MCScan is an algorithm able to scan multiple genomes or subgenomes in order to identify putative homologous chromosomal regions, and align these regions using genes as anchors. The MCScanX toolkit ...implements an adjusted MCScan algorithm for detection of synteny and collinearity that extends the original software by incorporating 14 utility programs for visualization of results and additional downstream analyses. Applications of MCScanX to several sequenced plant genomes and gene families are shown as examples. MCScanX can be used to effectively analyze chromosome structural changes, and reveal the history of gene family expansions that might contribute to the adaptation of lineages and taxa. An integrated view of various modes of gene duplication can supplement the traditional gene tree analysis in specific families. The source code and documentation of MCScanX are freely available at http://chibba.pgml.uga.edu/mcscan2/.
A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
Atmospheric concentrations of major reactive nitrogen (N
r) species were quantified using passive samplers, denuders, and particulate samplers at Dongbeiwang and Quzhou, North China Plain (NCP) in a ...two-year study. Average concentrations of NH
3, NO
2, HNO
3, pNH
4
+ and pNO
3
− were 12.0, 12.9, 0.6, 10.3, and 4.7 μg N m
−3 across the two sites, showing different seasonal patterns of these N
r species. For example, the highest NH
3 concentration occurred in summer while NO
2 concentrations were greater in winter, both of which reflected impacts of N fertilization (summer) and coal-fueled home heating (winter). Based on measured N
r concentrations and their deposition velocities taken from the literature, annual N dry deposition was up to 55 kg N ha
−1. Such high concentrations and deposition rates of N
r species in the NCP indicate very serious air pollution from anthropogenic sources and significant atmospheric N input to crops.
High concentrations and deposition rates of reactive N species in the North China Plain imply a serious air pollution problem from anthropogenic sources.
Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its ...stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated +8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2(-)/FLT3-ITD(+) genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.
Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk ...cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.
Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in ...BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).
Levels of γ-aminobutyric acid (GABA) and glutamic acid decarboxylase 1 (GAD1), the enzyme that synthesizes GABA, are significantly increased in neoplastic tissues. However, the mechanism underlying ...this increase remains elusive. Instead of silencing gene transcription, we showed that the GAD1 promoter was hypermethylated in both colon and liver cancer cells, leading to the production of high levels of GAD1. GAD1 is a target gene that is silenced by H3K27me3. The key locus responsible for GAD1 reactivation was mapped to a DNA methylation-sensitive CTCF-binding site (CTCF-BS3) within the third intron of GAD1. Chromosome configuration capture (3C) analysis indicated that an intrachromosomal loop was formed by CTCF self-dimerisation in normal cells (CTCF binds to both unmethylated CTCF-BS3 and CTCF-BS2). The CTCF dimer then interacted with suppressor of zeste 12 homologue (SUZ12), which is a domain of Polycomb repressive complex 2 (PRC2), promoting the methylation of H3K27 and the silencing of GAD1 expression. This silencing was shown to be inhibited by DNA methylation in cancer cells. These findings strongly suggest that GAD1 is reactivated by DNA methylation, which provided a model for DNA methylation and the active orchestration of oncogenic gene expression by CTCF in cancer cells.
To improve the electrical conductivity and cycling stability of germanium compounds as anode materials for lithium ion batteries (LIBs), Zn
2
GeO
4
nanorods grown on carbon cloth (Zn
2
GeO
4
/CC) ...were designed and fabricated by a simple hydrothermal process combined with a post-annealing treatment. The Zn
2
GeO
4
/CC composites possess hierarchical porosity and a network structure. Serving as free-standing and binder-free anodes for LIBs, they exhibit high specific capacity and excellent reversibility. A discharge capacity as high as 1851.9 mA h g
−1
is attained at a current density of 200 mA g
−1
, and the Zn
2
GeO
4
/CC electrode still maintains a high reversible capacity of 1302.3 mA h g
−1
after 200 cycles. Even at a high specific current of 2000 mA g
−1
, it still retains a capacity of 847.5 mA h g
−1
. The superior electrochemical performance of the Zn
2
GeO
4
/CC composites is attributed to the synergistic effects of the hierarchical porosity, Zn
2
GeO
4
nanorods, and 3D carbon cloth network structure, which can effectively accommodate the huge volume change of the Zn
2
GeO
4
nanorods during cycling and maintain perfect electrical conductivity throughout the electrode. Moreover, the excellent mechanical flexibility of the Zn
2
GeO
4
/CC composites makes the material a promising candidate for self-supported and flexible electrodes for LIBs.
A novel strategy was proposed for the simultaneous preparation of a high performance flexible Zn
2
GeO
4
/CC electrode. The as-formed composites exhibited high reversible lithium storage capacity, long cyclability, and excellent rate capability.
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