A global description of the ground-state properties of nuclei in a wide mass range in a unified manner is desirable not only for understanding exotic nuclei but also for providing nuclear data for ...applications. We demonstrate that the KIDS (Korea–IBS–Daegu–SKKU) functional describes the ground states appropriately with respect to the existing data and predictions for a possible application of the functional to all the nuclei by taking Nd isotopes as examples. The Kohn–Sham–Bogoliubov equation is solved for the Nd isotopes with the neutron numbers ranging from 60 to 160 by employing the KIDS functionals constructed to satisfy both neutron-matter equation of state or neutron star observation and selected nuclear data. Considering the nuclear deformation improves the description of the binding energies and radii. We find that the discrepancy from the experimental data is more significant for both neutron-rich and neutron-deficient isotopes. This discrepancy can be reduced and is consequently independent of the neutron number in an isotopic chain by adjusting the slope parameter of the symmetry energy. The KIDS functional is competent to a global fitting for a better description of nuclear properties in the nuclear chart.
Although next‐generation sequencing‐based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical ...issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B‐cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B‐cell lymphoma; and UMIN000034243, childhood leukemia).
This multicenter prospective study investigated feasibility of target capture‐based panel testing, focusing on hematological malignancies. Our results suggest that panel testing for hematological malignancies is feasible given the availability of useful diagnostic and prognostic information.
Disseminated intravascular coagulation (DIC) associated with multiple organ dysfunction syndrome (MODS) plays pivotal roles in severe sepsis.
We performed a multicenter, prospective data collection ...study and retrospectively analyzed the data to confirm the role of DIC in severe sepsis.
Eligible patients were ICU patients who met the definitions of severe sepsis, and 1013 patients were included. DIC scores as well as disease severity and the development of MODS on the day of the diagnosis of severe sepsis (day 0) and at day 3 were evaluated. The primary outcome was hospital mortality, and MODS on days 0 and 3 was the secondary outcomes.
The overall mortality rate of severe sepsis was 21.5%, and the prevalence of DIC was 50.9% (516/1013). DIC patients were more seriously ill and exhibited a higher prevalence of MODS (32.0% vs. 13.1%) on day 0 and worse mortality rate (24,8% vs. 17.5%) than non-DIC patients. DIC patients also showed a lower survival probability than non-DIC patients (Log rank p = 0.028). Logistic regression analyses after propensity score adjustment for potential confounders confirmed a significant association between DIC and MODS and hospital death in the patients with severe sepsis. The new development of DIC and persistent DIC from days 0 to 3 were associated with a high incidence of MODS and low survival probability.
The mortality rate of severe sepsis has been improved; however, DIC is still associated with the poor prognosis of these patients. Evaluating the dynamic changes in the DIC status may improve the prediction capability.
•The role of DIC in severe sepsis remains unclear.•An association between DIC and the prognosis of severe sepsis was investigated.•Mortality of DIC associated with organ dysfunctions in severe sepsis was still high.•Changes in DIC status were important for predicting the prognosis of severe sepsis.
Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain ...poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo
missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects.
encodes IKK2, which activates NF-κB signaling. IKK2
results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2
is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in
using CRISPR/Cas9. Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes. Accurate mouse models engineered by CRISPR/Cas9 can help characterize novel syndromes arising from de novo germline mutations and yield insight into pathogenesis.
To the Editor:
We report on two previously healthy Japanese brothers with a newly discovered recessively inherited syndrome similar to Wernicke's encephalopathy that developed in the second decade of ...life; this syndrome was manifested clinically as thiamine-responsive diplopia and ptosis without serum thiamine deficiency. The patients had complex partial seizures resulting in status epilepticus. The administration of high-dose thiamine (up to 600 mg) improved the seizures within 24 hours, although the ophthalmoplegia, nystagmus, and ataxia continued for several weeks. There were no extrapyramidal features. Magnetic resonance imaging (MRI) of the brain showed high-intensity signals in the bilateral medial thalamus and . . .
Background Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to ...mutations in 2 PI3K genes, PIK3CD and PIK3R1 , causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. Objective This study aimed to identify novel genes responsible for APDS. Methods Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. Results We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. Conclusion PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.
Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, ...we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival OS: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.
Key Points
Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and ...continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.
In the endoplasmic reticulum (ER), secretory and membrane proteins are properly folded and modified, and the failure of these processes leads to ER stress. At the same time, unfolded protein response ...(UPR) genes are activated to maintain homeostasis. Despite the thorough characterization of the individual gene regulation of UPR genes to date, further investigation of the mutual regulation among UPR genes is required to understand the complex mechanism underlying the ER stress response. In this study, we aimed to reveal a gene regulatory network formed by UPR genes, including immunoglobulin heavy chain-binding protein (BiP), X-box binding protein 1 (XBP1), C/EBP CCAAT/enhancer-binding protein-homologous protein (CHOP), PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring 1 (IRE1), activating transcription factor 6 (ATF6), and ATF4. For this purpose, we focused on promoter-luciferase reporters for BiP, XBP1, and CHOP genes, which bear an ER stress response element (ERSE), and p5 × ATF6-GL3, which bears an unfolded protein response element (UPRE). We demonstrated that the luciferase activities of the BiP and CHOP promoters were upregulated by all the UPR genes, whereas those of the XBP1 promoter and p5 × ATF6-GL3 were upregulated by all the UPR genes except for BiP, CHOP, and ATF4 in HeLa cells. Therefore, an ERSE- and UPRE-centered gene regulatory network of UPR genes could be responsible for the robustness of the ER stress response. Finally, we revealed that BiP protein was degraded when cells were treated with DNA-damaging reagents, such as etoposide and doxorubicin; this finding suggests that the expression level of BiP is tightly regulated at the post-translational level, rather than at the transcriptional level, in the presence of DNA damage.
Somatic internal tandem duplications (ITDs) are known to play important roles in cancer pathogenesis. Although recent advances in high-throughput sequencing technologies have enabled genome-wide ...detection of various types of genomic mutations, including single nucleotide variants, indels and structural variations, only a few studies have focused on ITDs. We have developed an analytical tool called 'Genomon ITDetector' for genome-wide detection of somatic ITDs. After evaluating the sensitivity and precision of the proposed approach using synthetic data, we have demonstrated that it can successfully detect not only common ITDs involving FLT3, but also a number of ITDs affecting other putative driver genes in acute myeloid leukemia exome sequencing data. Availability and implementaion: Genomon ITDetector is freely available at https://github.com/ken0-1n/Genomon-ITDetector.
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