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.
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.
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.
Display omitted
•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.
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.
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.
Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and ...inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs' activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs in vitro and in vivo. Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis.
Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and
. In order ...to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing.
First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several
analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing.
expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence
hybridization.
A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified
, and
as likely driver mutations. Copy-number alteration analysis showed regions spanning
as recurrently deleted, and
as recurrently amplified.
, and
amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence
analysis validated
amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of
amplification status was observed in some cases.
Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.
Precise genetic diagnosis of inherited bone marrow failure syndromes (IBMFS), a heterogeneous group of genetic disorders, is challenging but essential for precise clinical decision making.
We ...analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES).
We achieved successful genetic diagnoses for 53 of 121 patients (44%) using targeted sequencing and for 68 of 250 patients (27%) using WES. In the majority of cases (targeted sequencing: 45/53, 85%; WES: 63/68, 93%), the detected variants were concordant with, and therefore supported, the clinical diagnoses. However, in the remaining 13 cases (8 patients by target sequencing and 5 patients by WES), the clinical diagnoses were incompatible with the detected variants.
Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.Genet Med advance online publication 19 January 2017.
Low-frequency modes of excitation in deformed neutron-rich nuclei are studied by means of the quasiparticle random-phase approximation on the Skyrme-Hartree-Fock-Bogoliubov mean field. We investigate ...the microscopic structure of the soft
modes systematically in neutron-rich magnesium isotopes with
N
= 22, 24, 26 and 28 close to the drip line, and it is found that the strong collectivity in
34
Mg and
40
Mg is acquired due to the coherent coupling between the
vibration and the pairing vibration of neutrons. Microscopic structure of the
modes changes gradually associated with the location of the Fermi level of neutrons, and it is found that the proton particle-hole excitation generating the
-vibrational mode in
24
Mg continues to play a key role in the near-drip-line nucleus
40
Mg . The low-frequency octupole excitations are also investigated and the microscopic mechanism for the enhancement of transition strengths is discussed.
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