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| 2. |
- Rich, Rebecca L., et al.
(författare)
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A global benchmark study using affinity-based biosensors
- 2009
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Ingår i: Analytical Biochemistry. - : Elsevier BV. - 0003-2697 .- 1096-0309. ; 386:2, s. 194-216
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Tidskriftsartikel (refereegranskat)abstract
- To explore the variability in biosensor studies, 150 participants from 20 countries were given the same protein samples and asked to determine kinetic rate constants for the interaction. We chose a protein system that was amenable to analysis using different biosensor platforms as well as by users of different expertise levels. The two proteins (a 50-kDa Fab and a 60-kDa glutathione S-transferase [GST] antigen) form a relatively high-affinity complex, so participants needed to optimize several experimental parameters, including ligand immobilization and regeneration conditions as well as analyte concentrations and injection/dissociation times. Although most participants collected binding responses that could be fit to yield kinetic parameters, the quality of a few data sets could have been improved by optimizing the assay design. Once these outliers were removed, the average reported affinity across the remaining panel of participants was 620 pM with a standard deviation of 980 pM. These results demonstrate that when this biosensor assay was designed and executed appropriately, the reported rate constants were consistent, and independent of which protein was immobilized and which biosensor was used.
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| 3. |
- Weinstock, Joshua S, et al.
(författare)
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Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
- 2023
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Ingår i: Nature. - 1476-4687. ; 616:7958, s. 755-763
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, butthis effect was not seen inclones withdriver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimentalknockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
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| 4. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 5. |
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| 6. |
- Borrelli, P., et al.
(författare)
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AI-based detection of lung lesions in F-18 FDG PET-CT from lung cancer patients
- 2021
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Ingår i: Ejnmmi Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background[F-18]-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT) is a well-established modality in the work-up of patients with suspected or confirmed diagnosis of lung cancer. Recent research efforts have focused on extracting theragnostic and textural information from manually indicated lung lesions. Both semi-automatic and fully automatic use of artificial intelligence (AI) to localise and classify FDG-avid foci has been demonstrated. To fully harness AI's usefulness, we have developed a method which both automatically detects abnormal lung lesions and calculates the total lesion glycolysis (TLG) on FDG PET-CT.MethodsOne hundred twelve patients (59 females and 53 males) who underwent FDG PET-CT due to suspected or for the management of known lung cancer were studied retrospectively. These patients were divided into a training group (59%; n = 66), a validation group (20.5%; n = 23) and a test group (20.5%; n = 23). A nuclear medicine physician manually segmented abnormal lung lesions with increased FDG-uptake in all PET-CT studies. The AI-based method was trained to segment the lesions based on the manual segmentations. TLG was then calculated from manual and AI-based measurements, respectively and analysed with Bland-Altman plots.ResultsThe AI-tool's performance in detecting lesions had a sensitivity of 90%. One small lesion was missed in two patients, respectively, where both had a larger lesion which was correctly detected. The positive and negative predictive values were 88% and 100%, respectively. The correlation between manual and AI TLG measurements was strong (R-2 = 0.74). Bias was 42 g and 95% limits of agreement ranged from -736 to 819 g. Agreement was particularly high in smaller lesions.ConclusionsThe AI-based method is suitable for the detection of lung lesions and automatic calculation of TLG in small- to medium-sized tumours. In a clinical setting, it will have an added value due to its capability to sort out negative examinations resulting in prioritised and focused care on patients with potentially malignant lesions.
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| 7. |
- Grossmann, Igor, et al.
(författare)
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Insights into the accuracy of social scientists' forecasts of societal change
- 2023
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Ingår i: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 7, s. 484-501
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Tidskriftsartikel (refereegranskat)abstract
- How well can social scientists predict societal change, and what processes underlie their predictions? To answer these questions, we ran two forecasting tournaments testing the accuracy of predictions of societal change in domains commonly studied in the social sciences: ideological preferences, political polarization, life satisfaction, sentiment on social media, and gender-career and racial bias. After we provided them with historical trend data on the relevant domain, social scientists submitted pre-registered monthly forecasts for a year (Tournament 1; N = 86 teams and 359 forecasts), with an opportunity to update forecasts on the basis of new data six months later (Tournament 2; N = 120 teams and 546 forecasts). Benchmarking forecasting accuracy revealed that social scientists' forecasts were on average no more accurate than those of simple statistical models (historical means, random walks or linear regressions) or the aggregate forecasts of a sample from the general public (N = 802). However, scientists were more accurate if they had scientific expertise in a prediction domain, were interdisciplinary, used simpler models and based predictions on prior data. How accurate are social scientists in predicting societal change, and what processes underlie their predictions? Grossmann et al. report the findings of two forecasting tournaments. Social scientists' forecasts were on average no more accurate than those of simple statistical models.
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| 8. |
- Ly, Han, et al.
(författare)
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The association of circulating amylin with β-amyloid in familial Alzheimer's disease.
- 2021
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Ingår i: Alzheimer's & dementia. - : Wiley. - 2352-8737. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD).Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats.Amylin-Aβ cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ42 concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aβ exchange and amylin-Aβ cross-seeding.These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aβ-related pathology/symptoms.
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| 9. |
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| 10. |
- Ly, John, et al.
(författare)
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Post-reconstruction enhancement of [18F]FDG PET images with a convolutional neural network
- 2021
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of the study was to develop and test an artificial intelligence (AI)-based method to improve the quality of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) images. Methods: A convolutional neural network (CNN) was trained by using pairs of excellent (acquisition time of 6 min/bed position) and standard (acquisition time of 1.5 min/bed position) or sub-standard (acquisition time of 1 min/bed position) images from 72 patients. A test group of 25 patients was used to validate the CNN qualitatively and quantitatively with 5 different image sets per patient: 4 min/bed position, 1.5 min/bed position with and without CNN, and 1 min/bed position with and without CNN. Results: Difference in hotspot maximum or peak standardized uptake value between the standard 1.5 min and 1.5 min CNN images fell short of significance. Coefficient of variation, the noise level, was lower in the CNN-enhanced images compared with standard 1 min and 1.5 min images. Physicians ranked the 1.5 min CNN and the 4 min images highest regarding image quality (noise and contrast) and the standard 1 min images lowest. Conclusions: AI can enhance [18F]FDG-PET images to reduce noise and increase contrast compared with standard images whilst keeping SUVmax/peak stability. There were significant differences in scoring between the 1.5 min and 1.5 min CNN image sets in all comparisons, the latter had higher scores in noise and contrast. Furthermore, difference in SUVmax and SUVpeak fell short of significance for that pair. The improved image quality can potentially be used either to provide better images to the nuclear medicine physicians or to reduce acquisition time/administered activity.
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| 11. |
- Ly, John, et al.
(författare)
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Semi-automatic analysis of standard uptake values in serial PET/CT studies in patients with lung cancer and lymphoma
- 2012
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Ingår i: BMC Medical Imaging. - : Springer Science and Business Media LLC. - 1471-2342. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Changes in maximum standardised uptake values (SUVmax) between serial PET/CT studies are used to determine disease progression or regression in oncologic patients. To measure these changes manually can be time consuming in a clinical routine. A semi-automatic method for calculation of SUVmaxin serial PET/CT studies was developed and compared to a conventional manual method. The semi-automatic method first aligns the serial PET/CT studies based on the CT images. Thereafter, the reader selects an abnormal lesion in one of the PET studies. After this manual step, the program automatically detects the corresponding lesion in the other PET study, segments the two lesions and calculates the SUVmaxin both studies as well as the difference between the SUVmaxvalues. The results of the semi-automatic analysis were compared to that of a manual SUVmaxanalysis using a Philips PET/CT workstation. Three readers did the SUVmaxreadings in both methods. Sixteen patients with lung cancer or lymphoma who had undergone two PET/CT studies were included. There were a total of 26 lesions.Results: Linear regression analysis of changes in SUVmaxshow that intercepts and slopes are close to the line of identity for all readers (reader 1: intercept = 1.02, R2= 0.96; reader 2: intercept = 0.97, R2= 0.98; reader 3: intercept = 0.99, R2= 0.98). Manual and semi-automatic method agreed in all cases whether SUVmaxhad increased or decreased between the serial studies. The average time to measure SUVmaxchanges in two serial PET/CT examinations was four to five times longer for the manual method compared to the semi-automatic method for all readers (reader 1: 53.7 vs. 10.5 s; reader 2: 27.3 vs. 6.9 s; reader 3: 47.5 vs. 9.5 s; p < 0.001 for all).Conclusions: Good agreement was shown in assessment of SUVmaxchanges between manual and semi-automatic method. The semi-automatic analysis was four to five times faster to perform than the manual analysis. These findings show the feasibility of using semi-automatic methods for calculation of SUVmaxin clinical routine and encourage further development of programs using this type of methods. © 2012 Ly et al; licensee BioMed Central Ltd.
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| 12. |
- Ly, John, et al.
(författare)
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The use of a proposed updated EARL harmonization of 18F-FDG PET-CT in patients with lymphoma yields significant differences in Deauville score compared with current EARL recommendations
- 2019
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Deauville score (DS) is a clinical tool, based on the comparison between lesion and reference organ uptake of 18F-fluorodeoxyglucose (FDG), used to stratify patients with lymphoma into categories reflecting their disease status. With a plethora of positron emission tomography with computed tomography (PET-CT) hard- and software algorithms, standard uptake value (SUV) in lesions and reference organs may differ which affects DS classification and therefore medical treatment. The EANM Research Ltd. (EARL) harmonization program from the European Association of Nuclear Medicine (EANM) partly mitigates this issue, but local preferences are common in clinical practice. We have investigated the discordance in DS calculated from patients with lymphoma referred for 18F-FDG PET-CT reconstructed with three different algorithms: the newly introduced block-sequential regularization expectation-maximization algorithm commercially sold as Q. Clear (QC, GE Healthcare, Milwaukee, WI, USA), compliant with the newly proposed updated EARL recommendations, and two settings compliant with the current EARL recommendations (EARLlower and EARLupper, representing the lower and upper limit of the EARL recommendations). Methods: Fifty-two patients with non-Hodgkin and Hodgkin lymphoma were included (18 females and 34 males). Segmentation of mediastinal blood pool and liver were semi-automatically performed, whereas segmentation of lesions was done manually. From these segmentations, SUVmax and SUVpeak were obtained and DS calculated. Results: There was a significant difference in DS between the QC algorithm and EARLlower/EARLupper (p < 0.0001 for both) but not between EARLlower and EARLupper (p = 0.102) when SUVmax was used. For SUVpeak, there was a significant difference between QC and EARLlower (p = 0.001), but not for QC vs EARLupper (p = 0.071) or EARLlower vs EARLupper (p = 0.102). Five non-responders (DS 4–5) for QC were classified as responders (DS 1–3) when EARLlower/EARLupper was used, both when SUVmax and SUVpeak were investigated. Conclusion: Using the proposed updated EARL recommendations compared with the current recommendations will significantly change DS classification. In select cases, the discordance would affect the choice of medical treatment. Specifically, the current EARL recommendations were more often prone to classify patients as responders.
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| 13. |
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| 14. |
- Vu, Ly P., et al.
(författare)
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Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:6, s. 866-875
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Tidskriftsartikel (refereegranskat)abstract
- The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.
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