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Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

Objective: To investigate the clinic-pathological features, diagnosis and treatment of 8p11 myeloproliferative syndrome (EMS) . Methods: Five patients diagnosed as EMS from Jan 2014 to May 2018 at Blood Disease Hospital, Chinese Academy of Medical Sciences were enrolled. The clinical manifestations, laboratory characteristics, treatment and outcome of these patients were summarized. Results: The peripheral blood leukocyte count of 5 patients with EMS increased significantly, accompanied with an elevated absolute eosinophils value (the average as 18.89×10(9)/L) . The hypercellularity of myeloid cells was common in bone marrow, always with the elevated proportion of eosinophils (the average as 17.24%) , but less than 5% of blast cells. The chromosome karyotype of the 5 cases differed from each other, but presenting with the same rearrangement of FGFR1 gene by fluorescence in situ hybridization technology. The average interval between onset and diagnosis was 4.8 months with a median survival of only 14 months. Conclusion: EMS was a rare hematologic malignancy with poor prognosis and short survival. It was commonly to be misdiagnosed. Analysis of cytogenetics and molecular biology were helpful for early diagnosis.

Background: Heart disease (HD) is the major cause of morbidity and mortality in patients with hypereosinophilic diseases. Due to a lack of adequate animal models, our understanding of the pathophysiology of eosinophil-mediated diseases with heart complications is limited. We have discovered a mouse mutant, now maintained on an A/J inbred background, that spontaneously develops hypereosinophilia in multiple organs. Cellular infiltration into the heart causes an eosinophilic myocarditis, with affected mice of the mutant line (i.e., A/J HD ) demonstrating extensive myocardial damage and remodeling that leads to HD and premature death, usually by 15-weeks old., Results: Maintaining the A/J HD line for many generations established that the HD trait was heritable and implied the mode of inheritance was not too complex. Backcross and intercross populations generated from mating A/J HD males with females from four different inbred strains produced recombinant populations with highly variable rates of affected offspring, ranging from none in C57BL/6 J intercrosses, to a few mice with HD using 129S1/SvImJ intercrosses and C57BL/6 J backcrosses, but nearly 8% of intercrosses and > 17% of backcrosses from SJL/J related populations developed HD. Linkage analyses of these SJL/J derived recombinants identified three highly significant loci: a recessive locus mapping to distal chromosome 5 (LOD = 4.88; named Emhd1 for eosinophilic myocarditis to heart disease-1); and two dominant variants mapping to chromosome 17, one (Emhd2; LOD = 7.51) proximal to the major histocompatibility complex, and a second (Emhd3; LOD = 6.89) that includes the major histocompatibility region. Haplotype analysis identified the specific crossovers that defined the Emhd1 (2.65 Mb), Emhd2 (8.46 Mb) and Emhd3 (14.59 Mb) intervals., Conclusions: These results indicate the HD trait in this mutant mouse model of eosinophilic myocarditis is oligogenic with variable penetrance, due to multiple segregating variants and possibly additional genetic or nongenetic factors. The A/J HD mouse model represents a unique and valuable resource to understand the interplay of causal factors that underlie the pathology of this newly discovered eosinophil-associated disease with cardiac complications.

Human leukocyte antigen (HLA) alleles have been implicated as risk factors for immune-mediated adverse drug reactions. The authors recently reported a strong association between HLA-A*32:01 and vancomycin-induced drug reaction with eosinophilia and systemic symptoms. Identification of individuals with the risk allele before or shortly after the initiation of vancomycin therapy is of great clinical importance to prevent morbidity and mortality, and improve drug safety and antibiotic treatment options. A prerequisite to the success of pharmacogenetic screening tests is the development of simple, robust, cost-effective single HLA allele test that can be implemented in routine diagnostic laboratories. In this study, the authors developed a simple, real-time allele-specific PCR for typing the HLA-A*32:01 allele. Four-hundred and fifty-eight DNA samples including 30 HLA-A*32:01-positive samples were typed by allele-specific PCR. Compared with American Society for Histocompatibility and Immunogenetics-accredited, sequence-based, high-resolution, full-allelic HLA typing, this assay demonstrates 100% accuracy, 100% sensitivity (95% CI, 88.43% to 100%), and 100% specificity (95% CI, 99.14% to 100%). The lowest limit of detection of this assay using PowerUp SYBR Green is 10 ng of template DNA. The assay demonstrates a sensitivity and specificity to differentiate the HLA-A*32:01 allele from closely related non-HLA-A*32 alleles and may be used in clinical settings to identify individuals with the risk allele before or during the course of vancomycin therapy., (Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background Chronic rhinosinusitis (CRS) current therapeutic approaches still fail in some patients with severe persistent symptoms and recurrences after surgery. We aimed to evaluate the master transcription factors gene expression levels of T cell subtypes in chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) that could represent new, up-stream targets for topical DNAzyme treatment. Patients and methods Twenty-two newly diagnosed CRS patients (14 CRSwNP and 8 CRSsNP) were prospectively biopsied and examined histopathologically. Gene expression levels of T-box transcription factor (T-bet, TBX21), GATA binding protein 3 (GATA3), Retinoic acid-related orphan receptor C (RORC) and Forkhead box P3 (FOXP3) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Results Eosinophilic CRSwNP was characterized by higher level of GATA3 gene expression compared to noneosinophilic CRSwNP, whereas there was no difference in T-bet, RORC and FOXP3 between eosinophilic and noneosinophilic CRSwNP. In CRSsNP, we found simultaneous upregulation of T-bet, GATA3 and RORC gene expression levels in comparison to CRSwNP; meanwhile, there was no difference in FOXP3 gene expression between CRSwNP and CRSsNP. Conclusions In eosinophilic CRSwNP, we confirmed the type 2 inflammation by elevated GATA3 gene expression level. In CRSsNP, we unexpectedly found simultaneous upregulation of T-bet and GATA3 that is currently unexplained; however, it might originate from activated CD8+ cells, abundant in nasal mucosa of CRSsNP patients. The elevated RORC in CRSsNP could be part of homeostatic nasal immune response that might be better preserved in CRSsNP patients compared to CRSwNP patients. Further data on transcription factors expression rates in CRS phenotypes are needed.

Asthma exacerbations are often caused by rhinovirus (RV). We and others have shown that Toll-like receptor 2 (TLR2), a membrane surface receptor that recognizes bacterial lipopeptides and lipoteichoic acid, is required and sufficient for RV-induced proinflammatory responses in vitro and in vivo. We hypothesized that viral protein-4 (VP4), an internal capsid protein that is myristoylated upon viral replication and externalized upon viral binding, is a ligand for TLR2. Recombinant VP4 and myristoylated VP4 (MyrVP4) were purified by Ni-affinity chromatography. MyrVP4 was also purified from RV-A1B-infected HeLa cells by urea solubilization and anti-VP4 affinity chromatography. Finally, synthetic MyrVP4 was produced by chemical peptide synthesis. MyrVP4-TLR2 interactions were assessed by confocal fluorescence microscopy, fluorescence resonance energy transfer (FRET), and monitoring VP4-induced cytokine mRNA expression in the presence of anti-TLR2 and anti-VP4. MyrVP4 and TLR2 colocalized in TLR2-expressing HEK-293 cells, mouse bone marrow-derived macrophages, human bronchoalveolar macrophages, and human airway epithelial cells. Colocalization was absent in TLR2-null HEK-293 cells and blocked by anti-TLR2 and anti-VP4. Cy3-labeled MyrVP4 and Cy5-labeled anti-TLR2 showed an average fractional FRET efficiency of 0.24 ± 0.05, and Cy5-labeled anti-TLR2 increased and unlabeled MyrVP4 decreased FRET efficiency. MyrVP4-induced chemokine mRNA expression was higher than that elicited by VP4 alone and was attenuated by anti-TLR2 and anti-VP4. Cytokine expression was similarly increased by MyrVP4 purified from RV-infected HeLa cells and synthetic MyrVP4. We conclude that, during RV infection, MyrVP4 and TLR2 interact to generate a proinflammatory response.

Background: Siglec-7 is an inhibitory receptor (IR) expressed on human blood eosinophils. Whereas activation of other IRs, including Siglec-8 and CD300a, has been shown to downregulate eosinophil function, little is known about the role of Siglec-7 on human eosinophils., Objective: To examine Siglec-7 expression and function in eosinophils from normal (ND) and eosinophilic (EO) donors., Methods: Eosinophil expression of Siglec-7 was quantified by flow cytometry and quantitative PCR. Soluble Siglec-7 (sSiglec-7) levels were measured by ELISA in serum. The effect of Siglec-7 on eosinophil viability and degranulation was assessed in vitro by AnnexinV-FITC/7-AAD staining and by measuring GM-CSF-induced mediator release in culture supernatants. Signal transduction was studied by Western blot., Results: Siglec-7 was expressed ex vivo on blood eosinophils from all eosinophilic and normal individuals studied. Siglec-7 surface, but not SIGLEC-7mRNA expression, was correlated with absolute eosinophil count (AEC). Siglec-7 was upregulated on purified eosinophils after in vitro stimulation with GM-CSF or IL-5. Serum sSiglec-7 was detectable in 133/144 subjects tested and correlated with AEC. Siglec-7 cross-linking inhibited GM-CSF-induced release of eosinophil peroxidase, TNF-α, and IL-8 (n = 7-8) but did not promote eosinophil apoptosis (n = 5). Finally, Siglec-7 cross-linking on GM-CSF-activated eosinophils induced phosphorylation of SHP-1 and de-phosphorylation of ERK1/2 and p38., Conclusions: Siglec-7 is constitutively expressed on human eosinophils and downmodulates eosinophil activation. Targeting of Siglec-7 on eosinophils might enhance treatment efficacy in eosinophil-driven disorders. Conversely, therapeutic interventions that inhibit Siglec-7 could have unanticipated consequences and promote eosinophilic inflammation., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a rare primary cancer of the thyroid. This tumor is analogous to other primary tumors of the salivary glands, breast, pancreas, and esophagus. We present a case of this rare tumor with characteristic clinical features, ultrasound images, cytopathology, histopathology, and a heretofore undocumented somatic gene mutation. Additionally, we provide a succinct review of the controversial literature for this uncommon lesion., (© 2019 Wiley Periodicals, Inc.)

Steroids are commonly used in patients with eosinophilic meningitis caused by A. cantonensis infections. The mechanism steroids act on eosinophilic meningitis remains unclear. In this mouse experiments, expressions of 14-3-3 isoform β and γ proteins significantly increased in the CSF 2-3 weeks after the infection, but not increasedin the dexamethasone-treated group. Expression of 14-3-3 β, γ, ε, and θ isoforms increased in brain meninges over the 3-week period after infection and decreased due to dexamethasone treatment. In conclusion, administration of dexamethasone in mice with eosinophilic meningitis decreased expressions of 14-3-3 isoform proteins in the CSF and in brain meninges.

Objective: Recently, JESREC score and mucosal eosinophil count have been used to diagnose eosinophilic chronic rhinosinusitis (ECRS) in Japan. However, it remains unknown whether the subtypes of CRS diagnosed by these criteria have different endotypes. In the present study, we investigated whether JESREC score and mucosal eosinophil count were appropriate for classification of CRS subgroups into endotypes., Methods: A cross-sectional study involving 71 consecutive patients with CRS with nasal polyps (CRSwNP) and 13 control patients was performed. Nasal polyp tissues from CRSwNP patients and uncinate process tissues from control patients were collected for analysis of inflammatory cells by immunohistochemistry and measurement of cytokines and chemokines by ELISA and quantitative real-time PCR. We compared the differences between subtypes according to JESREC score and mucosal eosinophil count and investigated the subgroups with different endotypes by cluster analysis and principal component analysis., Results: In the 71 CRSwNP patients, 9 patients had JESREC score <11 and mucosal eosinophil count <70/HPF (Group A), 20 patients had JESREC score ≥11 and mucosal eosinophil count <70/HPF (Group C), and 42 patients had JESREC score ≥11 and mucosal eosinophil count ≥70/high-power field (HPF) (Group D). Semiquantitative analysis of inflammatory cells showed that eosinophils, neutrophils, macrophages, mast cells, and basophils differed significantly between the subgroups. At the mRNA level, CLC, IL5, IL13, CCL11, CCL24, CCL26, POSTN, CSF3, and IL8 showed significant differences. At the protein level, eotaxin-2/CCL24, eotaxin-3/CCL26, and G-CSF had significant differences. Cluster analysis using gene expression levels in 55 CRS patients and 11 control patients revealed that the patients could be classified into five clusters. Cluster 1 (n=27) contained all patients with Group D. Cluster 2 (n=11) comprised all control patients. Cluster 3 (n=4) included mixed subtypes: one with Group A and three with Group D. Cluster 4 (n=7) and Cluster 5 (n=17) contained all patients with Groups A and C, respectively. Furthermore, the principal component analysis revealed that the subtypes had different characteristics., Conclusion: CRS subtypes based on JESREC score and mucosal eosinophil count showed different inflammatory patterns, and unsupervised statistical analyses supported the classification that can predict endotypes. From these results, we concluded that the classification based on JESREC score and mucosal eosinophil count was useful for predicting CRS endotypes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The role of IL-38, a new member of the IL-1 family, in airway eosinophilic inflammatory conditions such as asthma is unclear. To investigate the role of IL-38 in airway eosinophilic inflammation, an IL-38-gene deficient (KO) murine asthma model was analyzed., Methods: The numbers of eosinophils and neutrophils, and levels of IL-5, IL-13 and IL-17A protein and mRNA in bronchoalveolar lavage fluid (BALF) and lung tissue were compared between wild-type (WT) and IL-38-KO mice after OVA sensitization and challenge. The effects of additional purified recombinant mouse (rm) IL-38 protein were investigated in the IL-38-KO murine asthma model., Results: The IL-38 and IL-5 mRNA in WT mice was significantly higher after OVA challenge than after saline challenge (p<0.05). The number of airway eosinophils in IL-38-KO mice was significantly lower than in WT mice after OVA challenge (p<0.01). BALF analysis confirmed the lower number of airway eosinophils in IL-38-KO mice and showed that this was significantly associated with lower IL-5 protein levels (r=0.92, p<0.0001). However, the additional rm IL-38 protein did not neutralize airway eosinophilia in IL-38-KO mice., Conclusion: IL-38 may enhance airway eosinophilic inflammation in asthma through IL-5 induction.

Squamous cell carcinoma is the most common malignant oral tumor in cats. The late presentation is one of the factors contributing to the detrimental prognosis of this disease. The immunohistochemical expression of the p53 tumor suppressor protein has been reported in 24% to 65% of feline oral squamous cell carcinomas, but no study has systematically evaluated in this tumor the presence of p53 encoding gene (TP53) mutations. The aim of this retrospective study was to determine whether p53 immunohistochemistry accurately reflects the mutational status of the TP53 gene in feline oral squamous cell carcinoma. Additionally, the prevalence of p53 dysregulation in feline oral squamous cell carcinoma was compared with that of feline non-neoplastic oral mucosa, in order to investigate the relevance of these dysregulations in cancer development. The association between p53 dysregulations and exposure to environmental tobacco smoke and tumor characteristics was further assessed. Twenty-six incisional biopsies of oral squamous cell carcinomas and 10 cases each of lingual eosinophilic granuloma, chronic gingivostomatitis and normal oral mucosa were included in the study. Eighteen squamous cell carcinomas (69%) expressed p53 and 18 had mutations in exons 5-8 of TP53. The agreement between immunohistochemistry and mutation analysis was 77%. None of non-neoplastic oral mucosa samples had a positive immunohistochemical staining, while one case each of eosinophilic granuloma and chronic gingivostomatitis harbored TP53 mutations. Unlike previously hypothesized, p53 dysregulations were not associated with exposure to environmental tobacco smoke. These results suggest an important role of p53 in feline oral tumorigenesis. Additionally, the immunohistochemical detection of p53 expression appears to reflect the presence of TP53 mutations in the majority of cases. It remains to be determined if the screening for p53 dysregulations, alone or in association with other markers, can eventually contribute to the early detection of this devastating disease., Competing Interests: The authors have declared that no competing interests exist.

Background: The KMT2A gene encoded lysine methyltransferase plays an essential role in regulating gene expression during early development and hematopoiesis. To date, 92 different mutations of KMT2A have been curated in the human gene mutation database (HGMD), resulting in Wiedemann-Steiner syndrome (WDSTS) and intellectual disability (ID)/developmental delay (DD)., Case Presentation: In this report, we present a de novo heterozygous deletion mutation [c.74delG; p. (Gly26Alafs*2)] in the KMT2A gene, which was identified by trio-based whole exome sequencing from a 5.5-year-old boy with ID/DD, stereotypic hand movements and blood eosinophilia. Many deleterious germline mutations of KMT2A have been documented to affect development of central nervous system, oral and craniofacial tissues, but not blood eosinophils., Conclusions: This is the first report of a rare case with ID/DD as well as eosinophilia, resulting from a previously undescribed null mutation of KMT2A. Our findings expand the phenotypical spectrum in affected individuals with KMT2A mutations, and may shed some insight into the role of KMT2A in eosinophil metabolism.

Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0-4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.

Eosinophilia is a severe disease with increased eosinophil count. The transcript of FIP1L1-PDGFRA fusion gene is a genetic biomarker of clonal eosinophilia screened routinely by reverse transcript PCR (RT-PCR) during diagnosis. Another significant genetic biomarker is the PDGFRA gene alone as some of its mutations are targets of imatinib. In this study, we identified a patient who had typical symptoms of Eosinophilia but had no response to the first-line treatment of hormonotherapy. This patient also showed bone rupture and eosinophil bone infiltration, which are extremely rare among all known eosinophilia patients. We identified the FIP1L1-PDGFRA fusion gene via RT-PCR and Sanger sequencing. Using next generation sequencing (NGS), we detected point mutations in PDGFRA, MYOM2, and ASXL3. The patient then received imatinib therapy, leading to the complete disappearance of FIP1L1-PDGFRA fusion gene and mutated MYOM2. The level of PDGFRA point mutation was also decreased from pre-treatment: 57.86% down to 42.99% at 6 months and to 38.80% at one-year after treatment. The level of ASXL3 mutations did not change significantly. To the best of our knowledge, this is the first case in which the point mutation of PDGFRA has been identified at p.P6L in exon 2, likely making it sensitive to imatinib and thus should be further studied as a potential new molecular target of imatinib therapy.

Genetic rearrangements involving FLT3 are rare and only recently have been detected in myeloid/lymphoid neoplasms associated with eosinophilia (MLN-eos) and chronic myeloproliferative disorders. Here we report two cases with FLT3 fusions in patients demonstrating mixed features of myelodysplastic/myeloproliferative neoplasms. In the first case, FLT3 was fused with a new fusion partner MYO18A in a patient with marrow features most consistent with atypical chronic myeloid leukemia; the second case involving ETV6 - FLT3 fusion was observed in a case with bone marrow features most consistent with chronic myelomonocytic leukemia. Notably, we observed that samples from both patients demonstrated FLT3 inhibitor (quizartinib and sorafenib) sensitivity in ex vivo drug screening assay., (© 2018 Zhang et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Asthma represents a significant public health burden; however, novel biological therapies targeting immunoglobulin E (IgE)-mediated pathways have widened clinical treatment options for the disease., Objective: In this study, we sought to identify gene transcripts and gene networks involved in the determination of serum IgE levels in people with asthma that can help inform the development of novel therapeutic agents., Methods: We analysed gene expression data from a cross-sectional study of 326 Costa Rican children with asthma, aged 6 to 12 years, from the Genetics of Asthma in Costa Rica Study and 610 young adults with asthma, aged 16 to 25 years, from the Childhood Asthma Management Program trial. We utilized differential gene expression analysis and performed weighted gene coexpression network analysis on 25 060 genes, to identify gene transcripts and network modules associated with total IgE, adjusting for age and gender. We used pathway enrichment analyses to identify key biological pathways underlying significant modules. We compared findings that replicated between both populations., Results: We identified 31 transcripts associated with total IgE that replicated between the two study cohorts. These results were notable for increased eosinophil-related transcripts (including IL5RA, CLC, SMPD3, CCL23 and CEBPE). Pathway enrichment identified the regulation of T cell tolerance as important in the determination of total IgE levels, supporting a key role for IDO1., Conclusions and Clinical Relevance: These results provide robust evidence that biologically meaningful gene expression profiles (relating to eosinophilic and regulatory T cell pathways in particular) associated with total IgE levels can be identified in individuals diagnosed with asthma during childhood. These profiles and their constituent genes may represent novel therapeutic targets., (© 2018 John Wiley & Sons Ltd.)

Background: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) has not been fully elucidated. This study sought to explore the role and mechanism of transient receptor potential canonical channel 6 (TRPC6) in the pathogenesis of CRSwNP., Methods: Immunohistochemistry (IHC) was employed to evaluate TRPC6 immunolabeling. Real-time polymerase chain reaction (PCR) was conducted to assay TRPC6, stromal interaction molecule 1 (STIM1), and calcium release-activated calcium channel protein 1 (Orai1) messenger RNA (mRNA) levels in 70 patients with CRSwNP, including eosinophilic CRSwNP (ECRSwNP) or non-eosinophilic CRSwNP (nECRSwNP), and 28 control subjects. The concentrations of inflammatory mediators, including interleukin (IL)-1β, IL-5, and IL-25, were assayed by enzyme-linked immunosorbent assay (ELISA). In experiments on human nasal epithelial cell (HNEC) culture and stimulation, the mean fluorescence intensity (MFI) of intracellular Ca 2+ was assayed by flow cytometry. Western blotting, real-time PCR, and ELISA were also conducted to assess the effects and mechanisms of TRPC6 activator 1-oleoyl-2-acetyl-glycerol (OAG) and TRPC6 inhibitor 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) on HNECs., Results: Upregulation of TRPC6, STIM1, and Orai1 levels was found in CRSwNP patients, particularly in those with ECRSwNP. TRPC6-positive cells correlated positively with the numbers of eosinophils and neutrophils, respectively. Moreover, TRPC6 mRNA was positively correlated with STIM1 and Orai1 mRNA levels. The concentrations of inflammatory mediators, including IL-1β, IL-5, and IL-25, were elevated in CRSwNP, especially in ECRSwNP. In cultured HNECs, TRPC6, STIM1, Orai1, Ca 2+ MFI levels, and inflammatory mediators were upregulated by lipopolysaccharide (LPS) and OAG but were inhibited by SKF-96365., Conclusion: TRPC6 plays a pro-inflammatory role in the pathogenesis of CRSwNP via regulating Ca 2+ flow., (© 2018 ARS-AAOA, LLC.)

Background: Although current American guidelines distinguish proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) from eosinophilic oesophagitis (EoE), these entities are broadly similar. While two microarray studies showed that they have similar transcriptomes, more extensive RNA sequencing studies have not been done previously., Aim: To determine whether RNA sequencing identifies genetic markers distinguishing PPI-REE from EoE., Methods: We retrospectively examined 13 PPI-REE and 14 EoE biopsies, matched for tissue eosinophil content, and 14 normal controls. Patients and controls were not PPI-treated at the time of biopsy. We did RNA sequencing on formalin-fixed, paraffin-embedded tissue, with differential expression confirmation by quantitative polymerase chain reaction (PCR). We validated the use of formalin-fixed, paraffin-embedded vs RNAlater-preserved tissue, and compared our formalin-fixed, paraffin-embedded EoE results to a prior EoE study., Results: By RNA sequencing, no genes were differentially expressed between the EoE and PPI-REE groups at the false discovery rate (FDR) ≤0.01 level. Compared to normal controls, 1996 genes were differentially expressed in the PPI-REE group and 1306 genes in the EoE group. By less stringent criteria, only MAPK8IP2 was differentially expressed between PPI-REE and EoE (FDR = 0.029, 2.2-fold less in EoE than in PPI-REE), with similar results by PCR. KCNJ2, which was differentially expressed in a prior study, was similar in the EoE and PPI-REE groups by both RNA sequencing and real-time PCR., Conclusion: Eosinophilic oesophagitis and PPI-REE have comparable transcriptomes, confirming that they are part of the same disease continuum., (© 2018 John Wiley & Sons Ltd.)

Eosinophilic solid and cystic renal cell carcinomas (ESC RCC) is a rare, unique tumor type not yet included in the World Health Organization classification of renal neoplasia. Separately, RCCs found in patients with tuberous sclerosis complex (TSC) have recently been categorized into 3 morphologic groups: RCC with a tubulopapillary architecture separated by smooth muscle stroma, chromophobe-like, and eosinophilic-microcytic type. The third classification has been identified in ∼11% of TSC-associated RCC and have histology identical to ESC RCCs. The sporadic form of ESC RCC, not associated with TSC, have only been characterized on the cytogenetic level and the full molecular underpinnings have yet to be examined. Using next-generation sequencing we present 2 cases of sporadic ESC RCC in patients without clinical features of tuberous sclerosis, which demonstrate pathogenic somatic TSC2 gene mutations. These mutations are without other alterations in any other genes associated with RCC, suggesting that sporadic ESC RCC may be characterized by somatic tuberous sclerosis gene mutations (TSC2).

There are similarities between the immune response following immunization with aluminum adjuvants and the immune response elicited by some helminthic parasites, including stimulation of immunoglobulin E (IgE) and eosinophilia. Immunization with aluminum adjuvants, as with helminth infection, induces a Th2 type cell mediated immune response, including eosinophilia, but does not induce an environment conducive to the induction of regulatory mechanisms. Helminths play a role in what is known as the hygiene hypothesis, which proposes that decreased exposure to microbes during a critical time in early life has resulted in the increased prevalence and morbidity of asthma and atopic disorders over the past few decades, especially in Western countries. In addition, gut and lung microbiome composition and their interaction with the immune system plays an important role in a properly regulated immune system. Disturbances in microbiome composition are a risk factor for asthma and allergies. We propose that immunization with aluminum adjuvants in general is not favorable for induction of regulatory mechanisms and, in the context of the hygiene hypothesis and microbiome theory, can be viewed as an amplifying factor and significant contributing risk factor for allergic diseases, especially in a genetically susceptible subpopulation., Competing Interests: The authors declare no conflict of interest.

Background: Eosinophilic inflammation is a major pathologic feature of chronic rhinosinusitis (CRS) and is frequently associated with severe refractory disease. Prostaglandin (PG) D 2 levels are increased in patients with CRS, and PGD 2 is an important contributing factor to eosinophilic inflammation. Autophagy has a pleiotropic effect on immune responses and disease pathogenesis. Recent studies suggest the potential involvement of autophagy in patients with CRS and the PG pathway., Objective: We sought to investigate whether altered function of autophagy is associated with eosinophilic inflammation and dysregulated production of PGD 2 in patients with CRS., Methods: We used myeloid cell-specific deletion of autophagy-related gene 7 (Atg7), which is vital for autophagy, and investigated the effects of impaired autophagy on eosinophilic inflammation in a murine model of eosinophilic chronic rhinosinusitis (ECRS). The effect of autophagy on PGD 2 production and gene expression profiles associated with allergy and the PG pathway were assessed., Results: We found that impaired autophagy in myeloid cells aggravated eosinophilia, epithelial hyperplasia, and mucosal thickening in mice with ECRS. This aggravation was associated with gene expression profiles that favor eosinophilic inflammation, T H 2 response, mast cell infiltration, and PGD 2 dysregulation. Supporting this, PGD 2 production was also increased significantly by impaired autophagy. Among other myeloid cells, macrophages were associated with autophagy deficiency, leading to increased IL-1β levels. Macrophage depletion or blockade of IL-1 receptor led to alleviation of eosinophilic inflammation and sinonasal anatomic abnormalities associated with autophagy deficiency., Conclusion: Our results suggest that impaired autophagy in myeloid cells, particularly macrophages, has a causal role in eosinophilic inflammation and ECRS pathogenesis., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Long noncoding RNA (lncRNA) plays roles in many diseases including asthma. Several lncRNAs function in the early differentiation of T-helper cells. lncRNA controls gene transcription, protein expression, and epigenetic regulation. Of the 4 asthma phenotypes, eosinophilic asthma (EA) is the most common. However, the lncRNAs associated with eosinophilic asthma have yet to be identified.We designed a study to identify the circulating lncRNA signature in EA samples. We tested whether significant differences in lncRNA expression were observed between blood samples from patients with EA and healthy individuals (control). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for the lncRNA-mRNA (messenger RNA) co-expression network. lncRNA expression was measured using quantitative real-time PCR (polymerase chain reaction).A total of 41 dysregulated lncRNAs and 762 dysregulated mRNAs (difference ≥ 2-fold) were found in EA compared to control samples. GO terms and KEGG pathway annotation data revealed that several lncRNAs are significantly associated with EA. KEGG pathway annotation indicated that the pathways most enriched in EA were measles, T cell receptor signaling pathway, peroxisome proliferator activated-receptors (PPAR) signaling pathway, Fc gamma R-mediated phagocytosis, NF (nuclear factor) kappa B signaling pathway, chemokine signaling pathway, and primary immunodeficiency. Using qRT-PCR, lncRNA was confirmed to differ significantly between EA and control samples.The results presented here show that several lncRNAs may take part in the immune regulation of EA. Whether these lncRNAs can be used as biomarkers needs further study.

Objective: To investigate the clinical features and therapeutic strategies of childhood myeloid neoplasms associated with eosinophilia and platelet-derived growth factor receptor beta (PDGFRB) gene rearrangement. Methods: Clinical data of myeloid neoplasms associated with eosinophilia and t (1;5) (q21;q33) chromosomal translocation of PDGFRB gene rearrangement in a child hospitalized in Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences on May 2015 was collected and analyzed. Using'eosinophilia child'and'PDGFRB'as keywords, the relevant reports in literature were searched from China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and Biomedical Literature Database (PubMed) until April 2017. Results: The patient was a boy, 19 months old, who began to get sick at six months after birth, with the main clinical manifestations of high fever, diarrhea, epistaxis and hepatosplenomegaly. Peripheral blood smear showed a significant elevation in white blood cells (127×10(9)/L) and eosinophils(20.32×10(9)/L). Bone marrow examination showed hyperplastic marrow, increased proportion of granulocytes, apparent visible eosinophils and decreased megakaryocytes. Chromosome karyotype detection revealed t (1; 5) (q21; q33) translocation. Fluorescence in situ hybridization (FISH) examination uncovered that PDGFRB gene rearrangement was positive. The final diagnosis was myeloid neoplasms with eosinophilia and PDGFRB gene rearrangement. After treatment with oral imatinib 100 mg, once a day for 2 months, complete hematologic remission, complete cytogenetic and molecular remission were all achieved. The relevant literature was reviewed, no Chinese cases had been reported, 6 reports in English literature have complete clinical data. Four cases had t (1; 5) translocation. Four pediatric patients treated with imatinib achieved complete remission. Conclusion: Myeloid neoplasms associated with eosinophilia and PDGFRB gene rearrangement is extremely rare in children. Imatinib treatment can make these patients quickly achieve complete hematologic remission, complete cytogenetic and molecular remission. Imatinib should be recommended as the first line treatment of these patients.

Myeloid neoplasms with eosinophilia associated with PDGFRA rearrangement are very responsive to tyrosine kinase inhibitors (TKIs). Herein, we report a case of a 53-year-old man with eosinophilia and a well-differentiated extramedullary myeloid tumor with evidence of FIP1L1/PDGFRA rearrangement by fluorescent in situ hybridization in the extramedullary tissue. His bone marrow evaluation revealed a hypercellular marrow with eosinophilia but without evidence of a FIP1L1/PDGFRA rearrangement. The patient was treated with imatinib at a dose of 100 mg daily and responded with normalization of his peripheral eosinophil count. The case raises the possibility that an extramedullary myeloid tumor may represent a primary site for PDGFRA rearrangement, and highlights the importance of performing cytogenetic testing on extramedullary tissue. Detection of the chromosomal rearrangement is critical for initiation of effective targeted therapy that can improve patient outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Myeloproliferative disorders with eosinophilia may possess the FIP1L1-PDGFRα gene rearrangement. When this rearrangement is present, imatinib usually results in complete remission. In rare cases of imatinib resistance, there is poor evidence guiding second-line therapy. We present the case of a 71-year-old male who presented with abdominal discomfort, fevers, and leukocytosis with eosinophilia. The patient was diagnosed with a myeloproliferative neoplasm with eosinophilia and FIP1L1-PDGFRα rearrangement after a bone marrow evaluation revealed hypercellular marrow with eosinophilia and fluorescence in situ hybridization identified the FIP1L1-PDGFRα rearrangement. The patient was successfully treated with imatinib. Within months he relapsed and converted into acute myeloid leukemia. The patient was then treated with ponatinib which induced and maintained clinical and hematological remission for 2 months. That ponatinib briefly induced remission in our patient with acute myeloid leukemia arising from a myeloproliferative neoplasm with eosinophilia and FIP1L1-PDGFRα fusion may merit exploration of ponatinib as a potential second-line treatment option for this patient population. This is especially true given the lack of reliable therapies in instances of imatinib resistance., (© 2018 S. Karger AG, Basel.)

Background: Eosinophilic gastritis (EG) is clinicopathologically characterized by both marked gastric eosinophilia and clinical symptoms. The endoscopic findings in EG vary among patients, leading to clinical confusion. However, little is known about the relationship between precise endoscopic findings and the pathophysiological process responsible for EG., Objective: We aimed to elucidate whether the gross endoscopic findings of EG can be classified into distinct gene expression profiles., Methods: We enrolled pediatric patients who underwent gastrointestinal endoscopy for clinical symptoms suggestive of eosinophilic gastrointestinal disorder between 2011 and 2016. EG was diagnosed when gastric eosinophilia was greater than or equal to 30 eosinophils/hpf. The gene expression profiles of gastric biopsies were assessed using microarray technology., Results: Patients with EG and control subjects (n = 8, each) were examined. On the microarray, 1,999 genes were differentially expressed between EG and the controls (≥2-fold difference, adjusted P value < .05), including significant upregulation of eotaxin-3 (C-C chemokine ligand 26). The endoscopic findings of patients with EG fell roughly into 2 types, namely, ulcerative and nodular lesions. Despite identifying distinct patterns of gene expression, most differentially regulated genes overlapped between the 2 endoscopic finding types. Several gene ontology terms were enriched in the substantially overlapped genes, but not in each of the distinct genes., Conclusions: Our results strongly indicate that ulcerative and nodular lesions are a single disease, EG, or a variation thereof, in spite of morphological differences. Our findings may contribute to a better understanding of the pathogenesis of EG, as well as to more accurate diagnosis of this disease., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: IL1RL1 (ST2) is involved in Th2 inflammation including eosinophil activation. Single nucleotide polymorphisms (SNPs) of the IL1RL1 gene are associated with asthma development and increased peripheral blood eosinophil counts. However, the association between IL1RL1 SNPs and eosinophilic phenotype among adults with asthma remains unexplored., Methods: In a primary cohort of 110 adult Japanese patients with stable asthma, we examined the associations between IL1RL1 SNPs and clinical measurements including forced expiratory volume (FEV 1 ), airway reversibility of FEV 1 , exhaled nitric oxide (FeNO), serum soluble-ST2 (sST2) levels, peripheral blood eosinophil differentials and serum total IgE level. The findings in the primary cohort were confirmed in a validation cohort of 126 adult Japanese patients with stable asthma., Results: Patients with minor alleles in 3 SNPs (rs17026974, rs1420101, and rs1921622) had high FeNO, blood eosinophil differentials, and reversibility of FEV 1 , but low levels of serum sST2 and FEV 1 . Minor alleles of rs1041973 were associated with low serum sST2 levels alone. In the validation cohort, minor alleles of rs1420101 were associated with high FeNO and blood eosinophil differentials, whereas minor alleles of rs17026974 and rs1921622 were associated with high blood eosinophil differentials and FeNO, respectively. Multivariate analyses revealed that the minor allele of rs1420101 additively contributed to the FeNO, blood eosinophil differentials, and reversibility of FEV 1 ., Conclusions: The minor alleles of IL1RL1 SNPs were associated with high FeNO and peripheral blood eosinophilia among adult Japanese patients with stable asthma. IL1RL1 SNPs may characterize the eosinophilic phenotype with greater eosinophilic inflammation in the Japanese asthma cohort., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) has been recently described as a unique and indolent renal neoplasm, found in female patients with and without tuberous sclerosis complex. Although ESC RCC has a distinct morphology and frequent CK20 reactivity, its molecular karyotype has been previously studied only in few cases. We identified 19 ESC RCC from multiple institutions; all patients were female individuals without clinical features of tuberous sclerosis complex. Molecular karyotyping was performed in 13 cases (12 with informative result). The median age was 55 years (range: 32 to 79 y). The tumors were yellow-gray with a median size of 31 mm (range: 12 to 135 mm) and showed solid and cystic gross appearance. All tumors demonstrated typical microscopic features with solid areas admixed with variably sized macrocysts and microcysts. The cells showed eosinophilic cytoplasm with granular cytoplasmic stippling and round-to-oval nuclei. CK20 was positive in 14/19 (74%) cases. Stage pT1 was found in 17/19 (89%) patients (pT1a in 12, pT1b in 5); 1 patient each had pT2a and pT3a. A total of 15/16 patients with available follow-up were alive and without evidence of disease progression, after 1 to 169 months (median: 44 mo; mean: 49.6 mo); 3 died of other causes. The most common copy number gains were 16p13.3-16q23.1 (33% to 67%), 7p21.2-7q36.2 (42% to 50%), 13q14.2 (33%), and 19p12 (33%). The most common copy number losses included Xp11.21 (42%) and 22q11.23 (33%). Loss of heterozygosity was most frequently found at 16p11.2-11.1 (75%), Xq11.1-13.1 (75%), Xq13.1-21.1 (33%), 11p11.2-11.11 (33%), 9q21.1-22.2 (33%), and 9q33.1 (33%). ESC RCC demonstrates common molecular karyotype alterations, which further support its distinct nature.

Background: The cytogenetic aberrations inv(16)(p13.1q22)/t(16;16)(p13.1;q22), frequently detected in acute myelomonocytic leukemia with eosinophilia (FAB type M4eo), are generally considered a prognostically favorable subgroup. M4eo comprises a distinct morphology compared to M4 without eosinophilia (M4eo-) and therefore may be indicative for a different pathogenesis., Procedures: Morphology and cytogenetic/molecular analyses of a Dutch cohort of pediatric acute myelomonocytic leukemia (AML-M4) patients were performed and studied in order to analyze the association between the presence of eosinophilia morphology (M4eo+), inv(16)/t(16;16) (inv(16)+), clinical features, and outcome., Results: Of the 119 included patients with available combined morphological and cytogenetic results, 60% had M4eo- without inv(16) (inv(16)-), 10% had M4eo-/inv(16)+, 13% had M4eo+/inv(16)-, and 17% had M4eo+/inv(16)+. M4eo+ was significantly associated with the presence of inv(16)/t(16;16) (P < 0.001). Patients with M4eo+ had no significantly superior outcome compared with patients with M4eo-, whereas patients with inv(16)+ had significantly superior probabilities of event-free survival and probabilities of overall survival compared with patients without inv(16)-. Patients with M4eo+/inv(16)+ had no significantly better outcome than those with M4eo-/inv(16)+., Conclusion: The prognostically favorable impact of distinct morphology with eosinophilia probably relies on its association with inv(16)/t(16;16). Simultaneous presence of both eosinophilia and inv(16) was not associated with superior outcome in our study. These results may be relevant for risk-group classification and risk-group adapted treatment and underline the importance of accurate cytogenetic analysis., (© 2017 Wiley Periodicals, Inc.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disorder characterized by exaggerated local immune responses. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a novel protein with potential immune modulating function. The expression and function of TIPE2 in human airway diseases are unclear., Methods: The expression of TIPE2 in sinonasal mucosal samples was assessed by means of quantitative reverse transcript-polymerse chain reaction, immunohistochemistry, and Western blotting. The human monocytic/macrophage cell line, THP-1 cells, was stimulated with various cytokines. Computed tomography (CT) scan images, endoscopic findings, and symptoms were scored., Results: Compared with non-eosinophilic polyps and control mucosa, the mRNA and protein expression of TIPE2 was significantly upregulated in eosinophilic polyps, with a further increase in those with asthma. The number of CD68 + CD163 + alternatively activated (M2) macrophages was increased in eosinophilic polyps. TIPE2 was mainly expressed by M2 macrophages in sinonasal mucosa and its expression was upregulated in M2 macrophages in eosinophilic polyps. Interleukin (IL)-4 and IL-13, but not interferon (IFN)-γ or IL-17A, induced TIPE2 expression in differentiated THP-1 cells. The mRNA levels of IL-4 and IL-13 correlated with the mRNA levels of TIPE2 and M2 macrophage markers in sinonasal mucosa. Importantly, the number of TIPE2 + cells, particularly TIPE2 + CD163 + CD68 + M2 macrophages, correlated positively with the number of eosinophils and total inflammatory cells in sinonasal mucosa, as well as disease duration, CT scores, hyposmia scores, and polyp size in CRSwNP., Conclusion: The T-helper 2 milieu is able to induce TIPE2 expression in macrophages. TIPE2-positive M2 macrophages potentially contribute to eosinophilic inflammation and disease progression in CRSwNP., (© 2017 ARS-AAOA, LLC.)

We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20-80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×10 9 /L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0-13)​. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3-34) and 19 months (range 7-110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1-135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia,, ((c) presentation in chronic or blast phase, (d) rapid responses and long-term remission on low-dose imatinib, and (e) possible adverse prognostic impact of a complex karyotype.)

Nasal polyp (NP) is a common chronic inflammatory disease of the nasal cavity and sinuses. Although some authors have suggested that NP is related to inflammatory factors such as interleukin (IL)-1β, IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, and IL-17, the mechanisms underlying the pathogenesis and progression of NP remain obscure. This study investigated the expression and distribution of IL-17 and syndecan-1 in NP, and explored the roles of these two molecules in the pathogenesis of eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) and non-Eos CRSwNP. Real-time PCR and immunohistochemistry were used to detect the expression of IL-17 and syndecan-1 in samples [NP, unciform process (UP) from patients with CRS, and middle turbinate (MT) from healthy controls undergoing pituitary tumor surgery]. The results showed that the expression levels of IL-17 and syndecan-1 were upregulated in both NP and UP tissues, but both factors were higher in NP tissues than in UP tissues. There was no significant difference in IL-17 levels between the Eos CRSwNP and non-Eos CRSwNP samples, and syndecan-1 levels were increased in the non-Eos CRSwNP tissues as compared with those in Eos CRSwNP tissues. In all of the groups, there was a close correlation between the expression of IL-17 and syndecan-1 in nasal mucosa epithelial cells, glandular epithelial cells, and inflammatory cells, suggesting that IL-17 and syndecan-1 may play a role, and interact with each other, in the pathogenesis of non-Eos CRSwNP.

Eosinophilic colitis (EC) is a common cause of haematochezia in infants and young children. The exact pathomechanism is not understood, and the diagnosis is challenging. The role of microRNAs as key class of regulators of mRNA expression and translation in patients with EC has not been explored. Therefore, the aim of the present study was to explore the miRNA profile in EC with respect to eosinophilic inflammation. Patients enrolled in the study ( n = 10) had persistent rectal bleeding, and did not respond to elimination dietary treatment. High-throughput microRNA sequencing was carried out on colonic biopsy specimens of children with EC (EC: n = 4) and controls (C: n = 4) as a preliminary screening of the miRNA profile. Based on the next-generation sequencing (NGS) results and literature data, a potentially relevant panel of miRNAs were selected for further measurements by real-time reverse transcription (RT)-PCR (EC: n = 14, C: n = 10). Validation by RT-PCR resulted in significantly altered expression of miR-21, -31, -99b, -125a, -146a, -184, -221, -223, and -559 compared to controls ( p ≤ 0.05). Elevation in miR-21, -99b, -146a, -221, and -223 showed statistically significant correlation to the extent of tissue eosinophilia. Based on our results, we conclude that the dysregulated miRNAs have a potential role in the regulation of apoptosis by targeting Protein kinase B/Mechanistic target of rapamycin (AKT/mTOR)-related pathways in inflammation by modulating Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signalling and eosinophil cell recruitment and activation, mainly by regulating the expression of the chemoattractant eotaxin and the adhesion molecule CD44. Our results could serve as a basis for further extended research exploring the pathomechanism of EC.

The 8p11 eosinophilic myeloproliferative syndrome (EMS) is an aggressive neoplasm driven by translocation of the fibroblast growth factor receptor 1 and often transforms to leukemias and lymphomas that are refractory to treatment. The first case was identified in 1983, and to date over 70 cases have been reported in the literature. Despite those reports, no consensus exists on management of this condition, and inconsistency in treatment regimens is even more pronounced in the pediatric literature. We report a case of a male infant with the 8p11 EMS, review the published pediatric experience with EMS, and discuss treatment strategies for this enigmatic hematological disorder., (© 2016 Wiley Periodicals, Inc.)