Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of ...these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in ...multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cloud computing is being increasingly employed in the development of systems. For such systems, rapid cost estimation is required to start new business. This paper proposes a “Pay-Per-Use” billing ...model, and providers offer various strategic pricing options. There are many cost structures, and hence, users need to consider many pricing options when estimating system costs. Although companies often want to estimate the cost of their systems, it is difficult to obtain a comprehensive estimate that considers all components. Previously, researchers have implemented simulation-based and analytical approaches to solve this problem. In this study, we develop a cost-estimation method that employs directed acyclic graph (DAG)-based representation and matrix operations. Our method emphasizes simplicity through the use of a systematic procedure that can estimate the costs of new services in the pre-design stage.
Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of ...whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of
(90%) and copy-neutral loss of heterozygosity (CN-LOH) of
(10%). In addition, imprinting dysregulation of
as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment.
Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting.
.
Background
Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still ...unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing.
Methods
We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs.
Results
Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including
TP53
and
ARID1A
. In contrast,
TERT
promoter mutations were not detected in any of the RNs examined. Consistently,
TERT
expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of
TERT
expression.
Conclusion
Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.
Writer verification is a method to specify an authentic writer from handwriting. Automated writer verification methods are required for various applications (e.g., credit cards, checks, and ...passports). However, there is room for improvement in the performance of such methods compared with the performance of human beings, for example, forensic document examiners. Because automated writer verification systems do not always return correct results under any circumstances, which can lead to grave consequences, further research is required to improve the performance of such methods. Furthermore, problems caused by limited samples must be solved for real applications. To improve verification accuracy with limited samples, we propose a text and user generic model for writer verification that uses a combination of pen pressure information from ink intensity and writing indentations obtained by a multiband image scanner. We introduce a writer-specific dissimilarity representation to consider individual handwriting characteristics that affect model performance. Experimental results obtained using handwriting samples collected from 54 volunteers are reported. The results show a decrease in error rate compared with conventional methods from 10.0% to 4.0%.
Innate and adaptive lymphoid development is orchestrated by the activities of E proteins and their antagonist Id proteins, but how these factors regulate early T cell progenitor (ETP) and innate ...lymphoid cell (ILC) development remains unclear. Using multiple genetic strategies, we demonstrated that E proteins E2A and HEB acted in synergy in the thymus to establish T cell identity and to suppress the aberrant development of ILCs, including ILC2s and lymphoid-tissue-inducer-like cells. E2A and HEB orchestrated T cell fate and suppressed the ILC transcription signature by activating the expression of genes associated with Notch receptors, T cell receptor (TCR) assembly, and TCR-mediated signaling. E2A and HEB acted in ETPs to establish and maintain a T-cell-lineage-specific enhancer repertoire, including regulatory elements associated with the Notch1, Rag1, and Rag2 loci. On the basis of these and previous observations, we propose that the E-Id protein axis specifies innate and adaptive lymphoid cell fate.
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•E2A and HEB act in concert to specify T cell fate•E protein activity in lymphoid progenitors suppresses aberrant ILC development•E2A and HEB establish a T-lineage-specific program of gene expression•The E-Id protein axis specifies the adaptive and innate lymphoid cell fate
Previous studies established that E proteins act at multiple stages to promote T-cell-lineage development. Miyazaki et al. demonstrate that E proteins establish T cell identity and suppress the development of thymic ILCs by modulating enhancer repertoires of genes associated with Notch signaling and TCRβ locus assembly.
Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the ...mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase.
The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL.
We present a brute-force approach to analyze the concept drift behind time sequence data. This approach, named SELECT, searches for the optimal length of training data to minimize error metrics. In ...other words, SELECT searches for the start point of a new concept from the input sequence. Unlike many related methods, SELECT does not require a pre-specified error threshold to detect drift. In addition, the visual analysis obtained from SELECT enables us to understand how significant a drift has occurred. We test SELECT on two real-world datasets, stock price and COVID-19 infection data. The experimental results show that SELECT can improve the model performance of both datasets. In addition, the visual analysis shows the points of significant drifts, e.g., Lehman’s collapse in stock price data and the spread of variants in COVID-19 data. These results show the effectiveness of the brute-force approach in analyzing concept drift.
The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear ...whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.
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