We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ...ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis.
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► A Sleeping Beauty screen followed by MuTaME analysis discovered putative PTEN ceRNAs ► The PTEN ceRNA ZEB2 regulates PTEN in a miRNA-dependent manner ► ZEB2 loss activates PI3K/AKT signaling and promotes cell transformation ► Attenuated ZEB2 expression is found in melanoma and other human cancers
A transposon-based mutagenesis screen uncovers a striking enrichment of putative PTEN ceRNAs among mutated genes that accelerate tumorigenesis in a mouse model of melanoma. One candidate gene, ZEB2, regulates PI3K/AKT signaling and tumor-suppressive properties of PTEN.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove ...intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov , NCT00784134. Findings Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio RR 1·06 95% CI 0·88–1·28; p=0·554). A difference of 3·5% (RR 1·08 95% CI 0·90–1·29, p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 18% vs saline 73 29%, hazard ratio 0·60 95% CI 0·41–0·86, p=0·006), but a greater proportion with mRS 5 (42 17% vs 21 9%; RR 1·99 95% CI 1·22–3·26, p=0·007). Ventriculitis (17 7% alteplase vs 31 12% saline; RR 0·55 95% CI 0·31–0·97, p=0·048) and serious adverse events (114 46% alteplase vs 151 60% saline; RR 0·76 95% CI 0·64–0·90, p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six 2% in the alteplase group vs five 2% in the saline group; RR 1·21 95% CI 0·37–3·91, p=0·771) was similar. Interpretation In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. Funding National Institute of Neurological Disorders and Stroke.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors ...that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly ...understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
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•Pan-cancer resource of comprehensively annotated intra-tumor heterogeneity (ITH)•ITH is pervasive across cancers and shows cancer type-specific patterns•Branching phylogenies are common•Dynamic changes in mutational processes between subclonal expansions
Dentro et al. provide a comprehensive annotation of intra-tumor heterogeneity and its drivers in cancer evolution.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Web of Science (WoS) is the world’s oldest, most widely used and authoritative database of research publications and citations. Based on the Science Citation Index, founded by Eugene Garfield in ...1964, it has expanded its selective, balanced, and complete coverage of the world’s leading research to cover around 34,000 journals today. A wide range of use cases are supported by WoS from daily search and discovery by researchers worldwide through to the supply of analytical data sets and the provision of specialized access to raw data for bibliometric partners. A long- and well-established network of such partners enables the Institute for Scientific Information (ISI) to continue to work closely with bibliometric groups around the world to the benefit of both the community and the services that the company provides to researchers and analysts.
We develop a new strategy to prepare quantum dot (QD) barcode particles by polymerizing double-emulsion droplets prepared in capillary microfluidic devices. The resultant barcode particles are ...composed of stable QD-tagged core particles surrounded by hydrogel shells. These particles exhibit uniform spectral characteristics and excellent coding capability, as confirmed by photoluminescence analyses. By using double-emulsion droplets with two inner droplets of distinct phases as templates, we have also fabricated anisotropic magnetic barcode particles with two separate cores or with a Janus core. These particles enable optical encoding and magnetic separation, thus making them excellent functional barcode particles in biomedical applications.
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IJS, KILJ, NUK, PNG, UL, UM
Though a third of amphibian species worldwide are thought to be imperiled, existing assessments simply categorize extinction risk, providing little information on the rate of population losses. We ...conducted the first analysis of the rate of change in the probability that amphibians occupy ponds and other comparable habitat features across the United States. We found that overall occupancy by amphibians declined 3.7% annually from 2002 to 2011. Species that are Red-listed by the International Union for Conservation of Nature (IUCN) declined an average of 11.6% annually. All subsets of data examined had a declining trend including species in the IUCN Least Concern category. This analysis suggests that amphibian declines may be more widespread and severe than previously realized.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Solar X-ray jets are thought to be made by a burst of reconnection of closed magnetic field at the base of a jet with ambient open field. In the accepted version of the 'emerging-flux' model, such a ...reconnection occurs at a plasma current sheet between the open field and the emerging closed field, and also forms a localized X-ray brightening that is usually observed at the edge of the jet's base. Here we report high-resolution X-ray and extreme-ultraviolet observations of 20 randomly selected X-ray jets that form in coronal holes at the Sun's poles. In each jet, contrary to the emerging-flux model, a miniature version of the filament eruptions that initiate coronal mass ejections drives the jet-producing reconnection. The X-ray bright point occurs by reconnection of the 'legs' of the minifilament-carrying erupting closed field, analogous to the formation of solar flares in larger-scale eruptions. Previous observations have found that some jets are driven by base-field eruptions, but only one such study, of only one jet, provisionally questioned the emerging-flux model. Our observations support the view that solar filament eruptions are formed by a fundamental explosive magnetic process that occurs on a vast range of scales, from the biggest mass ejections and flare eruptions down to X-ray jets, and perhaps even down to smaller jets that may power coronal heating. A similar scenario has previously been suggested, but was inferred from different observations and based on a different origin of the erupting minifilament.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid ...progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
•Cytopenias and clonal hematopoiesis occur frequently during long-term continuous venetoclax therapy for patients with relapsed CLL.•Loss-of-function BAX mutations emerge in the myeloid compartment as an adaptation to ongoing venetoclax therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aim
To quantify the impact of the 2019–2020 megafires on Australian plant diversity by assessing burnt area across 26,062 species ranges and the effects of fire history on recovery potential. ...Further, to exemplify a strategic approach to prioritizing plant species affected by fire for recovery actions and conservation planning at a national scale.
Location
Australia.
Methods
We combine data on geographic range, fire extent, response traits and fire history to assess the proportion of species ranges burnt in both the 2019–2020 fires and the past.
Results
Across Australia, suitable habitat for 69% of all plant species was burnt (17,197 species) by the 2019–2020 fires and herbarium specimens confirm the presence of 9,092 of these species across the fire extent since 1950. Burnt ranges include those of 587 plants listed as threatened under national legislation (44% of Australia's threatened plants). A total of 3,998 of the 17,197 fire‐affected species are known to resprout after fire, but at least 2,928 must complete their entire life cycle—from germinant to reproducing adult—prior to subsequent fires, as they are killed by fire. Data on previous fires show that, for 257 species, the historical intervals between fire events across their range are likely too short to allow regeneration. For a further 411 species, future fires during recovery will increase extinction risk as current populations are dominated by immature individuals.
Main conclusion
Many Australian plant species have strategies to persist under certain fire regimes, and will recover given time, suitable conditions and low exposure to threats. However, short fire intervals both before and after the 2019–2020 fire season pose a serious risk to the recovery of at least 595 species. Persistent knowledge gaps about species fire response and post‐fire population persistence threaten the effective long‐term management of Australian vegetation in an increasingly pyric world.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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