Treatment of pyogenic granuloma in children with a 595 nm pulsed dye laser: A retrospective study of 212 patients.

BACKGROUND: Pyogenic granuloma (PG) is a common vascular neoplasm in children. Data on 595 nm pulsed dye lasers for the treatment of PG in children remain scarce. OBJECTIVE: To summarize the clinical characteristics and to evaluate the effectiveness and safety of the 595 nm pulsed dye laser for the treatment of PG in children. STUDY DESIGN: Retrospective case series. METHODS: A retrospective study was performed on 212 patients treated for PG with a 595 nm pulsed dye laser. SPSS version 19.0 was used for statistical analysis. RESULTS: Among all 212 patients treated, 208 showed complete resolution of the lesion, and 4 dropped out after one treatment due to bleeding. A single treatment was sufficient in 139 (66.8%) patients, while two or three treatments were sufficient in 69 (33.2%) patients. Male patients responded better than female patients (χ2 = 7.603, p =0.006). Lesions in the nonorbital region responded better than those in the orbital region (χ2 = 7.445, p =0.006). The size of the lesion affected the effectiveness, and lesions with smaller diameters (t = -5.776, p <0.01) and heights (t = -10.368, p <0.01) showed better results. COMPLICATIONS AND SIDE EFFECTS: Twelve patients (5.8%) were reported to have local complications and side effects, including edematous erythema, slight bleeding, hyperpigmentation, and hypopigmentation. The edematous erythema and slight bleeding disappeared gradually after several days. The localized pigment changes usually resolved spontaneously and disappeared completely after 6 months. CONCLUSIONS: Our experience confirmed the efficacy and safety of the 595 nm pulsed dye laser for the treatment of PG in children.

Confirming the TMEM232 gene associated with atopic dermatitis through targeted capture sequencing.

Atopic dermatitis (AD) is a common and complex skin disorder, and the 5q22.1 region had been reported to be associated with AD. To confirm the susceptibility gene for AD in the 5q22.1 region by haplotype and targeted capture sequencing. The haplotypes were reconstructed with the genotyping data of four SNPs and six deletions from 3624 Chinese Hans AD patients and 5076 controls. The targeted capture sequencing spanning 5q22.1 region was performed in the selected samples. The gene level enrichment analysis was done using loss of function variants. A total of 62 haplotypes were found, and the H15 haplotype had the strongest association with AD (P = 3.92 × 10-10, OR 0.17, 95% CI 0.09-0.32). However, no co-segregation mutation sites were found in the sequencing analysis within the 16 selected samples, while the enrichment analysis indicated that TMEM232 was significantly associated with AD (P = 7.33 × 10-5, OR 0.33, 95% CI 0.19-0.58). This study confirms previous findings that the TMEM232 gene is associated with AD by haplotype analysis and targeted capture sequencing.

A Common Variant at 11q23.3 Is Associated with Susceptibility to Atopic Dermatitis in the Han Chinese Population.

Background: Genome-wide association studies (GWASs) have identified many genetic variants that are risk factors for numerous immune-mediated diseases. In particular, different immune-mediated diseases have been found to share the same susceptibility loci. Therefore, exploring the genetic overlap between atopic dermatitis (AD) and other immune-mediated diseases in more detail may help identify additional shared susceptibility loci among common immune-mediated diseases. Recent evidence suggests that the 11q23.3 locus is a susceptibility locus shared among multiple immune-mediated diseases. Objective: This study was designed to investigated whether SNPs at the chromosome 11q23.3 locus are associated with AD in the Han Chinese population. Methods: In total, 16 SNPs within the 11q23.3 locus were genotyped using TaqMan assays for 1,012 AD cases and 1,362 controls. From these SNPs, we selected rs638893 with an association values of p < 5 × 10-2 for AD for further analysis in an independent replication study using the Sequenom MassARRAY system to genotype an additional (consisting of 1,288 cases and 1,380 controls). The combined analyses were performed in two stages using a meta-analytical method. Results: We identified a common variant at 11q23.3 (rs638893), that was significantly associated (p = 1.58 × 10-3, OR = 1.22) with AD. The genotype-based association analysis revealed that the recessive model provided the best fit for rs638893. Conclusion: Our study identified a variant on chromosome 11q23.3 that likely confers susceptibility to AD, thereby advancing our understanding of the genetic basis of this disease.

Molecular Diagnosis of Neurofibromatosis by Multigene Panel Testing.

Neurofibromatosis (NF) is an autosomal genetic disorder for which early and definite clinical diagnoses are difficult. To identify the diagnosis, five affected probands with suspected NF from unrelated families were included in this study. Molecular analysis was performed using multigene panel testing and Sanger sequencing. Ultradeep sequencing was used to analyze the mutation rate in the tissues from the proband with mosaic mutations. Three different pathogenic variants of the NF1 gene were found in three probands who mainly complained of café-au-lait macules (CALMs), including one frameshift variant c.5072_5073insTATAACTGTAACTCCTGGGTCAGGGAGTACACCAA:p.Tyr1692Ilefs in exon 37, one missense variant c.3826C > T:p.Arg1276Ter in exon 28, and one splicing variant c.4110 + 1G > T at the first base downstream of the 3'-end of exon 30. One NF1 gene mosaic variant was found in a proband who complained of cutaneous neurofibroma with the frameshift variant c.495_498del:p.Thr165fs in exon 5, and ultradeep sequencing showed the highest mutation rate of 10.81% in cutaneous neurofibromas. A frameshift variant, c.36_39del:p.Ser12fs in exon 1 of the NF2 gene, was found in a proband who presented with skin plaques and intracranial neurogenic tumors. All of these pathogenic variants were heterozygous, one was not reported, and one not in Chinese before. This study expands the pathogenic variant spectrum of NF and demonstrates the clinical diagnosis.

Validation of Susceptibility Loci for Vitiligo Identified by GWAS in the Chinese Han Population.

Forty-nine susceptible loci have been reported to be significantly associated with vitiligo by genome-wide association studies (GWASs) in European-derived whites. To date, some of these reported susceptibility loci have not yet been validated in the Chinese Han population. The purpose of this study was to examine whether the 16 reported susceptible loci in European-derived whites were associated with vitiligo in the Chinese Han population. Imputation was performed using our previous GWAS dataset by IMPUTE v2.2.2. The 16 imputed top single-nucleotide polymorphisms (SNPs) with suggestive signals, together with the reported SNPs, were genotyped in a total of 2581 patients and 2579 controls by the Sequenom MassARRAY system. PLINK 2.0 software was used to perform association analysis. The dbSNP database, HaploReg, and eQTL data were adopted to annotate the biological function of the SNPs. Finally, four SNPs from three loci were significantly associated with vitiligo, including rs3747517 (P = 1.29 × 10-3, OR = 0.87) in 2q24.2, rs4807000 (P = 7.78 × 10-24, OR = 0.66) and rs6510827 (P = 3.65 × 10-5, OR = 1.19) in 19p13.3, and rs4822024 (P = 6.37 × 10-10, OR = 0.67) in 22q13.2. According to the dbSNP database, rs3747517 is a missense variant of IFIH1, rs4807000 and rs6510827 are located in TICAM1, and rs4822024 is located 6 kb upstream of TEF. Further bioinformatics analysis by HaploReg and eQTL found that rs4807000, rs6510827, and rs4822024 are involved in regulating gene expression. Our study revealed the strong association of 2q24.2 (rs3747517), 19p13.3 (rs4807000, rs6510827), and 22q13.2 (rs4822024) with the risk of vitiligo in the Chinese Han population, which implicates common factors for vitiligo across different ethnicities, and helps expand the understanding of the genetic basis of this disease.

Five novel and highly efficient endophytic fungi isolated from Huperzia serrata expressing huperzine A for the treatment of Alzheimer's disease.

Huperzine A (Hup A) is an important drug for treating Alzheimer's disease (AD) and mainly extracted from the Huperzia serrata (Thunb.) Trevis. (Lycopodiaceae) (HS). Nevertheless, the content of Hup A in HS is very low of 0.007% with growing circle of 8 to 10 years, and the chemical synthesis of Hup A still has some insurmountable limitations in the industrialized production. So, the available resources of Hup A for clinical treatment of AD are scarce. The purpose of this work was to construct a biosynthesis platform based on the endophytic fungi from HS. In this work, five endophytic fungi Mucor racemosus NSH-D, Mucor fragilis NSY-1, Fusarium verticillioides NSH-5, Fusarium oxysporum NSG-1, and Trichoderma harzianum NSW-V were firstly found and isolated from the Chinese folk medicine HS, which were identified according to their morphological characteristics and nuclear ribosomal DNA ITS sequences. The highest efficient fungus could effectively biosynthesize Hup A in a liquid culture of 319.8 ± 0.17 mg/L which were 112 times higher than that of other reported conventional endophytic fungi. Moreover, these fungi with higher hereditary stability could possess the initial expressing ability of Hup A after 40 generations, and the expressed Hup A from these biosynthesis systems has prior physicochemical properties, a better inhibition activity of acetylcholinesterase and a lower cytotoxicity compared with the listed active pharmaceutical ingredients (APIs) of Hup A. These results provide promising alternative resources for producing Hup A at an industrial scale by biosynthesis, and it may also shed light on millions of AD patients. KEY POINTS: • Five novel endophytic fungi with high stability could highly express prior Hup A Graphical abstract.

GWAS Follow-up Study Discovers a Novel Genetic Signal on 10q21.2 for Atopic Dermatitis in Chinese Han Population.

Atopic dermatitis (AD) is a common inflammatory skin disease with high heritability. Two susceptibility loci have been confirmed in our previous AD genome-wide association study (GWAS). To look for additional genetic factors in Chinese Han ethnicity, we performed a large-scale GWAS follow-up study. Forty-nine top single nucleotide polymorphisms (SNPs) that had never been reported previously were genotyped using Sequenom Massarray system in an independent cohort, which consist of northern Chinese (1634 cases and 1263 controls) and southern Chinese (2985 cases and 9526 controls). Association analyses were performed using PLINK 2 software. Three SNPs in northern and ten SNPs in southern were found exhibiting association evidence with AD (P < 0.05). Finally, SNP rs224108 on 10q21.2 showed high significance for AD in joint analysis of GWAS and replication study (P meta = 4.55 × 10-9, OR = 1.21), and was confirmed as an independent genetic marker by Linkage disequilibrium calculation and conditional logistic regression analysis. Bioinformatics analysis strongly suggested that rs224108 may have the potential to alter the target gene expression through non-coding epigenetic regulation effects. Meanwhile, SNP rs11150780 on 17q25.3 was also found suggestive association with AD (P meta = 7.64 × 10-7, OR = 1.18). Our findings confirmed a novel susceptibility signal on 10q21.2 for AD in Chinese Han population and advanced the understanding of the genetic contribution to AD.

Molecular mechanism of Notch signaling with special emphasis on microRNAs: Implications for glioma.

Glioma is the most aggressive primary brain tumor and is notorious for resistance to chemoradiotherapy. Although its associated mechanisms are still not completely understood, Notch signaling, an evolutionarily conserved pathway, appears to be the key processes involved. Nevertheless, its mechanisms are sophisticated, due to a variety of targets and signal pathways, especially microRNA. MicroRNAs, which are small noncoding regulatory RNA molecules, have been proposed as one of the key mechanisms in glioma pathogenesis. Among the known glioma associated microRNA, microRNA-129, microRNA-34 family, and microRNA-326 have been shown to influence the progress of glioma through Notch signaling. Evidence also indicates that recurrence is due to development or persistence of the glioma stem-like cells and active angiogenesis, which are tightly regulated by a variety of factors, including Notch signaling. In this review, we summarize the recent progress regarding the functional roles of Notch signaling in glioma, including Notch ligand, microRNA, intracellular crosstalk, glioma stem-like cells and active angiogenesis and explore their clinical implications as diagnostic or prognostic biomarkers and molecular therapeutic targets for glioma.

A variant on chromosome 2p13.3 is associated with atopic dermatitis in Chinese Han population.

BACKGROUND: Multi-ancestry genome-wide association study (GWAS) has recently identified 11 new susceptibility loci for Atopic dermatitis (AD). The replication of these new susceptibility loci in different populations should not be ignored. OBJECTIVE: To examine whether these 11 new identified susceptibility loci are also associated with AD in the Chinese Han population. METHODS: These 11 variants were imputed using our genome-wide array dataset. The selected SNPs with suggestive signals were genotyped in a large-scale replication study with a total of 4619 cases and 10,789 controls using the Sequenom Massarray system. Association analyses were performed using PLINK 1.07 software. Results were combined across our previous AD-GWAS stage and the replication stage by meta-analysis. Bioinformatic analysis was done to predict the possible causal gene. RESULTS: Of the 11 SNPs investigated, four SNPs showed suggestive association (P<0.05) in our previously published GWAS datasets. Association evidence for an intergenic variant rs112111458 at 2p13.3 with AD was replicated in Chinese Han population (P=7.37×10-7, OR=0.86), showing significance in Meta analysis of GWAS and replication study (Pmeta=8.18×10-08, OR=0.69). Further functional annotation by HaploReg indicated that transcriptional regulation activity exists at this locus for the CD207 gene in skin tissue. CONCLUSIONS: Our study confirmed a previously reported susceptibility loci in the Chinese Han population, which implicates CD207 might be a new susceptibility gene for AD and highlights the crucial role of immune responses in AD.

Association analyses identify two susceptibility loci 5q31 and 5q22.1 for atopic dermatitis in Chinese Han population.

BACKGROUND: Atopic dermatitis (AD) and other atopic diseases often share some common genetic and pathogenic bases. Recent genome-wide association studies (GWAS) have identified several loci associated with atopic diseases, allergic sensitization and asthma in different populations. The aim of this study was to investigate whether these susceptibility loci were related to AD in Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNPs) from recent atopic diseases and allergic sensitization GWAS were genotyped in 3,013 AD patients and 5,483 healthy controls in Chinese Han population using Sequenom MassArray system. Data was analyzed with PLINK 1.07 software. RESULTS: We identified that the susceptibility loci at 5q31 (RAD50/IL13, rs2158177, P = 1.08×10-3, OR = 1.15) and 5q22.1 (TSLP, rs1837253, P = 2.66×10-3, OR = 0.91) were significantly associated with AD. Genotype-based association testing revealed that the dominant model provided the best fit for both rs2158177 (P = 3.75×10-3) and rs1837253 (P = 5.30×10-3). Pathway analysis conformed that both loci were associated with the JAK-STAT signaling pathway. CONCLUSIONS: We identified two susceptibility loci 5q31 and 5q22.1 for AD that might bear candidate genes conferring susceptibility to AD.

Scanning indels in the 5q22.1 region and identification of the TMEM232 susceptibility gene that is associated with atopic dermatitis in the Chinese Han population.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. The 5q22.1 region was found to have an association with AD in our previous genome-wide association study (GWAS). OBJECTIVE: To identify the AD susceptibility gene in 5q22.1 and observe its expression in AD tissues. METHODS: Suggestive indels from the GWAS data were genotyped in 3013 AD patients and 5075 controls from the Chinese Han population with the SequenomMassArray system. Association, Bayesian and bioinformatics analyses were used to identify possible causal indels and genes in the 5q22.1 region. Immunohistochemistry (IHC) was performed to observe protein expression in the tissues. PLINK 1.07 software was used for all statistical analyses. RESULTS: The genotyping and association analysis showed that six deletions and four SNPs were associated with AD (P<0.005). The rs11357450 (Pcombined=7.79E-04, OR=1.39, logBayes Factor=1.29) deletion located in TMEM232 was identified to be the strongest variant. Analysis of the genetic model revealed that the dominant model best described rs11357450 (P=1.96E-03, OR=1.22; 95% CI=1.07-1.37). IHC showed that the expression of TMEM232 decreased gradually from the granular layer to the basal layer in AD, but in normal tissues, this trend was reversed. Additionally, positive cytoplasm staining was found in lymphocytes around the blood vessels in AD. CONCLUSIONS: The study indicates that TMEM232 in the 5q22.1 region is the causal gene for AD in the Chinese Han population.

Association of the chromosome 11p13.5 variant and atopic dermatitis with a family history of atopy in the Chinese Han population.

BACKGROUND: Recent genome-wide association studies (GWAS) and a meta-analysis of GWAS for atopic dermatitis (AD) have identified some AD genetic loci in European and Japanese populations. OBJECTIVE: To investigate whether some novel susceptibility loci are associated with AD in the Chinese Han population. METHODS: We first selected eight novel susceptibility loci to replicate in 2,205 AD patients and 2,116 healthy controls using the Sequenom platform. Data were analyzed with PLINK 1.07 software. RESULTS: We found that rs12634229 (3q13.2), rs7927894 (11p13.5) and rs878860 (11p15.4) showed a slight association with AD (P = 0.012, P = 0.033, P = 0.020, respectively); rs6780220 (3p21.33) was preferentially related to AD with keratosis pilaris, but did not reach the threshold of significance after correction. The frequency of rs7927894 allele T was significantly different between AD patients with a positive and negative family history of atopy. CONCLUSION: The loci rs7927894 (11p13.5) are related to AD with a positive family history of atopy in Chinese Han population, providing novel insight into the genetic pathogenesis of AD.

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Genetic polymorphisms in Matrix Metalloproteinases -1 and -7 and susceptibility to gastric cancer: an association study and meta-analysis.

Matrix Metalloproteinases (MMPs) play an important role in gastric cancer (GC). Accumulated evidence suggests that functional MMP-1 and MMP-7 gene polymorphisms are associated with several tumors. The aim of this study was to investigate two single nucleotide polymorphisms, MMP-1 -1607 1G/2G and MMP-7 -181 A/G, and their potential relationship with GC. We examined 246 GC patients and 252 age-and sex-matched controls from Sichuan province in China. Genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism strategy and DNA sequencing. We also performed a meta-analysis of relevant studies, involving 1084 cases and 1721 controls, to place our findings in a broader context. No significant relationship was observed between the MMP-1 -1607 1G/2G alleles and genotypes and the risk of GC. There were significant differences in the genotypes and allele distributions of the -181 A/G polymorphism of the MMP-7 gene between cases and controls. The -181 A allele carriers had a significantly increased risk of GC compared with -181 G allele carriers (OR=3.051, 95% CI, 1.475-6.310, P=0.002), and the AA genotype of -181 A/G was associated with an increased risk of GC compared with the AG genotype (OR=3.189, 95% CI, 1.523-6.676, P=0.001). A meta-analysis of six studies also showed a significant risk of GC associated with MMP-7 polymorphism.

Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.

Association analysis of single nucleotide polymorphisms at five loci: comparison between atopic dermatitis and asthma in the Chinese Han population.

Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10(-4), OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P(correction) = 3.60×10(-10), OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P(correction) = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.

Prediction of sudden cardiac death in patients after acute myocardial infarction using T-wave alternans: a prospective study.

BACKGROUND AND PURPOSE: We assessed the value of T-wave alternans (TWA) in prediction of sudden cardiac death (SCD) in patients with acute myocardial infarction (AMI). METHODS: Consecutive patients (N = 227) were enrolled and were monitored with 24-hour ambulatory electrocardiogram within 1 to 15 days after AMI. T-wave alternans was identified by a modified moving average (MMA) algorithm computer software. The primary end point was SCD or lethal ventricular arrhythmia. We analyzed the hazard ratios (HRs) using the previously determined 47 µV TWA cutpoint. RESULTS: During the 16 ± 7-month follow-up, 10 (4.4%) patients died suddenly. T-wave alternans (≥47 µV) predicted SCD (HR, 17.78 [95% confidence interval, 3.75-84.31]; P < .0001). Moreover, patients with 5 or more TWA episodes (≥47 µV) were at higher risk for SCD (HR, 20.75 [95% confidence interval, 5.77-74.57]; P < .0001). CONCLUSIONS: T-wave alternans (≥47 µV) monitored at 1 to 15 days after AMI-predicted heightened risk of SCD. Prediction is improved when the frequency of TWA episodes (≥47 µV) is analyzed.

Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.

Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.