; and RR, 2.07; 95% Cl, 1.62-2.64, respectively). In addition, a history of celiac disease, reactive arthritis (Reiter disease), and systemic sclerosis all were associated significantly with increased risk of esophageal cancer (RR, 1.86-2.86). Autoimmune diseases without localized alimentary tract effects generally were not associated with alimentary tract cancer risk, with the exception of decreased risk for multiple alimentary tract cancers associated with a history of multiple sclerosis. CONCLUSIONS: These findings support the importance of localized inflammation in alimentary tract carcinogenesis. Future research is needed to confirm the findings and improve understanding of underlying mechanisms by which autoimmune diseases contribute to alimentary tract carcinogenesis. Cancer 2011;117:1163-71. Published 2010 by the American Cancer Society*
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| 10. |
- Clarke, Robert, et al.
(författare)
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Lowering blood homocysteine with folic acid based supplements : Meta-analysis of randomised trials
- 1998
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Ingår i: British Medical Journal. - : BMJ. - 0959-8146. ; 316:7135, s. 894-898
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Forskningsöversikt (refereegranskat)abstract
- Objective: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. Design: Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentration. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. Subjects: Individual data on 1114 people included in 12 trials. Findings: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P < 0.001) and at lower pretreatment blood folate concentrations (P < 0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 μmol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P < 0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. Conclusions: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9 μmol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease.
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| 14. |
- Grahn, J. V., et al.
(författare)
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A low-complexity 62-GHz f(T) SiGe heterojunction bipolar transistor process using differential epitaxy and in situ phosphorus-doped poly-Si emitter at very low thermal budget
- 2000
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Ingår i: Solid-State Electronics. - 0038-1101 .- 1879-2405. ; 44:3, s. 549-554
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Tidskriftsartikel (refereegranskat)abstract
- A low-complexity SiGe heterojunction bipolar transistor process based on differential epitaxy and in situ phosphorus doped polysilicon emitter technology is described. Silane-based chemical vapor deposition at reduced pressure was used for low-temperature SiGe epitaxy. Following SiGe epitaxy, the process temperature budget was kept very low with 900 degrees C for 10 s as the highest temperature step. A very high current gain of almost 2000 and cut off frequency of 62 GHz were achieved for a uniform 12% Ge profile. The breakdown voltage BVCEO and forward Early voltage were equal to 2.9 and 6.5 V, respectively.
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| 15. |
- Hultcrantz, M., et al.
(författare)
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Elevated risk of venous but not arterial thrombosis in Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma
- 2014
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 12:11, s. 1816-1821
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMany malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenstrom macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). ObjectivesTo assess the risk of venous and arterial thrombosis in WM/LPL patients in a large population-based cohort study in Sweden. Patients/methodsA total of 2190 patients with WM/LPL and 8086 matched controls were identified through Swedish registers between 1987 and 2005. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL was obtained through the centralized Swedish Patient Register, with follow-up to 2006. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsPatients with WM/LPL had a significantly increased risk of venous thrombosis and the highest risk was observed during the first year following diagnosis (HR=4.0, 95% CI 2.5-6.4). The risk was significantly elevated 5 (HR=2.3, 95% CI 1.7-3.0) and 10years after diagnosis (HR=2.0, 95% CI 1.6-2.5). There was no increased risk of arterial thrombosis during any period of follow-up time (10-year HR=1.0, 95% CI 0.9-1.1). ConclusionsVenous thrombosis is a significant cause of morbidity in patients with WM/LPL. The potential role of thromboprophylaxis in WM/LPL, especially during the first year after diagnosis and in patients treated with thrombogenic agents, needs to be assessed to further improve outcome in WM/LPL patients.
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| 17. |
- Landgren, O, et al.
(författare)
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A prospective study on antibody response to repeated vaccinations with pneumococcal capsular polysaccharide in splenectomized individuals with special reference to Hodgkin's lymphoma
- 2004
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 255:6, s. 664-673
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Tidskriftsartikel (refereegranskat)abstract
- Background. Splenectomy is accompanied by a life-long risk of overwhelming postsplenectomy infection (OPSI), mainly caused by polysaccharide (PS) encapsulated bacteria such as Streptococcus pneumoniae. Despite extensive prophylactic efforts the mortality and morbidity rates remain high. The present study was based on a strategy with a predefined vaccination algorithm including repeated 23-valent pneumococcal vaccinations and monitoring of pneumococcal antibody levels. The antibody levels of splenectomized Hodgkin's lymphoma (HL) patients were compared with those patients splenectomized due to immune-mediated cytopenias [autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP)] and also individuals who were splenectomized because of trauma (TRAUMA). Methods. A total of 311 splenectomized individuals were included in this prospective study (208 HL; 15 AIHA; 60 ITP; 28 TRAUMA). Depending on their individual anti-PS antibody levels measured by enzyme-linked immunosorbent assay technique the patients were revaccinated with 23-valent pneumococcal PS vaccine up to four times in accordance with the predefined algorithm. For each vaccination occasion, serum was collected at vaccination, after 1 month +/- 2 weeks (peak), and after 1 year +/- 6 months (follow-up). Patient files, a national population-based database, and microbiological databases were checked for 124 HL patients to identify OPSI. Results. A significant response was recorded on primary vaccination as well as on two revaccination occasions for HL, AIHA/ITP, as well as TRAUMA patients. None of the variables age, gender, or time elapsed between splenectomy and first pneumococcal vaccination was found to be associated with mean PS antibody levels at prevaccination, peak or follow-up. No severe adverse events were reported. Amongst 124 clinically monitored HL patients, 10 OPSI were recorded in seven patients during the study period. One of these patients, a middle-aged female, died as a result of fulminant pneumococcal bacteraemia, which was her third OPSI during a 7-year period. Conclusions. A significant response to pneumococcal PS vaccination was found in all three groups (HL, AIHA/ITP and TRAUMA) of splenectomized patients. Importantly, both primary and repeated vaccinations were safe. Until further knowledge is gained regarding the protective concentration of serotype-specific antibody concentrations we believe that the value of vaccination and frequent revaccination (every 1-5 years) in combination with education of patients and health care professionals and clinical monitoring is beneficial for these patients at risk for OPSI.
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| 23. |
- Bjorck, E, et al.
(författare)
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High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma
- 2005
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 105:7, s. 2908-2915
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Tidskriftsartikel (refereegranskat)abstract
- Substantial research has been dedicated to the study of the relationship between genetic mechanisms regulating cell functions in tumors and how those tumors respond to various treatment regimens. Because these mechanisms are still not well understood, we have chosen to study the genetic makeup of 57 tumor samples from patients with follicular lymphoma (FL). Our goal was to develop a prognostic tool, which can be used as an aid in determining FL patients with tumors genetically predisposed to a successful treatment with the CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) regimen. To select relevant genes, high-density oligonucleotide arrays were used. There were 14 genes highly expressed in FL patients that responded well to CHOP chemotherapy, and 11 of these were involved in G(2)/M transition of the cell cycle, in mitosis, or in DNA modulation. A high expression of CCNB1 (cyclin B1), CDC2, CDKN3A, CKS1B, ANP32E, and KIAA0101, but not of the proliferation-related antigen Ki-67, was associated with better survival rate in a univariate analysis. CCNB1 expression had an independent prognostic value when included in a multivariate analysis together with the 5 parameters of the follicular lymphoma international prognostic index.
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| 25. |
- Bjorkholm, M., et al.
(författare)
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Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms
- 2011
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology: JCO. - 0732-183X .- 1527-7755. ; 29:17, s. 2410-2415
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). Methods: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. Results: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P32), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P32 greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. Conclusion: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P32 and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors. © 2011 by American Society of Clinical Oncology.
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