A goal of regenerative medicine is to use induced pluripotent stem cells to generate an autologous graft for transplantation. This study tests the feasibility of the approach to treat age-related ...macular degeneration.
Age-related macular degeneration (AMD) is one of the most prevalent retinal diseases that threaten vision in older populations in developed countries.
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Neovascular (also called “wet”) AMD is more prevalent than atrophic (or “dry”) AMD in Japan
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and is associated with the ectopic development of a choroidal neovascular membrane in the subretinal space of the center of the retina (the macula). Physical disruption and functional impairment of the retinal pigment epithelium (RPE), a monolayer sheet of cells that supports the overlying photoreceptors and underlying choroidal vasculature, occur in the course of wet AMD.
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Current treatments of AMD that involve the . . .
Tobacco smoking causes lung cancer
, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA
. The profound effects of tobacco on the genome of ...lung cancer cells are well-documented
, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0-6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.
We analyze the effect of managerial entrenchment on firms' corporate social responsibility (CSR) activities. We use the cross‐shareholding ratio and the stable shareholders ratio, which characterize ...the Japanese corporate system, as proxy variables for managerial entrenchment. We choose two CSR/environmental, social, and corporate governance scores: those for vendors targeting only Japan and those for vendors targeting the entire world. The results show that increases in the cross‐shareholding and stable shareholder ratios decrease CSR activities. These results are consistent with the view that CSR activities are considered a costly investment for managers rather than a type of agency cost. Finally, we reveal that after the enactment of Japan's Corporate Governance Code in 2015, the cross‐shareholding and the stable shareholder ratios have not significantly affected CSR activities and that foreign institutional investors have promoted CSR activities.
Background Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by ...mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype. Objective The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype. Methods Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. Results A de novo heterozygous frameshift mutation of TNF-α–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). Conclusion Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.
Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box ...helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.
Although aplastic anemia is responsive to immunosuppressive therapy, small subpopulations of hematopoietic cells with clonal gene mutations may exist, and different sets of mutations show distinct ...clinical behavior and response to therapy.
Acquired aplastic anemia is caused by immune-mediated destruction of hematopoietic stem and progenitor cells.
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CD34+ cells and early progenitors are uniformly reduced in aplastic anemia.
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Bone marrow transplantation is curative, and patients may also have a response to immunosuppressive therapy.
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With improved survival, the late development of myelodysplastic syndromes, acute myeloid leukemia (AML), or both has been noted in about 15% of patients and termed “clonal evolution.”
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Although “clonal evolution” historically has been used to describe the development of cancer in patients with an immune disease, this term is a misnomer, since there is evidence of clonal hematopoiesis associated . . .
Recent advances in high‐throughput sequencing technologies have unexpectedly revealed that somatic mutations of splicing factor genes frequently occurred in several types of hematological ...malignancies, including myelodysplastic syndromes, other myeloid neoplasms, and chronic lymphocytic leukemia. Splicing factor mutations have also been reported in solid cancers such as breast and pancreatic cancers, uveal melanomas, and lung adenocarcinomas. These mutations were heterozygous and mainly affected U2AF1 (U2AF35), SRSF2 (SC35), SF3B1 (SF3B155 or SAP155), and ZRSR2 (URP), which are engaged in the initial steps of RNA splicing, including 3′ splice‐site recognition, and occur in a large mutually exclusive pattern, suggesting a common impact of these mutations on RNA splicing. In this study, splicing factor mutations in various types of cancers, their functional/biological effects, and their potential as therapeutic targets have been reviewed. WIREs RNA 2014, 5:445–459. doi: 10.1002/wrna.1222
This article is categorized under:
RNA Processing > Splicing Mechanisms
Spliceosome mutations are frequently found in myelodysplasia. Splicing alterations induced by these mutations, their precise targets, and the effect at the transcript level have not been fully ...elucidated. Here we report transcriptomic analyses of 265 bone marrow samples from myelodysplasia patients, followed by a validation using CRISPR/Cas9-mediated gene editing and an assessment of nonsense-mediated decay susceptibility. Small but widespread reduction of intron-retaining isoforms is the most frequent splicing alteration in SF3B1-mutated samples. SF3B1 mutation is also associated with 3' splice site alterations, leading to the most pronounced reduction of canonical transcripts. Target genes include tumor suppressors and genes of mitochondrial iron metabolism or heme biosynthesis. Alternative exon usage is predominant in SRSF2- and U2AF1-mutated samples. Usage of an EZH2 cryptic exon harboring a premature termination codon is increased in both SRSF2- and U2AF1-mutated samples. Our study reveals a landscape of splicing alterations and precise targets of various spliceosome mutations.
Recent advances in high-throughput sequencing technologies have enabled a comprehensive dissection of the cancer genome clarifying a large number of somatic mutations in a wide variety of cancer ...types. A number of methods have been proposed for mutation calling based on a large amount of sequencing data, which is accomplished in most cases by statistically evaluating the difference in the observed allele frequencies of possible single nucleotide variants between tumours and paired normal samples. However, an accurate detection of mutations remains a challenge under low sequencing depths or tumour contents. To overcome this problem, we propose a novel method, Empirical Bayesian mutation Calling (https://github.com/friend1ws/EBCall), for detecting somatic mutations. Unlike previous methods, the proposed method discriminates somatic mutations from sequencing errors based on an empirical Bayesian framework, where the model parameters are estimated using sequencing data from multiple non-paired normal samples. Using 13 whole-exome sequencing data with 87.5-206.3 mean sequencing depths, we demonstrate that our method not only outperforms several existing methods in the calling of mutations with moderate allele frequencies but also enables accurate calling of mutations with low allele frequencies (≤ 10%) harboured within a minor tumour subpopulation, thus allowing for the deciphering of fine substructures within a tumour specimen.
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