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- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 8. |
- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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| 12. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Ren, WC, et al.
(författare)
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Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma
- 2018
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 131:24, s. 2670-2681
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.
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| 24. |
- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 26. |
- 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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| 27. |
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| 28. |
- Wu, K, et al.
(författare)
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Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 10131-
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Tidskriftsartikel (refereegranskat)abstract
- The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.
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| 30. |
- Wu, ZC, et al.
(författare)
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Tumor suppressor ZHX2 inhibits NAFLD-HCC progression via blocking LPL-mediated lipid uptake
- 2020
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 27:5, s. 1693-1708
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD–HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD–HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.
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| 33. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 37. |
- Bi, JL, et al.
(författare)
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RACK1 is indispensable for porcine reproductive and respiratory syndrome virus replication and NF-κB activation in Marc-145 cells
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 2985-
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Tidskriftsartikel (refereegranskat)abstract
- Porcine reproductive and respiratory syndrome virus (PRRSV) causes porcine reproductive and respiratory syndrome (PRRS), which is currently insufficiently controlled. RACK1 (receptor of activated protein C kinase 1) was first identified as a receptor for protein kinase C, with increasing evidence showing that the functionally conserved RACK1 plays important roles in cancer development, NF-κB activation and various virus infections. However, the roles of RACK1 during PRRSV infection in Marc-145 cells have not been described yet. Here we demonstrated that infection of Marc-145 cells with the highly pathogenic PRRSV strain YN-1 from our lab led to activation of NF-κB and upregulation of RACK1 expression. The siRNA knockdown of RACK1 inhibited PRRSV replication in Marc-145 cells, abrogated NF-κB activation induced by PRRSV infection and reduced the viral titer. Furthermore, knockdown of RACK1 could inhibit an ongoing PRRSV infection. We found that RACK1 is highly conserved across different species based on the phylogenetic analysis of mRNA and deduced amino acid sequences. Taken together, RACK1 plays an indispensable role for PRRSV replication in Marc-145 cells and NF-κB activation. The results would advance our further understanding of the molecular mechanisms underlying PRRSV infection in swine and indicate RACK1 as a promising potential therapeutic target.
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| 43. |
- Elfer, Katherine, et al.
(författare)
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Pilot study to evaluate tools to collect pathologist annotations for validating machine learning algorithms
- 2022
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Ingår i: Journal of Medical Imaging. - 2329-4302. ; 9:4, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Validation of artificial intelligence (AI) algorithms in digital pathology with a reference standard is necessary before widespread clinical use, but few examples focus on creating a reference standard based on pathologist annotations. This work assesses the results of a pilot study that collects density estimates of stromal tumor-infiltrating lymphocytes (sTILs) in breast cancer biopsy specimens. This work will inform the creation of a validation dataset for the evaluation of AI algorithms fit for a regulatory purpose. Approach: Collaborators and crowdsourced pathologists contributed glass slides, digital images, and annotations. Here, "annotations" refer to any marks, segmentations, measurements, or labels a pathologist adds to a report, image, region of interest (ROI), or biological feature. Pathologists estimated sTILs density in 640 ROIs from hematoxylin and eosin stained slides of 64 patients via two modalities: an optical light microscope and two digital image viewing platforms. Results: The pilot study generated 7373 sTILs density estimates from 29 pathologists. Analysis of annotations found the variability of density estimates per ROI increases with the mean; the root mean square differences were 4.46, 14.25, and 26.25 as the mean density ranged from 0% to 10%, 11% to 40%, and 41% to 100%, respectively. The pilot study informs three areas of improvement for future work: technical workflows, annotation platforms, and agreement analysis methods. Upgrades to the workflows and platforms will improve operability and increase annotation speed and consistency. Conclusions: Exploratory data analysis demonstrates the need to develop new statistical approaches for agreement. The pilot study dataset and analysis methods are publicly available to allow community feedback. The development and results of the validation dataset will be publicly available to serve as an instructive tool that can be replicated by developers and researchers.
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| 44. |
- Elfer, Katherine, et al.
(författare)
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Reproducible Reporting of the Collection and Evaluation of Annotations for Artificial Intelligence Models
- 2024
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Ingår i: Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. - 1530-0285. ; 37:4
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Tidskriftsartikel (refereegranskat)abstract
- This work advances and demonstrates the utility of a reporting framework for collecting and evaluating annotations of medical images used for training and testing artificial intelligence (AI) models in assisting detection and diagnosis. AI has unique reporting requirements, as shown by the AI extensions to the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklists and the proposed AI extensions to the STARD (Standards for Reporting Diagnostic Accuracy) and TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) checklists. AI for detection and/or diagnostic image analysis requires complete, reproducible, and transparent reporting of the annotations and metadata used in training and testing datasets. Prior work by Wahab et al. proposed an annotation workflow and quality checklist for computational pathology annotations. In this manuscript, we operationalize this workflow into an evaluable quality checklist that applies to any reader-interpreted medical images, and we demonstrate its use for an annotation effort in digital pathology. We refer to this quality framework as CLEARR-AI: The Collection and Evaluation of Annotations for Reproducible Reporting of Artificial Intelligence.
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| 45. |
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| 46. |
- Fang, MY, et al.
(författare)
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T Cell Repertoire Abnormality in Immunodeficiency Patients with DNA Repair and Methylation Defects
- 2022
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Ingår i: Journal of clinical immunology. - : Springer Science and Business Media LLC. - 1573-2592 .- 0271-9142. ; 42:2, s. 375-393
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Tidskriftsartikel (refereegranskat)abstract
- Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B,ZBTB24,RAG1,DCLRE1C, andJAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients withDNMT3BandZBTB24mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.
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| 47. |
- Garcia, Victor, et al.
(författare)
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Development of Training Materials for Pathologists to Provide Machine Learning Validation Data of Tumor-Infiltrating Lymphocytes in Breast Cancer
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:10, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- The High Throughput Truthing project aims to develop a dataset for validating artificial intelligence and machine learning models (AI/ML) fit for regulatory purposes. The context of this AI/ML validation dataset is the reporting of stromal tumor-infiltrating lymphocytes (sTILs) density evaluations in hematoxylin and eosin-stained invasive breast cancer biopsy specimens. After completing the pilot study, we found notable variability in the sTILs estimates as well as inconsistencies and gaps in the provided training to pathologists. Using the pilot study data and an expert panel, we created custom training materials to improve pathologist annotation quality for the pivotal study. We categorized regions of interest (ROIs) based on their mean sTILs density and selected ROIs with the highest and lowest sTILs variability. In a series of eight one-hour sessions, the expert panel reviewed each ROI and provided verbal density estimates and comments on features that confounded the sTILs evaluation. We aggregated and shaped the comments to identify pitfalls and instructions to improve our training materials. From these selected ROIs, we created a training set and proficiency test set to improve pathologist training with the goal to improve data collection for the pivotal study. We are not exploring AI/ML performance in this paper. Instead, we are creating materials that will train crowd-sourced pathologists to be the reference standard in a pivotal study to create an AI/ML model validation dataset. The issues discussed here are also important for clinicians to understand about the evaluation of sTILs in clinical practice and can provide insight to developers of AI/ML models.
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