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| 2. |
- Brofelth, Mattias, et al.
(författare)
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Multiplex profiling of serum proteins in solution using barcoded antibody fragments and next generation sequencing
- 2020
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Ingår i: Communications Biology. - : NATURE PUBLISHING GROUP. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- The composition of serum proteins is reflecting the current health status and can, with the right tools, be used to detect early signs of disease, such as an emerging cancer. An earlier diagnosis of cancer would greatly increase the chance of an improved outcome for the patients. However, there is still an unmet need for proficient tools to decipher the information in the blood proteome, which calls for further technological development. Here, we present a proof-of-concept study that demonstrates an alternative approach for multiplexed protein profiling of serum samples in solution, using DNA barcoded scFv antibody fragments and next generation sequencing. The outcome shows high accuracy when discriminating samples derived from pancreatic cancer patients and healthy controls and represents a scalable alternative for serum analysis. Brofelth, Ekstrand et al use DNA barcoded scFv antibody fragments and next generation sequencing for multiplex profiling of proteins in serum from pancreatic cancer patients with high accuracy. This approach can potentially be used in high throughput precision diagnosis.
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| 3. |
- Glodzik, Dominik, et al.
(författare)
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Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
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| 4. |
- Kvist, Patric, 1985, et al.
(författare)
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A multi-scale model for diffusion of large molecules in steam-exploded wood
- 2020
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Ingår i: Wood Science and Technology. - : Springer Science and Business Media LLC. - 0043-7719 .- 1432-5225. ; 54:4, s. 821-835
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, multi-scale modeling was used to resolve diffusion in steam-exploded wood at tracheid scales including sub-micrometer features of bordered pits. Simulations were performed using the lattice Boltzmann method with high-resolution X-ray tomography image data as the input for the microstructure. The results show an effective method for utilizing a variable diffusion coefficient to implement two length scales. This circumvents the need to resolve the bordered pits in detail, which requires massive computing power. Instead, the effective diffusion coefficient for one bordered pit is used as input for this model. Results based on the present model are comparable to experimental data. This methodology can be extended to more structural features at the microscale of wood, such as latewood and the cell wall. Obtaining a map of different diffusion coefficients based on features and scale gives a better overall understanding of diffusion and the importance of mass transport with regard to the pretreatment of wood.
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| 6. |
- Tigerstrand Grevnerts, Hanna, et al.
(författare)
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Decision Making for Treatment After ACL Injury From an Orthopaedic Surgeon and Patient Perspective: Results From the NACOX Study
- 2021
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Ingår i: The Orthopaedic Journal of Sports Medicine. - : Sage Publications. - 2325-9671. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the treatment of anterior cruciate ligament (ACL) injuries, there is little evidence of when and why a decision for ACL reconstruction (ACLR) or nonoperative treatment (non-ACLR) is made. Purpose: To (1) describe the key characteristics of ACL injury treatment decisions and (2) compare patient-reported knee instability, function, and preinjury activity level between patients with non-ACLR and ACLR treatment decisions. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 216 patients with acute ACL injury were evaluated during the first year after injury. The treatment decision was non-ACLR in 73 patients and ACLR in 143. Reasons guiding treatment decision were obtained from medical charts and questionnaires to patients and orthopaedic surgeons. Patient-reported instability and function were obtained via questionnaires and compared between patients with non-ACLR and ACLR treatment decisions. The ACLR treatment group was classified retrospectively by decision phase: acute phase (decision made between injury day and 31 days after injury), subacute phase (decision made between 32 days and up to 5 months after injury), and late phase (decision made 5-12 months after injury). Data were evaluated using descriptive statistics, and group comparisons were made using parametric or nonparametric tests as appropriate. Results: The main reasons for a non-ACLR treatment decision were no knee instability and no problems with knee function. The main reasons for an ACLR treatment decision were high activity demands and knee instability. Patients in the non-ACLR group were significantly older (P = .031) and had a lower preinjury activity level than did those in the acute-phase (P < .01) and subacute-phase (P = .006) ACLR decision groups. There were no differences in patient-reported instability and function between treatment decision groups at baseline, 4 weeks after injury, or 3 months after injury. Conclusion: Activity demands, not patient-reported knee instability, may be the most important factor in the decision-making process for treatment after ACL injury. We suggest a decision-making algorithm for patients with ACL injuries and no high activity demands; waiting for >3 months can help distinguish those who need surgical intervention from those who can undergo nonoperative management.
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| 7. |
- von Stedingk, Kristoffer, et al.
(författare)
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Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Up to 10% of pediatric cancer patients harbor pathogenic germline variants in one or more cancer susceptibility genes. A recent study from the US reported pathogenic variants in 22 out of 60 analyzed autosomal dominant cancer susceptibility genes, implicating 8.5% of pediatric cancer patients. Here we aimed to assess the prevalence of germline pathogenic variants in these 22 genes in a population-based Swedish cohort and to compare the results to those described in other populations. We found pathogenic variants in 10 of the 22 genes covering 3.8% of these patients. The prevalence of TP53 mutations was significantly lower than described in previous studies, which can largely be attributed to differences in tumor diagnosis distributions across the three cohorts. Matched family history for relatives allowed assessment of familial cancer incidence, however, no significant difference in cancer incidence was found in families of children carrying pathogenic variants compared to those who did not.
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| 8. |
- Wessman, Sandra, et al.
(författare)
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Precision oncology of high-grade ovarian cancer defined through targeted sequencing
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:20
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Tidskriftsartikel (refereegranskat)abstract
- Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel. Results: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy. Conclu-sions: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diag-nosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several so-matic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.
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| 9. |
- Yang, Xin, et al.
(författare)
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Cancer risks associated with germline PALB2 pathogenic variants : An international study of 524 families
- 2020
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 38:7, s. 674-685
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
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| 10. |
- Yang, Xin, et al.
(författare)
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Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D
- 2020
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 112:12, s. 1242-1250
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models. © The Author(s) 2020. Published by Oxford University Press.
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