| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
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| 3. |
- Modvig, S, et al.
(författare)
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Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting.
- 2021
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35, s. 1894-1906
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Tidskriftsartikel (refereegranskat)abstract
- PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p<0.0001), 29 (HzR 2.7, p<0.0001), and 79 (HzR 3.5, p<0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4×10-2 versus 5.2×10-3, p<0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y=3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD>10-4 associated with a CIR5y=22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.
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| 4. |
- Dahl, Maria, et al.
(författare)
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Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice
- 2015
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Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 23:5, s. 835-844
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Tidskriftsartikel (refereegranskat)abstract
- Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase beta-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease.
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| 5. |
- Gonzalez-Ericsson, Paula, et al.
(författare)
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The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers into breast cancer clinical trials and daily practice
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 250:5, s. 667-684
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
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| 6. |
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| 7. |
- Amgad, M, et al.
(författare)
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Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group
- 2020
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 6:1, s. 16-
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Hudeček, Jan, et al.
(författare)
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Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials
- 2020
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 6:1
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Forskningsöversikt (refereegranskat)abstract
- Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
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| 13. |
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| 14. |
- Jacobson, S G, et al.
(författare)
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Digenic inheritance of a ROM1 gene mutation with a peripherin/RDS or rhodopsin mutation in families with retinitis pigmentosa
- 1999
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Ingår i: Digital Journal of Ophthalmology. - 1542-8958. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- Two families with retinitis pigmentosa showed inheritance of an Arg-16-His ROM1 gene mutation with either an Arg-13-Trp RDS mutation or an Arg-135-Trp RHO mutation. The phenotypes of double and single heterozygotes were determined to examine the hypothesis that digenic inheritance may increase disease expression. In the family with ROM1 and RDS mutations, single heterozygotes were normal but one double heterozygote showed severe RP. Two other double heterozygotes, however, were normal by clinical and retinal function tests. In the family with ROM1 and RHO mutations, single heterozygotes with the RHO mutation all manifested RP, while a single heterozygote for the ROM1 mutation was normal. Disease severity was comparable in double heterozygotes and single heterozygotes HAVING the RHO mutation. We conclude that the Arg-16-His ROM1 gene mutation is non-pathogenic in the single heterozygous state, and there is no consistent evidence of digenic augmentation of pathogenicity in double heterozygotes carrying the Arg-16-His ROM1 mutation with either the benign Arg-13-Trp RDS mutation or the disease-causing Arg-135-Trp RHO mutation.
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| 15. |
- Leung, Samuel CY, et al.
(författare)
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Analytical validation of a standardized scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicenter collaboration
- 2019
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Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 75:2, s. 225-235
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections.Methods and results: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot‐spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot‐spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot‐spots varies between cases. The median times for scoring were 9 and 6 min for global and hot‐spot methods, respectively.Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.
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| 16. |
- Li, Constance H., et al.
(författare)
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Sex differences in oncogenic mutational processes
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
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| 17. |
- Ly, Amy, et al.
(författare)
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Training pathologists to assess stromal tumour-infiltrating lymphocytes in breast cancer synergises efforts in clinical care and scientific research
- 2024
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Ingår i: Histopathology. - 0309-0167 .- 1365-2559. ; 84:6, s. 915-923
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Forskningsöversikt (refereegranskat)abstract
- A growing body of research supports stromal tumour-infiltrating lymphocyte (TIL) density in breast cancer to be a robust prognostic and predicive biomarker. The gold standard for stromal TIL density quantitation in breast cancer is pathologist visual assessment using haematoxylin and eosin-stained slides. Artificial intelligence/machine-learning algorithms are in development to automate the stromal TIL scoring process, and must be validated against a reference standard such as pathologist visual assessment. Visual TIL assessment may suffer from significant interobserver variability. To improve interobserver agreement, regulatory science experts at the US Food and Drug Administration partnered with academic pathologists internationally to create a freely available online continuing medical education (CME) course to train pathologists in assessing breast cancer stromal TILs using an interactive format with expert commentary. Here we describe and provide a user guide to this CME course, whose content was designed to improve pathologist accuracy in scoring breast cancer TILs. We also suggest subsequent steps to translate knowledge into clinical practice with proficiency testing.
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| 18. |
- Modvig, S, et al.
(författare)
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Value of Flow Cytometry for MRD-Based Relapse Prediction in B-Cell Precursor Acute Lymphoblastic Leukemia in a Multi-Center Setting
- 2019
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Ingår i: Blood. - 0006-4971 .- 1528-0020.
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Konferensbidrag (refereegranskat)abstract
- Background: PCR of rearranged antigen receptor genes is the method of choice for MRD quantification in ALL. Although FCM-MRD is faster and biologically more informative than PCR, the analysis requires a high level of training. The only larger published studies using FCM-MRD based stratification (Borowitz, Blood, 2008 and 2015) showed a clear association with clinical outcome in BCP-ALL. However, MRD analyses were centralized and these studies included only one MRD-based stratification (MRD levels at the end of induction). Patients and methods: We examined FCM-MRD as stratification tool in BCP-ALL at various timepoints in a large-scale multicenter (18 MRD centers) study. A total of 1487 patients with BCP-ALL (1298 children (younger than 18 years) and 189 adults (18-45 years) are included in the study and were treated according to the NOPHO ALL2008 protocol between July 2008 and February 2016. The median follow-up time for patients in first remission was 51 months (IQR 32-75). MRD was measured by FCM and/or real time quantitative PCR on days 15, 29 (end of induction) and 79 (for standard (SR) and intermediate risk (IR) patients) and prior to and after high risk blocks. A 6-colour FCM analysis including 3 standardized antibody combinations was used and performed in 18 laboratories. Patients were stratified by FCM-MRD, or by PCR-MRD if no FCM-MRD marker was available. End-of-induction MRD (cut-off 10-3) was used to stratify patients to standard risk (SR) vs intermediate risk (IR) or IR vs high risk consolidation therapy (in case of WBC > 100 x 109/L at diagnosis). Patients with MRD >=2.5x10-1 on day 15 were stratified to high risk block therapy. Patients with MRD >=5x10-2 on day 29 or day 79/post high risk-2 block MRD >=10-3 were stratified to HSCT. Primary outcomes were 5year event-free survival (5y EFS) and 5year cumulative incidence of relapse (5y CIR). Results: Only two patients (0.14% of total) had neither an informative FCM nor a PCR marker, and an informative FCM marker combination for MRD monitoring was identified in 96.2% of patients. There was a significant correlation between FCM- and PCR-MRD levels on day 15 (r=0.77, p<0.0001, n=153) and 29 (r=0.81, p<0.0001, n=140). Based on FCM-MRD only, the median MRD level on day 15, 29 and 79/post high risk-2 block was 5x10-3, 1.1x10-4, and below detection limit, respectively. Adults had significantly higher MRD levels at all time-points (p<0.0001 for day 15 and 29, p=0.0019 for day 79, Mann-Whitney). The 5y EFS was 86.1% (95% CI 84.1-88.1) with a 5y CIR of 9.5% (95% CI 7.8-11.3, n=1487). The day 29 FCM-MRD level was closely associated with clinical outcome and a higher hazard of relapse was seen independently for a FCM-MRD >=10-3 (hazard ratio (HR) 2.4, CI 1.6-3.7, p<0.0001), age>18 year (HR 3.0, CI 1.7-5.3, p<0.0001), WBC>=100 (HR 2.7, CI 1.6-4.6, p=0.0001), and B-other (HR 2.1, CI 1.2-3.5, p=0.0052) or high risk B-ALL cytogenetic aberration (rearranged KMT2A/iAMPchr21/hypodiploid) (HR 3.2, CI 1.6-6.1, p=0.0006) (multivariate cause-specific Cox regression, n=1328). Patients with a day 79 FCM-MRD >=10-4 and <10-3 had a significantly higher CIR (22.1%, CI 10.8-33.5%, n=68) compared to FCM-MRD <10-4 (7.5%, CI 2.1-12.8%, n=110) or undetectable (6.3%, CI 4.5-8.2%, n=999, p=0.0087 for FCM-MRD >=10-4 and <10-3vs <10-4 or undetectable). After adjusting for WBC, age, and the day 29 FCM-MRD level, a day 79 FCM-MRD >=10-4 and <10-3 was still significantly associated with a worse 5y CIR for non-transplanted patients (HR 2.3, CI 1.19-4.36, p=0.012 compared to undetectable FCM-MRD, n=1171). Patients with day 15 FCM-MRD <10-3 had a significantly better 5y EFS (92.0%, CI 89.2-95.0%) and CIR (3.9%, CI 1.7-6.1%, n=432) than patients with FCM-MRD >=10-3 and <2.5x10-1, who had a 5y EFS of 85.5% (CI 82.7-88.3%, p=0.0016, n=837) and a 3-fold higher 5y CIR (11.0%, CI 8.4-13.5%, p<0.0001, n=432). Among patients with day 15 FCM-MRD<10-3, the relapse incidence was comparable for patients with FCM-MRD 10-4 - <10-3 and below 10-4 (CIR 3.6, CI 0.5-6.7 vs. CIR 4.1, CI 1.0-7.2, p=0.83, n=432). Conclusion: FCM-MRD performed in a multi-center setting is a clinically useful method for disease monitoring and MRD-based treatment stratification in BCP-ALL. Moreover, FCM-MRD is a reliable indicator of outcome in BCP-ALL independently of other key risk factors. Residual disease >=10-4 and <10-3 at day 79 in SR/IR patients not allocated to HSCT further identifies patients with a high risk of relapse.
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| 19. |
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| 20. |
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| 21. |
- Agardh, E., et al.
(författare)
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Gamma‐aminobutyric acid‐ and glutamic acid decarboxylase‐immunoreactive neurons in the retina of different vertebrates
- 1987
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967. ; 258:4, s. 622-630
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Tidskriftsartikel (refereegranskat)abstract
- The localization of gamma‐aminobutyric acid (GABA)‐ and L‐glutamate 1 carboxy‐lyase (GAD)‐immunoreactive neurons was compared in the skate, frog, pigeon, chicken, rabbit, and man. Horizontal cells show both GABA and GAD immunoreactivity in the skate, frog, and bird. Certain amacrine cells show GABA and GAD immunoreactivity in all species. The distribution of GABA‐ and GAD‐immunoreactive cell bodies and cell processes was very similar, if not identical, in the skate and man. In the other species, cell populations with GAD immunoreactivity also showed GABA immunoreactivity. However, in the bird, frog, and rabbit, the GABA‐immunoreactive amacrine cells were at least twice as numerous as the GAD‐immunoreactive cells. In birds, the distributions of the GAD and GABA immunoreactivities were different in the sublayers of the inner plexiform layer. The reason for the difference is currently unknown. GABA‐immunoreactive bipolar‐like cells were seen in the frog.
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| 22. |
- Al-Abbadi, Mousa A., et al.
(författare)
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A Proposal for the Performance, Classification, and Reporting of Lymph Node Fine-Needle Aspiration Cytopathology : The Sydney System
- 2020
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Ingår i: Acta Cytologica. - : S. Karger AG. - 0001-5547 .- 1938-2650. ; 64:4, s. 306-322
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The evaluation of lymph nodes (LN) by fine-needle aspiration cytology (FNAC) is routinely used in many institutions but it is not uniformly accepted mainly because of the lack of guidelines and a cytopathological diagnostic classification. A committee of cytopathologists has developed a system of performance, classification, and reporting for LN-FNAC. METHODS: The committee members prepared a document that has circulated among them five times; the final text has been approved by all the participants. It is based on a review of the international literature and on the expertise of the members. The system integrates clinical and imaging data with cytopathological features and ancillary techniques. The project has received the endorsement and patronage of the International Academy of Cytology and the European Federation of the Cytology Societies. RESULTS: Clinical, imaging, and serological data of lymphadenopathies, indications for LN-FNAC, technical procedures, and ancillary techniques are evaluated with specific recommendations. The reporting system includes two diagnostic levels. The first should provide basic diagnostic information and includes five categories: inadequate/insufficient, benign, atypical lymphoid cells of undetermined/uncertain significance, suspicious, and malignant. For each category, specific recommendations are provided. The second diagnostic level, when achievable, should produce the identification of specific benign or malignant entities and additional information by utilizing ancillary testing. CONCLUSION: The authors believe that the introduction of this system for performing and reporting LN-FNAC may improve the quality of the procedure, the report, and the communication between cytopathologists and the clinicians. This system may lead to a greater acceptance and utilization of LN-FNAC and to a better interdisciplinary understanding of the results of this procedure.
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| 23. |
- Andréasson, Sten, et al.
(författare)
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Phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene
- 1997
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Ingår i: American Journal of Ophthalmology. - 1879-1891. ; 124:1, s. 95-102
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the clinical phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene. METHODS: Three families from different parts of Sweden, including nine patients with retinitis pigmentosa and six female carriers of X-linked retinitis pigmentosa, were examined clinically. Ophthalmologic examination included kinetic perimetry with a Goldmann perimeter using standardized objects I4e and V4e, dark adaptation final thresholds with a Goldmann-Weeker adaptometer, and full-field electroretinograms. RESULTS: The clinical findings in the patients demonstrated a severe form of retinitis pigmentosa with visual handicap early in life. Patients with a microdeletion of exons 8 through 10 of the RPGR gene had a more severe phenotype compared to the patients with single base-pair mutations in the introns 10 and 13 of the RPGR gene, resulting in splicing defects. Furthermore, heterozygous carriers in these families displayed a wide spectrum of clinical features, from minor symptoms to severe visual disability. CONCLUSION: These three families show a variable clinical phenotype resulting from different mutations in the RPGR gene. A microdeletion spanning at least parts of exons 8 through 10 seems to result in a severe phenotype compared to the splice defects. Heterozygous carriers of X-linked retinitis pigmentosa with these specific RPGR genotypes also show a variability of the phenotype; carriers with the microdeletion may be severely visually handicapped.
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| 24. |
- Bailey, Matthew H., et al.
(författare)
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Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples
- 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
- The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.
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| 25. |
- Bauer, S, et al.
(författare)
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Phenotype in a Swedish family with X-linked retinitis pigmentosa caused by a novel splice defect in the RPGR gene
- 1998
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Ingår i: Investigative Ophthalmology & Visual Science. - 1552-5783. ; 39:12, s. 2470-2474
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the clinical phenotype in a Swedish family with X- linked retinitis pigmentosa (XLRP) resulting from a novel splice defect in the RPGR gene. METHODS: RPGR mutation analysis was performed in one family with XLRP, and several individuals from the family were examined clinically. RESULTS: The causative mutation in the family was demonstrated to be a single base-pair change at the splice donor site in intron 7 that resulted in skipping of the complete exon 7 in the mature RPGR transcript. The aberrant mRNA is predicted to produce an RPGR protein with an in-frame deletion of 53 amino acids, corresponding to an RCC1-homology repeat. Clinical studies that included ophthalmological examination and full-field electroretinography showed that this splice mutation resulted in a comparatively less severe form of RP. CONCLUSIONS: Correlation of a causative RPGR genotype with clinical findings in hemizygotes and carrier heterozygotes is an important step toward predictive diagnosis and should assist in the development of gene-based therapies in the future.
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| 26. |
- 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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| 27. |
- Czeszumski, Artur, et al.
(författare)
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#EEGManyLabs: Investigating the Replicability of Influential EEG Experiments
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- There is growing awareness across the neuroscience community that the replicability of findings on the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardized analysis pipelines. Inspired by efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.
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| 28. |
- El Bairi, Khalid, et al.
(författare)
-
The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group
- 2021
-
Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 7:1
-
Forskningsöversikt (refereegranskat)abstract
- The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.
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| 29. |
- Galera-Monge, Teresa, et al.
(författare)
-
Mitochondrial dysfunction and calcium dysregulation in leigh syndrome induced pluripotent stem cell derived neurons
- 2020
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:9
-
Tidskriftsartikel (refereegranskat)abstract
- Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G>A in heteroplasmy. We have performed mitochondrial characterization, analysis of electrophysiological properties and calcium imaging of LS neurons. Here, we show a clearly compromised oxidative phosphorylation (OXPHOS) function in LS patient neurons. This is also the first report of electrophysiological studies performed on iPSC-derived neurons harboring an mtDNA mutation, which revealed that, in spite of having identical electrical properties, diseased neurons manifested mitochondrial dysfunction together with a diminished calcium buffering capacity. This could lead to an overload of cytoplasmic calcium concentration and the consequent cell death observed in patients. Importantly, our results highlight the importance of calcium homeostasis in LS pathology.
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| 30. |
- Ghosh, F, et al.
(författare)
-
Graft-host connections in long-term full-thickness embryonic rabbit retinal transplants
- 1999
-
Ingår i: Investigative Ophthalmology and Visual Science. - 0146-0404. ; 40:1, s. 32-126
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To establish neuronal connections in the rod and cone pathway between laminated rabbit retinal transplants and the host retina.METHODS: Fourteen adult rabbits received a complete full-thickness embryonic transplant. After survival times of 3 to 10 months, the retinas were studied under light microscope and with immunohistochemistry. Antibodies against protein kinase C (PKC), parvalbumin, and calbindin were used to label rod bipolar cells, AII amacrine cells, and cone bipolar cells, respectively. The AB5 antibody was used to label ganglion cells.RESULTS: The transplants displayed laminated morphology with layers parallel to the host retinal pigment epithelium. In the oldest specimens (10 months after surgery), laminated layers of graft and host approached each other and almost reconstructed the normal retinal appearance. The ganglion and cone bipolar cells of the host survived well, as was seen with AB5 and calbindin double-labeling. Connections between cone bipolar cells in the graft and ganglion cells in the host were not common. PKC-labeled rod bipolar cells and parvalbumin-labeled AII amacrine cells of host and graft showed sprouting activity directed toward an intermediate plexiform layer located between the graft and host. In specimens double-labeled with PKC and parvalbumin, this intermediate plexiform layer was seen to contain numerous PKC- and parvalbumin-labeled processes. Direct connections between rod bipolar and AII amacrine cells in host and graft were seen in the 10-month specimens.CONCLUSIONS: Full-thickness embryonic transplants survive for at least 10 months, and normal laminated morphology develops. Host and graft fuse and together contribute nerve cell processes to an intermediate plexiform layer. Direct graft-host contacts are also present between neuronal types that in the normal retina participate in the rod pathway.
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| 31. |
- Ghosh, F, et al.
(författare)
-
Immunohistochemical markers in full-thickness embryonic rabbit retinal transplants
- 1999
-
Ingår i: Ophthalmic Research. - : S. Karger AG. - 0030-3747 .- 1423-0259. ; 31:1, s. 5-15
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To examine immunohistochemical markers in straight, well-laminated retinal transplants with special attention paid to the interphotoreceptor matrix, the Müller cells and the ganglion cells as these three retinal components have been abnormal in transplants produced by previous methods.METHODS: Nine rabbits underwent subretinal transplantation of a complete full-thickness embryonic neuroretina. After 31 or 49 days, the transplants were stained for light microscopy and processed for immunohistochemistry.RESULTS: Six of 9 eyes contained transplants with straight, well-laminated regions with all light-microscopic characteristics of a normal retina. In the outer segment region, the expression of peanut agglutinin showed segmental labeling of cone domains in the interphotoreceptor matrix, and interphotoreceptor retinoid binding protein immunoreactivity was found. Glial fibrillary acidic protein and vimentin immunoreactivity revealed normal Müller cell morphology. In 3 transplants the AB5-antibody-labeled ganglion cells in the ganglion cell layer and all transplants contained nerve fibers in the nerve fiber layer labeled by an antibody against neurofilament of 160 kD. The latter also labeled fibers connecting the transplant with the host.CONCLUSIONS: Full-thickness embryonic retinal transplants develop the normal retinal appearance and display several of the retinal components necessary for normal function which are not found in transplants produced by previous methods.
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Ju, Young Seok, et al.
(författare)
-
Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.
- 2015
-
Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 25:6, s. 814-824
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.
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| 37. |
- Junker, Alex, et al.
(författare)
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Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences : A multivariate meta-analysis
- 2022
-
Ingår i: FASEB Journal. - 0892-6638. ; 36:2
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence human development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in knowledge. This meta-analysis systematically examined four domains and six subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedge's g) of sex differences were computed for each measure using data in 2258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women's WAT and isolated leukocyte subpopulations (g = 0.20, χ2 p =.01), and higher ROS production in men's skeletal muscle (g = 0.49, χ2 p <.0001). Sex differences showed weak to no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = −.17, p <.001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.
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| 38. |
- Nielsen, Torsten O, et al.
(författare)
-
Abstract P2-03-01: Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration
- 2018
-
Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
-
Konferensbidrag (refereegranskat)abstract
- Aims: (i) Determine whether between-observer reproducibility for Ki67 when assessed on whole sections according to a standardized scoring protocol is adequate for clinical application. (ii) Compare between-observer reproducibility of Ki67 scores assessed on hot-spots to scores using a global method that averages across a tissue section.Background: The nuclear proliferation biomarker Ki67 has multiple potential roles in breast cancer, including aiding decisions based on prognosis, but unacceptable levels of between-laboratory variability have been observed. The International Ki67 in Breast Cancer Working Group has undertaken a systematic program to determine whether Ki67 measurement can be analytically validated and standardized across labs. In phase 1, variability in visual interpretation was identified as an important source of variability. Phases 2 and 3a showed that adherence to defined scoring methods substantially improved reproducibility in scoring tissue microarrays and core-cut biopsies. We now assess whether acceptable reproducibility can be achieved on whole sections.Methods: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 to assemble 4 sets of 30 stained tumor sections, circulated around 23 labs in 12 countries. Ki67 was scored by 2 methods by all labs: (a) global: 4 fields of 100 tumor cells each were selected to reflect observed heterogeneity in nuclear staining (b) hot-spot: the field with highest Ki67 percentage of tumor cells with nuclear staining was selected and up to 500 cells scored. Ki67 scores were log2-transformed for statistical analyses and back-transformed for presentation. The primary objective was to assess whether either method could achieve an intraclass correlation coefficient (ICC) significantly greater than 0.8, considered substantial to almost-perfect reproducibility. Secondary objectives were to assess which method had highest observed ICC and to assess whether observers identified the same “hot-spots”.Results: ICC for the global method was 0.87 (95%CI: 0.799-0.93), marginally meeting the prespecified success criterion. The ICC for the hot-spot method was 0.83 (95%CI: 0.74-0.90) and had a CI extending below the success criterion. Across the 23 labs, geometric mean value of the 30 scores ranged from 8.5 to 19.6 for the global method and from 12.8 to 30.3 for the hot-spot method. The overall mean (95% CI) of these values was 12.9 (11.9-14.0) and 20.9 (19.1-22.8), respectively. Visually, between-laboratory agreement in location of selected hot-spot varies between cases. The median times for scoring were 9 and 6 minutes for global and hot-spot methods respectively.Conclusions: The global method marginally met the prespecified criterion of success; it should now be evaluated for clinical validity in appropriate cohorts of cases. The hot-spot method was observed to have slightly less reproducibility between labs. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between labs further
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| 39. |
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| 40. |
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| 41. |
- Pettersson, Louise, et al.
(författare)
-
Comparison of RNA- and DNA-based methods for measurable residual disease analysis in NPM1-mutated acute myeloid leukemia
- 2021
-
Ingår i: International Journal of Laboratory Hematology. - : Wiley. - 1751-5521 .- 1751-553X. ; 43:4, s. 664-674
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Reverse transcriptase quantitative PCR (RT-qPCR) is considered the method of choice for measurable residual disease (MRD) assessment in NPM1-mutated acute myeloid leukemia (AML). MRD can also be determined with DNA-based methods offering certain advantages. We here compared the DNA-based methods quantitative PCR (qPCR), droplet digital PCR (ddPCR), and targeted deep sequencing (deep seq) with RT-qPCR. Methods: Of 110 follow-up samples from 30 patients with NPM1-mutated AML were analyzed by qPCR, ddPCR, deep seq, and RT-qPCR. To select DNA MRD cutoffs for bone marrow, we performed receiver operating characteristic analyses for each DNA method using prognostically relevant RT-qPCR cutoffs. Results: The DNA-based methods showed strong intermethod correlation, but were less sensitive than RT-qPCR. A bone marrow cutoff at 0.1% leukemic DNA for qPCR or 0.05% variant allele frequency for ddPCR and deep seq offered optimal sensitivity and specificity with respect to 3 log(10) reduction of NPM1 transcripts and/or 2% mutant NPM1/ABL. With these cutoffs, MRD results agreed in 95% (191/201) of the analyses. Although more sensitive, RT-qPCR failed to detect leukemic signals in 10% of samples with detectable leukemic DNA. Conclusion: DNA-based MRD techniques may complement RT-qPCR for assessment of residual leukemia. DNA-based methods offer high positive and negative predictive values with respect to residual leukemic NPM1 transcripts at levels of importance for response to treatment. However, moving to DNA-based MRD methods will miss a proportion of patients with residual leukemic RNA, but on the other hand some MRD samples with detectable leukemic DNA can be devoid of measurable leukemic RNA.
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| 42. |
- Piel, Sarah, et al.
(författare)
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Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest
- 2024
-
Ingår i: Scientific Reports. - 2045-2322. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF’s protective mechanisms and optimize its therapeutic application in post-arrest care.
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| 43. |
- Ponjavic, Vesna, et al.
(författare)
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Clinical expression of X-linked retinitis pigmentosa in a Swedish family with the RP2 genotype
- 1998
-
Ingår i: Ophthalmic Genetics. - 1744-5094. ; 19:4, s. 187-196
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To examine the clinical phenotype with emphasis on electroretinograms and visual fields in a Swedish family with X-linked retinitis pigmentosa (XLRP) type 2 (RP2), and compare it with Swedish XLRP families with the RP3 genotype. METHODS: Three affected brothers and their carrier mother were examined clinically and with kinetic perimetry, dark adaptation thresholds, and full-field electroretinograms. The genotype was determined by haplotype analysis using polymorphic markers spanning the XLRP loci at the short arm of the X chromosome. RESULTS: The phenotype was consistent in the three affected males. The first subjective symptom was night blindness and the visual disability was more pronounced with increasing age. Affected individuals had a slight decrease in visual acuity and were emmetropic. They demonstrated a pathologically elevated final rod threshold. The visual fields were constricted in a somewhat atypical pattern. The three patients had an early presenting atypical cataract with multiple opacities. The fundus appearance was typical for RP with narrowing of retinal vessels and bone spicule pigmentations. The rod electroretinograms were extinguished in both eyes of the patients. The combined rod-cone responses as well as the isolated cone responses were severely reduced in amplitude; however, atypically for RP, the implicit time for the isolated cone responses was normal. The carrier female demonstrated normal ophthalmological findings, with the exception of two minimal pigmentations in the lower quadrants of the left eye. Haplotype analysis demonstrated that the disease in this family segregates with the RP2 locus. CONCLUSION: The phenotype of the studied RP2 family is associated with early onset of night blindness, emmetropia, a slight decrease in visual acuity, constriction of visual fields, and atypical cataract formation. Electroretinograms demonstrate severe rod dysfunction and surprisingly normal cone response implicit times which may indicate a milder disease progression. These findings are different from earlier descriptions of the RP2 and RP3 phenotypes.
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| 44. |
- Senthil, Kumaran, et al.
(författare)
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Transcriptome and metabolome after porcine hemodynamic-directed CPR compared with standard CPR and sham controls
- 2022
-
Ingår i: Resuscitation Plus. - : Elsevier BV. - 2666-5204. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The effect of cardiac arrest (CA) on cerebral transcriptomics and metabolomics is unknown. We previously demonstrated hemodynamic-directed CPR (HD-CPR) improves survival with favorable neurologic outcomes versus standard CPR (Std-CPR). We hypothesized HD-CPR would preserve the cerebral transcriptome and metabolome compared to Std-CPR. Design: Randomized pre-clinical animal trial. Setting: Large animal resuscitation laboratory at an academic children's hospital. Subjects: Four-week-old female piglets (8–11 kg). Interventions: Pigs (1-month-old), three groups: 1) HD-CPR (compression depth to systolic BP 90 mmHg, vasopressors to coronary perfusion pressure 20 mmHg); 2) Std-CPR and 3) shams (no CPR). HD-CPR and Std-CPR underwent asphyxia, induced ventricular fibrillation, 10–20 min of CPR and post-resuscitation care. Primary outcomes at 24 h in cerebral cortex: 1) transcriptomic analysis (n = 4 per treatment arm, n = 8 sham) of 1727 genes using differential gene expression and 2) metabolomic analysis (n = 5 per group) of 27 metabolites using one-way ANOVA, post-hoc Tukey HSD. Measurements and main results: 65 genes were differentially expressed between HD-CPR and Std-CPR and 72 genes between Std-CPR and sham, but only five differed between HD-CPR and sham. Std-CPR increased the concentration of five AA compared to HD-CPR and sham, including the branched chain amino acids (BCAA), but zero metabolites differed between HD-CPR and sham. Conclusions: In cerebral cortex 24 h post CA, Std-CPR resulted in a different transcriptome and metabolome compared with either HD-CPR or sham. HD-CPR preserves the transcriptome and metabolome, and is neuroprotective. Global molecular analyses may be a novel method to assess efficacy of clinical interventions and identify therapeutic targets. Institutional protocol number: IAC 16-001023.
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| 45. |
- Skov, Vibe, et al.
(författare)
-
A 7-gene signature depicts the biochemical profile of early prefibrotic myelofibrosis
- 2016
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
-
Tidskriftsartikel (refereegranskat)abstract
- Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to theWorld Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between themmay be challenging and several studies have not been able to distinguish between them.Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH.Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100%and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, andMMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of "ET" patients.
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| 46. |
- Snyder, Joel S., et al.
(författare)
-
#EEGManyLabs: Investigating the replicability of influential EEG experiments
- 2021
-
Ingår i: Cortex. - : Elsevier. - 1973-8102 .- 0010-9452. ; 144, s. 213-229
-
Tidskriftsartikel (refereegranskat)abstract
- There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalog-raphy (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound in-fluence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and se-lection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 47. |
- Vallon-Christersson, J., et al.
(författare)
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RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer
- 2022
-
Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 33:Suppl 3, s. 144-145
-
Konferensbidrag (refereegranskat)abstract
- BackgroundMultigene expression assays for molecular subtypes and biomarkers can aid clinical management of early invasive breast cancer. Based on RNA-sequencing we aimed to develop single-sample predictor (SSP) models for conventional clinical markers, molecular intrinsic subtype and risk of recurrence (ROR).MethodsA uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set and a reserved test set. We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna® in two external cohorts. Prognostic value was assessed using distant recurrence-free interval.ResultsIn the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC was assessed as equivalent. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade, respectively. SSP concordance with Prosigna® was high for subtype and moderate and high for ROR risk category. In pooled analysis, concordance between SSP and Prosigna® for emulated treatment recommendation for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of chemotherapy.ConclusionsSSP models for histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and outcome analyses suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level. Retrospective evaluation in postmenopausal ER+/HER2-/N0 patients suggested that molecular testing could lead to a changed therapy recommendation for almost one-fifth of patients.
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| 48. |
- Walker, C. L., et al.
(författare)
-
Ultrasound prediction of Zika virus-associated congenital injury using the profile of fetal growth
- 2020
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
-
Tidskriftsartikel (refereegranskat)abstract
- Zika virus (ZIKV) is a mosquito-transmitted flavivirus, recently linked to microcephaly and central nervous system anomalies following infection in pregnancy. Striking findings of disproportionate growth with a smaller than expected head relative to body length have been observed more commonly among fetuses with exposure to ZIKV in utero compared to pregnancies without ZIKV infection regardless of other signs of congenital infection including microcephaly. This study's objective was to determine the diagnostic accuracy of femursparing profile of intrauterine growth restriction for the identification of ZIKV-associated congenital injuries on postnatal testing. A retrospective cohort study of pregnant women with possible or confirmed ZIKV infection between January 1, 2016 and December 31, 2017 were included. Subjects were excluded if no prenatal ultrasound was available. A femursparing profile of growth restriction determined using INTERGROWTH-21st sonographic standard for head circumference to femur length (HC: FL). Congenital injuries were determined postnatally by imaging, comprehensive eye exam and standard newborn hearing screen. A total of 111 pregnant women diagnosed with ZIKV infection underwent fetal ultrasound and 95 neonates had complete postnatal evaluation. Prenatal microcephaly was detected in 5% of fetuses (6/111). Postnatal testing detected ZIKV-associated congenital injuries in 25% of neonates (24/95). A HC: FL Z-score <=-1.3 had a 52% specificity (95% CI 41-63%), 82% negative predictive value (NPV, 95% CI 73-88%) for the detection of ZIKV-associated congenital injuries in the neonatal period. A more stringent threshold with a Z-score <=-2 was associated with a 90% specificity (95% CI 81-95%), 81% NPV (95% CI 77-85%). Excluding cases of fetal microcephaly, HC: FL (Z-score <=-2) demonstrated a similar specificity (89%, 95% CI 81-95%) with superior NPV (87%, 95% CI 84-90%). The sono-graphic recognition of a normally proportioned fetus may be useful prenatally to exclude a wider spectrum of ZIKV-associated congenital injuries detected postnatally.
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| 49. |
- Walker, C. L., et al.
(författare)
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Zika virus and the nonmicrocephalic fetus: why we should still worry
- 2019
-
Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier BV. - 0002-9378 .- 1097-6868. ; 220:1, s. 45-56
-
Forskningsöversikt (refereegranskat)abstract
- Zika virus is a mosquito-transmitted flavivirus and was first linked to congenital microcephaly caused by a large outbreak in northeastern Brazil. Although the Zika virus epidemic is now in decline, pregnancies in large parts of the Americas remain at risk because of ongoing transmission and the potential for new outbreaks. This review presents why Zika virus is still a complex and worrisome public health problem with an expanding spectrum of birth defects and how Zika virus and related viruses evade the immune response to injure the fetus. Recent reports indicate that the spectrum of fetal brain and other anomalies associated with Zika virus exposure is broader and more complex than microcephaly alone and includes subtle fetal brain and ocular injuries; thus, the ability to prenatally diagnose fetal injury associated with Zika virus infection remains limited. New studies indicate that Zika virus imparts disproportionate effects on fetal growth with an unusual femur-sparing profile, potentially providing a new approach to identify viral injury to the fetus. Studies to determine the limitations of prenatal and postnatal testing for detection of Zika virus-associated birth defects and long-term neurocognitive deficits are needed to better guide women with a possible infectious exposure. It is also imperative that we investigate why the Zika virus is so adept at infecting the placenta and the fetal brain to better predict other viruses with similar capabilities that may give rise to new epidemics. The efficiency with which the Zika virus evades the early immune response to enable infection of the mother, placenta, and fetus is likely critical for understanding why the infection may either be fulminant or limited. Furthermore, studies suggest that several emerging and related viruses may also cause birth defects, including West Nile virus, which is endemic in many parts of the United States. With mosquito-borne diseases increasing worldwide, there remains an urgent need to better understand the pathogenesis of the Zika virus and related viruses to protect pregnancies and child health.
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| 50. |
- Walsh, SH, et al.
(författare)
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Mutated V-H genes and preferential V(H)3-21 use define new subsets of mantle cell lymphoma
- 2003
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 101:10, s. 4047-4054
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is believed to originate from a naive B cell. However, we recently demonstrated that a subset of MCL displayed mutated V-H genes. We also reported restricted use of certain V-H genes. To assess the prognostic impact of these new findings, we performed V-H gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%) patients had unmutated V-H genes. Because the mutation rate was low in the mutated group (2.2%-6.7%), further investigation of the germline V-H gene in T cells from 5 patients with mutated V-H genes was carried out; results showed that the unrearranged V-H gene was identical to the published sequence. These data confirm that the base pair substitutions within the rearranged V-H genes represent hyper-mutations, and indicate germinal center exposure. However, V-H gene mutation status did not correlate with prognosis because there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently used V-H genes were V(H)3-21 (21 patients) and V(H)4-34 (19 patients). A novel finding was that V(H)3-21(+) MCL almost exclusively ex-pressed X light chains and displayed highly restricted use of the V(lambda)3-19 gene. V(H)3-21(+) patients had longer median survival than the remaining patients (53 vs 34 months; P = .03), but they tended to be younger at diagnosis. The combined use Of V(H)3-21/V(lambda)3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that V(H)3-21(+) patients constitute a new MCL entity. (C) 2003 by The American Society of Hematology.
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