Summary
Background
Atopic dermatitis (AD) often manifests in early childhood and has variable disease course among individual patients. Previous studies regarding the natural course of AD have ...usually been of small sample size and were not based on nationwide populations.
Objectives
We aimed to find out the disease duration and remission rate of children with early‐onset AD (onset in the first 2 years of life) in Taiwan, and to determine whether the presence of allergic rhinitis (AR) or asthma affects the disease course.
Methods
The patients with early‐onset AD in a nationally representative cohort were selected using the National Health Insurance Research Database of Taiwan and were followed from birth to 10 years of age. Kaplan–Meier survival analysis was carried out to analyse the disease duration and remission of AD. Between‐group analysis using the log‐rank test was carried out to analyse the influence of risk factors on the disease course.
Results
Of the 1404 children with early‐onset AD, 19·4% had disease duration < 1 year and 48·7% had disease duration < 4 years. During the follow‐up, 69·8% of the patients went into remission. Sex, onset age, presence of AR, presence of asthma and presence of respiratory atopy (either AR or asthma) did not show statistically significant influence on disease course.
Conclusions
Children in Taiwan with early‐onset AD had disease of variable natural course, and the median disease duration was 4·2 years. About 70% of the patients went into remission eventually. The presence of AR or asthma did not affect the disease course of AD.
What's already known about this topic?
Atopic dermatitis (AD) commonly affects infants and children.
The natural course of AD varies among individual patients.
Spontaneous resolution occurs in some children as they grow older.
What does this study add?
The probability of children with early‐onset AD healing in a given time is calculated using nationwide population‐based data.
About 70% of the patients with early‐onset AD went into remission eventually.
Presence of allergic rhinitis or asthma did not affect the course of AD.
Background
Lichen planus (LP) is a chronic inflammatory disorder with unknown aetiology. The association between LP and various autoimmune diseases has been reported, but nationwide study of the ...relationship of LP with associated diseases is quite limited.
Objective
Our study aims to clarify the association between LP and a variety of autoimmune diseases in Taiwanese.
Methods
Data were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan from 1997 to 2011. In total, 12 427 patients with LP and 49 708 age‐ and gender‐matched controls were enrolled.
Results
Among patients with LP, there were significant associations with systemic lupus erythematosus (SLE) (multivariate odds ratio mOR: 2.87; 95% CI: 1.97–4.17), Sjögren's syndrome (mOR: 3.75; 95% CI: 2.66–5.28), dermatomyositis (mOR: 6.34; 95% CI: 1.82–22.16), vitiligo (mOR: 2.09; 95% CI: 1.31–3.32) and alopecia areata (mOR: 2.82; 95% CI: 2.20–3.62). On gender‐stratified analyses, SLE and alopecia areata were significantly associated with LP in both genders. The association with Sjögren's syndrome was significant only in female patients. The associations with dermatomyositis and vitiligo became insignificant in both genders.
Conclusion
Lichen planus is associated with various autoimmune diseases. Further study is required to elucidate the possible underlying mechanisms and roles of autoimmunity in the aetiology of LP.
Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome ...EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat-shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs.
Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the ...underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.
Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for ...cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.
Landscape of Noncoding RNA in Prostate Cancer Hua, Junjie T.; Chen, Sujun; He, Housheng H.
Trends in genetics,
November 2019, 2019-11-00, 20191101, Volume:
35, Issue:
11
Journal Article
Peer reviewed
The transcriptome of prostate cancer is highly heterogeneous, with noncoding transcripts being essential players. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two unique classes of ...noncoding RNA drawing increasing attention. Biologically, they have intriguing properties with important regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Recent advancements in technologies have opened up new directions for noncoding RNA research, which include RNA–protein interaction, RNA secondary structure, and spatial transcriptomics. Furthermore, recent work has also evaluated the clinical applications of these noncoding RNAs in noninvasive liquid biopsy and RNA-based therapies. In this review, we summarize recent findings on lncRNAs and circRNAs in prostate cancer, discuss their clinical utilities, and highlight these exciting areas of research.
Long noncoding RNA (lncRNA) and circular RNA (circRNA) are pervasive noncoding RNA classes with important functional roles, and are frequently dysregulated in prostate cancer.While circRNAs share similarities with lncRNAs, the circular conformation leads to novel functional mechanisms, increased stability and unique clinical applications.Recent technological advancements impel noncoding (nc)RNA research in RNA–protein interaction, RNA secondary structure, and spatial transcriptomics, which may reveal novel findings for clinical translation.Both lncRNAs and circRNAs are promising biomarkers due to their expression specificity, and may be exploited for noninvasive liquid biopsy applications.RNAi and antisense oligonucleotides (ASOs) are therapeutic strategies for targeting oncogenic ncRNAs, and can be delivered through nanoparticles or conjugated antibodies or receptors.
Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of ...260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.
Our experimental results demonstrate that full-field hard-X-ray microscopy is finally able to investigate the internal structure of cells in tissues. This result was made possible by three main ...factors: the use of a coherent (synchrotron) source of X-rays, the exploitation of contrast mechanisms based on the real part of the refractive index and the magnification provided by high-resolution Fresnel zone-plate objectives. We specifically obtained high-quality microradiographs of human and mouse cells with 29nm Rayleigh spatial resolution and verified that tomographic reconstruction could be implemented with a final resolution level suitable for subcellular features. We also demonstrated that a phase retrieval method based on a wave propagation algorithm could yield good subcellular images starting from a series of defocused microradiographs. The concluding discussion compares cellular and subcellular hard-X-ray microradiology with other techniques and evaluates its potential impact on biomedical research.
Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired ...with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.
Azacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for ...this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria.
We retrospectively studied 91 patients with CMML treated with at least one cycle of AZA from the Spanish Registry of MDS. As it was a real-world study, the response rate was evaluated between cycle 4 and 6, applying the MDS/MPN response criteria
The overall response rate at cycle 4–6 was 58%. Almost half of the patients achieved transfusion independence and one quarter showed clinical benefit, regardless of the CMML French-American-British (FAB) and World Health Organization (WHO) subtypes and CMML Specific Prognosis Scoring (CPSS) risk groups. Toxicity was higher in the MD-CMML subtype.
In our series, most CMML patients achieved an overall response rate with AZA according to the overlap-MDS/MPN response criteria regardless of the CMML FAB and WHO subtypes and CPSS risk groups. Thus, AZA may also be a treatment option for patients with the myeloproliferative CMML subtype and those with a lower-risk CPSS, but symptomatic.
•Chronicmyelomonocytic leukemia patients treated with azacitidine achieve a highoverall response rate.•Myeloproliferativechronic myelomonocytic leukemia could also benefit of treatment with azacitidine,as the myelodysplastic subtype.•Myelodysplastic/myeloproliferativeresponse criteria also allow to analyze the clinical benefit to azacitidine inchronic myelomonocytic leukemia patients.
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