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- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)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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- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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- Zhu, RJ, et al.
(author)
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Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms
- 2021
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In: Cell research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 31:12, s. 1244-1262
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Journal article (peer-reviewed)abstract
- The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.
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- Ren, WC, et al.
(author)
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Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma
- 2018
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 131:24, s. 2670-2681
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Journal article (peer-reviewed)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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- Stener-Victorin, E, et al.
(author)
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Acupuncture or metformin to improve insulin resistance in women with polycystic ovary syndrome: study protocol of a combined multinational cross sectional case-control study and a randomised controlled trial
- 2019
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In: BMJ open. - : BMJ. - 2044-6055. ; 9:1, s. e024733-
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Journal article (peer-reviewed)abstract
- Polycystic ovary syndrome (PCOS) is linked to hyperinsulinemia and insulin resistance with dysfunctional glucose metabolism. Pilot studies suggests that acupuncture treatment with combined manual and low-frequency electrical stimulation (electroacupuncture (EA)) of the needles decrease circulating glycated haemoglobulin (HbA1c) and homeostatic model assessment-insulin resistance. Therefore, we here aim to investigate if acupuncture treatment or metformin together with lifestyle or lifestyle management alone improves insulin sensitivity and related symptoms in overweight/obese women with PCOS.Methods and analysisThis is a two-centre multinational (Sweden and China), cross-sectional case–control study combined with an open-labelled randomised controlled trial (RCT). Participants are randomised to one of three groups: (1) EA 2–3 times/week during 4 months+lifestyle management; (2) metformin, 500 mg, three/day during 4 months+lifestyle management; or (3) lifestyle management alone. The primary outcome measure in the RCT is changes in HbA1C. A total of 123 obese overweight women with PCOS will be enrolled and randomised into one of the three groups with a target power of at least 80% and 5% significance level based on two-sided tests.Ethics and disseminationThe study has been approved by the Regional Ethical Review Board of Stockholm and of Peking University Third Hospital, China. Primary outcome data of the RCT will be published in a relevant journal together with supporting secondary outcome measurements. Further, outcome measurements will be published in separate papers as well as case–control data.Expected resultsWe anticipate that EA and metformin, both with lifestyle management, are equally effective and superior to lifestyle management alone for improvement of glycaemic control.Trial registration numbersNCT02647827and EudraCT2015-004250-18.
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- Xie, ZJ, et al.
(author)
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Light-induced tumor theranostics based on chemical-exfoliated borophene
- 2022
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In: Light, science & applications. - : Springer Science and Business Media LLC. - 2047-7538. ; 11:1, s. 324-
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Journal article (peer-reviewed)abstract
- Among 2D materials (Xenes) which are at the forefront of research activities, borophene, is an exciting new entry due to its uniquely varied optical, electronic, and chemical properties in many polymorphic forms with widely varying band gaps including the lightest 2D metallic phase. In this paper, we used a simple selective chemical etching to prepare borophene with a strong near IR light-induced photothermal effect. The photothermal efficiency is similar to plasmonic Au nanoparticles, with the added benefit of borophene being degradable due to electron deficiency of boron. We introduce this selective chemical etching process to obtain ultrathin and large borophene nanosheets (thickness of ~4 nm and lateral size up to ~600 nm) from the precursor of AlB2. We also report first-time observation of a selective Acid etching behavior showing HCl etching of Al to form a residual B lattice, while HF selectively etches B to yield an Al lattice. We demonstrate that through surface modification with polydopamine (PDA), a biocompatible smart delivery nanoplatform of B@PDA can respond to a tumor environment, exhibiting an enhanced cellular uptake efficiency. We demonstrate that borophene can be more suitable for safe photothermal theranostic of thick tumor using deep penetrating near IR light compared to gold nanoparticles which are not degradable, thus posing long-term toxicity concerns. With about 40 kinds of borides, we hope that our work will open door to more discoveries of this top-down selective etching approach for generating borophene structures with rich unexplored thermal, electronic, and optical properties for many other technological applications.
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- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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- Khatri, C, et al.
(author)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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In: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Journal article (peer-reviewed)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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