Malignant rhabdoid tumors (MRTs) are rare lethal tumors of childhood that most commonly occur in the kidney and brain. MRTs are driven by SMARCB1 loss, but the molecular consequences of SMARCB1 loss ...in extra-cranial tumors have not been comprehensively described and genomic resources for analyses of extra-cranial MRT are limited. To provide such data, we used whole-genome sequencing, whole-genome bisulfite sequencing, whole transcriptome (RNA-seq) and microRNA sequencing (miRNA-seq), and histone modification profiling to characterize extra-cranial MRTs. Our analyses revealed gene expression and methylation subgroups and focused on dysregulated pathways, including those involved in neural crest development.
•Extra-cranial malignant rhabdoid tumors (MRTs) exhibit molecular heterogeneity•Evidence is presented for epigenetic reprogramming of HOX genes•MRTs exhibit dysregulated expression of genes involved in neural crest development•Dysregulation of oncogenes and tumor suppressor genes is reported
Chun et al. perform integrated molecular analyses of extra-cranial malignant rhabdoid tumors (MRTs) and show that, although SMARCB1 loss drives nearly all MRTs, there are two subgroups of MRTs that are associated with patient age and differentially expressed genes.
Genome size, a fundamental aspect of any organism, is subject to a variety of mutational and selection pressures. We investigated genome size evolution in haploid, diploid, and tetraploid initially ...isogenic lines of the yeast Saccharomyces cerevisiae. Over the course of approximately 1,800 generations of mitotic division, we observed convergence toward diploid DNA content in all replicate lines. This convergence was observed in both unstressful and stressful environments, although the rate of convergence was dependent on initial ploidy and evolutionary environment. Comparative genomic hybridization with microarrays revealed nearly euploid DNA content by the end of the experiment. As the vegetative life cycle of S. cerevisiae is predominantly diploid, this experiment provides evidence that genome size evolution is constrained, with selection favouring the genomic content typical of the yeast's evolutionary past.
Oral lichen planus (OLP) is a chronic T cell-mediated inflammatory disease of unknown etiology. We previously proposed that the intracellular bacteria detected in OLP lesions are important triggering ...factors for T cell infiltration. This study aimed to identify OLP-associated bacterial species through the characterization of intratissue bacterial communities of OLP lesions. Seven pairs of bacterial communities collected from the mucosal surface and biopsied tissues of OLP lesions were analyzed by high-throughput sequencing of the 16S rRNA gene. The intratissue bacterial communities were characterized by decreased alpha diversity but increased beta diversity compared with those on the mucosal surface. While the relative abundance of most taxa was decreased within the tissues, that of Escherichia coli was significantly increased. Four E. coli strains were isolated from additional OLP biopsies and verified as K12 strains by whole-genome sequencing. The distribution of E. coli in sections of control (n = 12) and OLP (n = 22) tissues was examined by in situ hybridization. E. coli was detected in most OLP tissues, suggesting its potential role in the pathogenesis of OLP. The oral E. coli strains isolated from OLP tissues will be useful to investigate their role as triggering factors for T cell infiltration.
Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular ...relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.
Display omitted
•MYC subgroup of cranial RTs (ATRT-MYC) is molecularly similar to extra-cranial RTs•Five DNA methylation subgroups are identified in RTs across multiple organ sites•Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and PD1 and PD-L1 expression
Chun et al. report similarities between the MYC subgroup of cranial and extra-cranial rhabdoid tumors (RTs) at genetic, gene-expression, and epigenetic levels. They identify five DNA methylation subgroups of RTs across multiple organ sites, and some subgroups exhibit increased levels of immune cell infiltration and immune checkpoint expression.
Background/AimsWe examined the efficacy and safety of tegoprazan as a part of first-line triple therapy for Helicobacter pylori eradication. MethodsA randomized, double-blind, controlled, multicenter ...study was performed to evaluate whether tegoprazan (50 mg)-based triple therapy (TPZ) was noninferior to lansoprazole (30 mg)- based triple therapy (LPZ) (with amoxicillin 1 g and clarithromycin 500 mg; all administered twice daily for 7 days) for treating H. pylori. The primary endpoint was the H. pylori eradication rate. Subgroup analyses were performed according to the cytochrome P450 (CYP) 2C19 genotype, the minimum inhibitory concentration (MIC) of amoxicillin and clarithromycin, and underlying gastric diseases. ResultsIn total, 350 H. pylori-positive patients were randomly allocated to the TPZ or LPZ group. The H. pylori eradication rates in the TPZ and LPZ groups were 62.86% (110/175) and 60.57% (106/175) in an intention-to-treat analysis and 69.33% (104/150) and 67.33% (101/150) in a per-protocol analysis (non-inferiority test, p=0.009 and p=0.013), respectively. Subgroup analyses according to MICs or CYP2C19 did not show remarkable differences in eradication rate. Both first-line triple therapies were well-tolerated with no notable differences. ConclusionsTPZ is as effective as proton pump inhibitor-based triple therapy and is as safe as first-line H. pylori eradication therapy but does not overcome the clarithromycin resistance of H. pylori in Korea (ClinicalTrials.gov identifier NCT03317223).
The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that ...promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole-transcriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
Although chemical modifications (grafting 'onto') of CNCs have been successfully adopted to enhance their dispersibility in apolar matrices and solvents, the problem of the dispersion level of mCNCs ...(chemically modified CNCs) in apolar matrices above a certain loading of nanoparticles remains an issue. CNCs were successfully modified using toluene diisocyanate, and the effects of the molar mass (Mw) and crystallinity (Xc) of semicrystalline poly(lactic acid) (PLA) on the mechanical and thermal properties of mCNC filled PLA nanocomposites were investigated. An increase in the mechanical properties of the PLA nanocomposites with mCNCs implied that Mw and Xc of PLA can be key factors to improve the dispersion level of mCNCs. In our solvent dilute polymer system, despite a reduction in the crystallinity of PLA with increasing mCNC loading level, the melting temperature of the PLAs remained constant due to the mCNC effect, which hinders the chain mobility of the PLAs. The results demonstrated that a fundamental understanding of the crystallinity and molar mass of polymers as well as surface modification of CNCs can be a reasonable approach to take full advantage of the potential usage of CNCs as reinforcements.
Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent ...mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1E912A mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1’s effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.
Display omitted
•JAK2 signaling activates ADAR1-mediated A-to-I RNA editing•JAK2 and BCR-ABL1 signaling converge on ADAR1 activation through STAT5a•ADAR1-mediated microRNA editing impairs let-7 biogenesis and enhances LSC self-renewal•JAK2 and BCR-ABL1 inhibition reduces ADAR1 expression and prevents LSC self-renewal
Zipeto, Court, and colleagues show a pivotal role for let-7 microRNA editing in leukemia stem cell self-renewal. Impairment of let-7 is dependent on JAK2 and BCR-ABL-mediated activation of ADAR1 editing. This provides a novel mechanism of malignant reprogramming that can be targeted through combined JAK2 and BCR-ABL or ADAR1 inhibition.
Tumour‐promoting inflammation is an emerging hallmark of cancer that is increasingly recognised as a therapeutic target. As a constituent measure of inflammation, tumour‐infiltrating neutrophils ...(TINs) have been associated with inferior prognosis in several cancers. We analysed clinically annotated cohorts of clear cell renal cell carcinoma (ccRCC) to assess the presence of neutrophils within the tumour microenvironment as a function of outcome. We centrally reviewed ccRCC surgical resection and fine‐needle aspiration (FNA) specimens, including primary and metastatic sites, from three centres. TINs were scored based on the presence of neutrophils in resection and FNA specimens by two pathologists. TIN count was correlated with tumour characteristics including stage, WHO/ISUP grade, and immunohistochemistry (IHC). In parallel, we performed CIBERSORT analysis of the tumour microenvironment in a cohort of 516 ccRCCs from The Cancer Genome Atlas (TCGA). We included 102 ccRCC cases comprising 65 resection specimens (37 primary and 28 metastatic resection specimens) and 37 FNAs from primary lesions. High TINs were significantly associated with worse overall survival (p = 0.009) independent of tumour grade and stage. In ccRCCs sampled via FNA, all cases with high TINs had distant metastasis, whereas they were seen in only 19% of cases with low TINs (p = 0.0003). IHC analysis showed loss of E‐cadherin in viable tumour cells in areas with high TINs, and neutrophil activation was associated with elastase and citrullinated histone H3 expression (cit‐H3). In the TCGA cohort, neutrophilic markers were also associated with worse survival (p < 0.0001). TINs are an independent predictor of worse prognosis in ccRCC, which have the potential to be assessed at the time of first biopsy or FNA. Neutrophils act directly on tumour tissue by releasing elastase, a factor that contributes to the breakdown of cell–cell adhesion and to facilitate tumour dissemination.
•Right dorsolateral prefrontal cortex and frontal pole FA correlated with impulsivity.•Dorsolateral prefrontal cortex and frontal pole FA was related to symptom severities.•Treatment response ...associated with dorsolateral prefrontal cortex and frontal pole FA.
It is known that increased impulsivity in schizophrenia patients causes poor treatment outcomes by increasing cost, stigma, hospitalization, treatment challenge, and physical harm. Dysfunction in the prefrontal cortex appears to be involved in the impulsivity associated with schizophrenia; nonetheless, there is a dearth of research on specific white matter alterations in the prefrontal cortex related to impulsivity.
We enrolled in the present study 119 first-episode schizophrenia patients. We measured their symptom severity at baseline and after eight weeks of treatment, using the positive and negative syndrome scale. We performed neuroimaging analysis using the Tract-Based Spatial Statistics program and by specifying the prefrontal white matter as a region of interest.
In voxel-wise correlational analysis, we observed white matter regions showing significant positive correlations with poor impulse control scores, in both the right dorsolateral prefrontal cortex and the right frontal pole region. The fractional anisotropy values of these areas correlated positively with symptom severity at baseline. Moreover, after eight weeks, treatment non responders showed significantly higher fractional anisotropy values in the same areas.
The results of the present study suggest that white matter tracts in the right dorsolateral prefrontal cortex and the right frontal pole may underlie dysfunctional impulse control and could be potential predictive markers for short-term treatment in patients with first-episode schizophrenia.
PDF
