C/EBPα (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of ...C/EBPα p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBPα, TRIB2 was unable to induce AML. Only in the presence of C/EBPα p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBPα. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBPα p42 is required for TRIB2-mediated AML.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
The clinical findings among children with postnatally acquired Zika virus disease are not well characterized. We describe and compare clinical signs and symptoms for children aged ...<18 years.
Methods
Zika virus disease cases were included if they met the national surveillance case definition, had illness onset in 2016 or 2017, resided in a participating state, and were reported to the Centers for Disease Control and Prevention. Pediatric cases were aged <18 years; congenital and perinatal infections were excluded. Pediatric cases were matched to adult cases (18‒49 years). Clinical information was compared between younger and older pediatric cases and between children and adults.
Results
A total of 141 pediatric Zika virus disease cases were identified; none experienced neurologic disease. Overall, 28 (20%) were treated in an emergency department, 1 (<1%) was hospitalized; none died. Of the 4 primary clinical signs and symptoms associated with Zika virus disease, 133 (94%) children had rash, 104 (74%) fever, 67 (48%) arthralgia, and 51 (36%) conjunctivitis. Fever, arthralgia, and myalgia were more common in older children (12‒17 years) than younger children (1‒11 years). Arthralgia, arthritis, edema, and myalgia were more common in adults compared to children.
Conclusions
This report supports previous findings that Zika virus disease is generally mild in children. The most common symptoms are similar to other childhood infections, and clinical findings and outcomes are similar to those in adults. Healthcare providers should consider a diagnosis of Zika virus infection in children with fever, rash, arthralgia, or conjunctivitis, who reside in or have traveled to an area where Zika virus transmission is occurring.
Zika virus disease in children is generally mild, and severe illnesses are unusual. The symptoms frequently reported among children with Zika virus disease are common to many childhood illnesses and are not notably different than those experienced by adults.
Today, the classification systems for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) already incorporate cytogenetic and molecular genetic aberrations in an attempt to better ...reflect disease biology. However, in many MDS/AML patients no genetic aberrations have been identified yet, and even within some cytogenetically well-defined subclasses there is considerable clinical heterogeneity. Recent advances in genomics technologies such as gene expression profiling (GEP) provide powerful tools to further characterize myeloid malignancies at the molecular level, with the goal to refine the MDS/AML classification system, incorporating as yet unknown molecular genetic and epigenetic pathomechanisms, which are likely reflected by aberrant gene expression patterns. In this study, we provide a comprehensive review on how GEP has contributed to a refined molecular taxonomy of MDS and AML with regard to diagnosis, prediction of clinical outcome, discovery of novel subclasses and identification of novel therapeutic targets and novel drugs. As many challenges remain ahead, we discuss the pitfalls of this technology and its potential including future integrative studies with other genomics technologies, which will continue to improve our understanding of malignant transformation in myeloid malignancies and thereby contribute to individualized risk-adapted treatment strategies for MDS and AML patients.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by somatic cell nuclear transfer (SCNT) has been envisioned as an approach for generating patient-matched nuclear transfer ...(NT)-ESCs for studies of disease mechanisms and for developing specific therapies. Past attempts to produce human NT-ESCs have failed secondary to early embryonic arrest of SCNT embryos. Here, we identified premature exit from meiosis in human oocytes and suboptimal activation as key factors that are responsible for these outcomes. Optimized SCNT approaches designed to circumvent these limitations allowed derivation of human NT-ESCs. When applied to premium quality human oocytes, NT-ESC lines were derived from as few as two oocytes. NT-ESCs displayed normal diploid karyotypes and inherited their nuclear genome exclusively from parental somatic cells. Gene expression and differentiation profiles in human NT-ESCs were similar to embryo-derived ESCs, suggesting efficient reprogramming of somatic cells to a pluripotent state.
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•Cytoplasm of human oocytes reprograms transplanted somatic cell nuclei to pluripotency•NT-ESCs can be efficiently derived from high-quality human oocytes•Human NT-ESCs are similar to ESCs derived from fertilized embryos
For the first time, diploid human embryonic stem cells are derived from somatic cell nuclear transfer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical ...progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.
•Germ-line CEBPA mutations are highly penetrant, causing early-onset de novo AML associated with favorable survival outcomes.•Familial CEBPA-mutated AML displays a unique model of disease progression, with recurrence caused by novel, independent leukemic episodes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction Clonal cytopenia of undetermined significance (CCUS) is a recently recognized hematological disorder characterized by the presence of one or more cytopenias, evidence of clonal ...hematopoiesis and not fulfilling the criteria for a myeloid neoplasm. In contrast to myelodysplastic syndromes (MDS) where 95% of the patients are anemic at time of diagnosis, that is only the case for around 60% of patients with CCUS (Weeks et al. Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis. NEJM Evid. 2023). Furthermore, as recent studies on survival in CCUS primarily included younger patients (Weeks et al. NEJM Evid. 2023) or population-based cohorts not specifically referred for diagnostic work up of unexplained cytopenia (UC) (Rossi et al. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years, Blood 2021) additional survival data on patients with CCUS are warranted. In this study, we investigated survival outcomes in patients with CCUS referred for primary work up of UC. Methods We included 241 patients with CCUS and compared them to 144 patients with low-risk MDS, defined as having less than 5% blasts in the bone marrow. Bone marrow biopsies and next-generation sequencing (NGS) were performed in all patients and cytogenetic analyses using G-band karyotyping was done in 362 (94%) of cases. For NGS, we used a gene panel with the most commonly mutated genes in MDS. The patients were included at 6 different institutions in Denmark from 2013 and onwards. A cut-point of 5 years follow-up was chosen for more robust survival data, and patients were censored at this time point if followed for more than 5 years. Patients with CCUS were stratified into 3 groups dependent on the type of cytopenia present at diagnosis. CCUS patients with pancytopenia (n = 35), and CCUS patients without pancytopenia were split based on whether they were anemic (n = 143) or not (n =63). We compared overall survival between the CCUS groups and low-risk MDS in a Cox proportional hazards model adjusted for age, sex, number of variants and presence of high-risk variants. Results Of the 241 CCUS patients, 178 (74%) were anemic (hemoglobin < 12 and 13 g/dL for women and men, respectively), while this was the case for 130 (90%) of the patients with MDS. A total of 772 variants were identified in the entire cohort with a median of 2 (IQR: 1-3) per patient for both CCUS and MDS patients. The overall survival at 5 years was 45% for low-risk MDS patients and 62% for CCUS patients. For CCUS patients without anemia, CCUS patients with anemia and CCUS patients with pancytopenia overall survival at 5 years was 85%, 52% and 55%, respectively (p < 0.0001). In the adjusted Cox proportional hazards model, we found a significantly superior overall survival for CCUS patients without anemia compared to those with anemia (HR: 0.28, 95%-CI: 0.13-0.58, p = 0.001) and pancytopenia (HR: 0.22, 95%-CI: 0.09-0.53, p = 0.001) and patients with low-risk MDS (HR: 0.18, 95%-CI: 0.09-0.38, p < 0.001). There was no significant survival difference between CCUS patients with pancytopenia and low-risk MDS patients (HR: 0.67, 95%-CI: 0.46-1.50, p = 0.5). Of the remaining variables, age was the strongest prognostic factor with hazard ratio increasing with a factor 1.05 (95%-CI: 1.03-1.07, p < 0.001) per year aged. Predicted survival probabilities for a 65-year-old and 80-year-old person demonstrate a substantial difference in overall survival across all 3 categories of CCUS (figure 1). Discussion Here we show that the presence of anemia impacts overall survival among CCUS patients. We observe that CCUS patients without anemia, representing 26% of CCUS patients in our cohort, have a superior overall survival compared to those with anemia, even with a comparable mutational profile. Our findings indicate that other factors than mutational signatures impact overall survival. Moreover, the prevalence of CCUS increases with age, and our findings demonstrate a considerable difference in survival between a 65-year-old and 80-year-old person diagnosed with CCUS. This raises the concern that prediction models can overestimate the survival rates if the elderly group of CCUS patients is not well represented in these models. In conclusion, we show that age and hemoglobin levels are important factors in overall survival for CCUS patients, and that patients with CCUS without anemia have a superior overall survival and should be considered as a separate group within the CCUS category.
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The important task of tracking seismic activity requires both sensitive detection and accurate earthquake location. Approximate earthquake locations can be estimated promptly and automatically; ...however, accurate locations depend on precise seismic phase picking, which is a laborious and time‐consuming task. We adapted a deep neural network (DNN) phase picker trained on local seismic data to mesoscale hydraulic fracturing experiments. We designed a novel workflow, transfer learning‐aided double‐difference tomography, to overcome the 3 orders of magnitude difference in both spatial and temporal scales between our data and data used to train the original DNN. Only 3,500 seismograms (0.45% of the original DNN data) were needed to retrain the original DNN model successfully. The phase picks obtained with transfer‐learned model are at least as accurate as the analyst's and lead to improved event locations. Moreover, the effort required for picking once the DNN is trained is a small fraction of the analyst's.
Plain Language Summary
Seismic sensors are widely used to monitor many energy‐related systems. To monitor these systems effectively, we need to process a very large amount of data, which is very labor intensive. A few deep learning models have been developed to perform these tasks for earthquake‐generated signals. We adopted one of these deep learning models developed for kilometer scale and updated it for signals recorded from a meter‐scale project. This process not only allows us to overcome the significant spatial and temporal scale difference between our data and the data used by the original deep learning model but also significantly reduces the amount of required training data. Our results show that the updated model matches human performance but with a much faster speed. A workflow that combines the deep learning algorithm with existing imaging technologies enables improvements for both monitoring small earthquakes and studying subsurface structure.
Key Points
We successfully applied transfer learning to a neural network for data with orders of difference in spatial and temporal characteristics
We created a novel workflow by combining deep learning and double‐difference seismic imaging
New workflow provides better seismic catalog and larger amount of phase picks compared to human analysts
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A
SXL1
is one of the most commonly mutated genes in myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In order to further our understanding of the role ...of ASXL1 lesions in malignant hematopoiesis, we generated a novel knockin mouse model carrying the most frequent
ASXL1
mutation identified in MDS patients,
ASXL1
p.G643WfsX12. Mutant mice neither displayed any major hematopoietic defects nor developed any apparent hematological disease. In AML patients,
ASXL1
mutations co-occur with mutations in
CEBPA
and we therefore generated compound
Cebpa
and
Asxl1
mutated mice. Using a transplantation model, we found that the mutated
Asxl1
allele significantly accelerated disease development in a CEBPA mutant context. Importantly, we demonstrated that, similar to the human setting,
Asxl1
mutated mice responded poorly to chemotherapy. This model therefore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.
Transcription factors play a key role in lineage commitment and differentiation of stem cells into distinct mature cells. In hematopoiesis, they regulate lineage-specific gene expression in a ...stage-specific manner through various physical and functional interactions with regulatory proteins that are simultanously recruited and activated to ensure timely gene expression. The transcription factor CCAAT/enhancer binding protein α (C/EBPα) is such a factor and is essential for the development of granulocytic/monocytic cells. The activity of C/EBPα is regulated on several levels including gene expression, alternative translation, protein interactions and posttranslational modifications, such as phosphorylation. In particular, the phosphorylation of serine 248 of the transactivation domain has been shown to be of crucial importance for granulocytic differentiation of 32Dcl3 cells in vitro.
Here, we use mouse genetics to investigate the significance of C/EBPα serine 248 in vivo through the construction and analysis of Cebpa(S248A/S248A) knock-in mice. Surprisingly, 8-week old Cebpa(S248A/S248A) mice display normal steady-state hematopoiesis including unaltered development of mature myeloid cells. However, over time some of the animals develop a hematopoietic disorder with accumulation of multipotent, megakaryocytic and erythroid progenitor cells and a mild impairment of differentiation along the granulocytic-monocytic lineage. Furthermore, BM cells from Cebpa(S248A/S248A) animals display a competitive advantage compared to wild type cells in a transplantation assay.
Taken together, our data shows that the substitution of C/EBPα serine 248 to alanine favors the selection of the megakaryocytic/erythroid lineage over the monocytic/granulocytic compartment in old mice and suggests that S248 phosphorylation may be required to maintain proper hematopoietic homeostasis in response to changes in the wiring of cellular signalling networks. More broadly, the marked differences between the phenotype of the S248A variant in vivo and in vitro highlight the need to exert caution when extending in vitro phenotypes to the more appropriate in vivo context.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Messenger RNA transcripts that contain premature stop codons are degraded by a process termed nonsense-mediated mRNA decay (NMD). Although previously thought of as a pathway that rids the cell of ...non-functional mRNAs arising from mutations and processing errors, new research suggests a more general and evolutionarily important role for NMD in the control of gene expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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