| 1. |
- Hoshino, Ayuko, et al.
(författare)
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Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers
- 2020
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Ingår i: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 182:4, s. 1044-
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Tidskriftsartikel (refereegranskat)abstract
- There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n =151) and plasma-derived (n =120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
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| 2. |
- Arcavi, Iair, et al.
(författare)
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Energetic eruptions leading to a peculiar hydrogen-rich explosion of a massive star
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 551:7679, s. 210-213
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Tidskriftsartikel (refereegranskat)abstract
- Every supernova so far observed has been considered to be the terminal explosion of a star. Moreover, all supernovae with absorption lines in their spectra show those lines decreasing in velocity over time, as the ejecta expand and thin, revealing slower-moving material that was previously hidden. In addition, every supernova that exhibits the absorption lines of hydrogen has one main light-curve peak, or a plateau in luminosity, lasting approximately 100 days before declining(1). Here we report observations of iPTF14hls, an event that has spectra identical to a hydrogen-rich core-collapse supernova, but characteristics that differ extensively from those of known supernovae. The light curve has at least five peaks and remains bright for more than 600 days; the absorption lines show little to no decrease in velocity; and the radius of the line-forming region is more than an order of magnitude bigger than the radius of the photosphere derived from the continuum emission. These characteristics are consistent with a shell of several tens of solar masses ejected by the progenitor star at supernova-level energies a few hundred days before a terminal explosion. Another possible eruption was recorded at the same position in 1954. Multiple energetic pre-supernova eruptions are expected to occur in stars of 95 to 130 solar masses, which experience the pulsational pair instability(2-5). That model, however, does not account for the continued presence of hydrogen, or the energetics observed here. Another mechanism for the violent ejection of mass in massive stars may be required.
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| 3. |
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| 4. |
- Ellinghaus, David, et al.
(författare)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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| 5. |
- Hoshino, Ayuko, et al.
(författare)
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Tumour exosome integrins determine organotropic metastasis
- 2015
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 527:7578, s. 329-
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Tidskriftsartikel (refereegranskat)abstract
- Ever since Stephen Pagets 1889 hypothesis, metastatic organotropism has remained one of cancers greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver-and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
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| 6. |
- Markmann, James F., et al.
(författare)
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Executive Summary of IPITA-TTS Opinion Leaders Report on the Future of beta-Cell Replacement
- 2016
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 100:7, s. E25-E31
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Forskningsöversikt (refereegranskat)abstract
- The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation.
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| 7. |
- Neuwirth, Christoph, et al.
(författare)
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Implementing Motor Unit Number Index (MUNIX) in a large clinical trial : Real world experience from 27 centres
- 2018
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Ingår i: Clinical Neurophysiology. - : Elsevier. - 1388-2457 .- 1872-8952. ; 129:8, s. 1756-1762
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of motor neurons in Amyotrophic Lateral Sclerosis (ALS) in longitudinal studies. It has been utilized in one natural history ALS study and one drug trial (Biogen USA) after training and qualification of raters.METHODS: Prior to testing patients, evaluators had to submit test-retest data of 4 healthy volunteers. Twenty-seven centres with 36 raters measured MUNIX in 4 sets of 6 different muscles twice. Coefficient of variation of all measurements had to be <20% to pass the qualification process. MUNIX COV of the first attempt, number of repeated measurements and muscle specific COV were evaluated.RESULTS: COV varied considerably between raters. Mean COV of all raters at the first measurements was 12.9% ± 13.5 (median 8.7%). Need of repetitions ranged from 0 to 43 (mean 10.7 ± 9.1, median 8). Biceps and first dorsal interosseus muscles showed highest repetition rates. MUNIX variability correlated considerably with variability of compound muscle action potential.CONCLUSION: MUNIX revealed generally good reliability, but was rater dependent and ongoing support for raters was needed.SIGNIFICANCE: MUNIX can be implemented in large clinical trials as an outcome measure after training and a qualification process.
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