| 1. |
- Taipale, K, et al.
(författare)
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Predictive and prognostic clinical variables in cancer patients treated with adenoviral oncolytic immunotherapy
- 2016
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Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 24:7, s. 1323-1332
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Tidskriftsartikel (refereegranskat)abstract
- The development of oncolytic viruses has recently made great progress towards being available to cancer patients. With the breakthrough into clinics, it is crucial to analyze the existing clinical experience and use it as a basis for treatment improvements. Here we report clinical data from 290 patients treated with oncolytic adenovirus. Using clinical variables and treatment characteristics, we constructed statistical models with regard to treatment response and overall survival. Additionally, we investigated effects of neutralizing antibodies, tumor burden and peripheral blood leucocyte counts on these outcomes. We found the absence of liver metastases to correlate with an improved rate of disease control (p=0.021). In multivariate evaluation, patients treated with viruses coding for immunostimulatory granulocyte macrophage colony-stimulating factor were linked to better prognosis (HR 0.378, p<0.001), as well as women with any cancer type (HR 0.694, p=0.017). In multivariate analysis for imaging response, patients treated via intraperitoneal injection were more likely to achieve disease control (OR 3.246, p=0.027). Patients with low neutrophil-to-lymphocyte ratio before treatment, had significantly longer overall survival (p<0.001). These findings could explain some of the variation seen in treatment outcomes after virotherapy. Furthermore, the results offer hypotheses for treatment optimization and patient selection in oncolytic adenovirus immunotherapy.Molecular Therapy (2016); doi:10.1038/mt.2016.67.
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| 2. |
- Dias, J D, et al.
(författare)
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Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4
- 2012
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Ingår i: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 19:10, s. 988-998
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Tidskriftsartikel (refereegranskat)abstract
- Promising clinical results have been achieved with monoclonal antibodies (mAbs) such as ipilimumab and tremelimumab that block cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152). However, systemic administration of these agents also has the potential for severe immune-related adverse events. Thus, local production might allow higher concentrations at the target while reducing systemic side effects. We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Δ24aCTLA4 expressing complete human mAb specific for CTLA-4 and tested it in vitro, in vivo and in peripheral blood mononuclear cells (PBMCs) of normal donors and patients with advanced solid tumors. mAb expression was confirmed by western blotting and immunohistochemistry. Biological functionality was determined in a T-cell line and in PBMCs from cancer patients. T cells of patients, but not those of healthy donors, were activated by an anti-CTLA4mAb produced by Ad5/3-Δ24aCTLA4. In addition to immunological effects, a direct anti-CTLA-4-mediated pro-apoptotic effect was observed in vitro and in vivo. Local production resulted in 43-fold higher (P<0.05) tumor versus plasma anti-CTLA4mAb concentration. Plasma levels in mice remained below what has been reported safe in humans. Replication-competent Ad5/3-Δ24aCTLA4 resulted in 81-fold higher (P<0.05) tumor mAb levels as compared with a replication-deficient control. This is the first report of an oncolytic adenovirus producing a full-length human mAb. High mAb concentrations were seen at tumors with lower systemic levels. Stimulation of T cells of cancer patients by Ad5/3-Δ24aCTLA4 suggests feasibility of testing the approach in clinical trials.
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| 3. |
- Galluzzi, L, et al.
(författare)
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Consensus guidelines for the definition, detection and interpretation of immunogenic cell death
- 2020
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
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| 6. |
- Stacey, Simon N, et al.
(författare)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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| 12. |
- Berggren, P, et al.
(författare)
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p53 mutations in urinary bladder cancer
- 2001
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 84:11, s. 1505-1511
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Tidskriftsartikel (refereegranskat)
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| 13. |
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| 14. |
- Da Silva Filho, M. I., et al.
(författare)
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Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts : Comparison with myeloma
- 2017
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:8, s. 1735-1742
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10 -5 with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 × 10 -11; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 × 10 -8). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated.
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| 18. |
- Gissler, M, et al.
(författare)
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Sex differences in child and adolescent mortality in the Nordic countries, 1981--2000
- 2009
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Ingår i: Scandinavian journal of public health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 37:4, s. 340-346
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Unlike the situation for infant and adult mortality, there are only a few studies on child and adolescent mortality. The purpose of this study was to examine sex differences in child and adolescent mortality by age and cohort in four Nordic countries over a 20-year period. Methods: Data on all live-born children were received from national population-covering birth registries from 1981 to 2000 (Denmark, n = 1,184,926; Finland, n = 841,470 (from 1987 to 2000); Norway, n = 1,090,127; and Sweden, n = 1,961,911). Data on mortality and causes of death until the age of 20 years were received from the national cause-of-death registers. Results: The overall mortality rates were higher in Denmark and Norway than in Finland and Sweden, among both boys and girls, and the difference between countries increased over time. In all countries, boys had higher mortality rates than girls. Overall, the sex difference was larger in Denmark and Norway (36% and 33% higher, respectively) than in Finland and Sweden (both 24%). The sex differences were more pronounced for deaths of those aged 5—19 years than for those aged 0—4 years. Twelve per cent of all deaths among boys and 10% of those among girls were due to external causes, mainly unintentional injury deaths or intentional deaths. For children and adolescents aged 5—19 years, the corresponding figures were 43% for boys and 35% for girls. Conclusions: Boys have excess mortality, but the sex difference is lower in countries with lower mortality. Boys' excess mortality was only partly accounted for by deaths from external causes. Avoidable deaths and causes of death need further investigation.
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| 25. |
- Johnson, D C, et al.
(författare)
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Genetic factors influencing the risk of multiple myeloma bone disease.
- 2016
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 30, s. 883-888
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Tidskriftsartikel (refereegranskat)abstract
- A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totalling 3774) which had been radiologically surveyed for MBD. Each patient had been genotyped for ~600 000 SNPs with genotypes for six million common variants imputed using 1000Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio [OR]=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, OR=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.Leukemia accepted article preview online, 16 December 2015. doi:10.1038/leu.2015.342.
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| 30. |
- Landgren, O, et al.
(författare)
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Patterns of autoimmunity and subsequent chronic lymphocytic leukemia in Nordic countries
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 108:1, s. 292-296
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Tidskriftsartikel (refereegranskat)abstract
- A population-based case-control study was conducted to evaluate risk of developing chronic lymphocytic leukemia (CLL) associated with personal and/or family history of autoimmune and related diseases. Data were obtained for all (n = 7764) patients diagnosed with CLL in Sweden and Denmark over a 40-year period and with linkable relatives, 16 658 matched control subjects, and first-degree relatives of patients (n = 17 991) and control subjects (n = 39 388). Odds ratios (ORs) were calculated to quantify risk of CLL in relation to personal/family history of 32 autoimmune and related disorders. The risk of CLL was significantly increased among subjects with a personal history of pernicious anemia (OR = 1.94; 1.18-3.18), mainly in the 0- to 1-year latency period. A significantly decreased risk of CLL was found among individuals with a personal history of chronic rheumatic heart disease (OR = 0.55; 0.33-0.93), particularly persons with a long latency (10+ years) between the 2 conditions. We found no association between personal or familial occurrence of other autoimmune or related disorders and CLL. If our results are confirmed, mechanistic studies examining how pernicious anemia might promote increased occurrence of CLL and how chronic rheumatic heart disease protects against CLL, perhaps related to long-term antibiotics use, may provide insights to the as-yet-unknown etiology of CLL. (Blood. 2006;108:292-296)
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| 35. |
- Morgan, G. J., et al.
(författare)
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Inherited genetic susceptibility to multiple myeloma
- 2014
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 28:3, s. 518-524
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Forskningsöversikt (refereegranskat)abstract
- Although the familial clustering of multiple myeloma (MM) supports the role of inherited susceptibility, only recently has direct evidence for genetic predisposition been demonstrated. A meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localising to a number of genomic regions that are robustly associated with MM risk. In this review, we provide an overview of the evidence supporting a genetic contribution to the predisposition to MM and MGUS (monoclonal gammopathy of unknown significance), and the insight this gives into the biological basis of disease aetiology. We also highlight the promise of future approaches to identify further specific risk factors and their potential clinical utility.
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| 38. |
- Saunders, Charlie N., et al.
(författare)
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Search for AL amyloidosis risk factors using Mendelian randomization
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:13, s. 2725-2731
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Tidskriftsartikel (refereegranskat)abstract
- In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencingALamyloidosis risk.Weperformed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.
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| 39. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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