ORN: Inferring patient-specific dysregulation status of pathway modules in cancer with OR-gate Network.

Pathway level understanding of cancer plays a key role in precision oncology. However, the current amount of high-throughput data cannot support the elucidation of full pathway topology. In this study, instead of directly learning the pathway network, we adapted the probabilistic OR gate to model the modular structure of pathways and regulon. The resulting model, OR-gate Network (ORN), can simultaneously infer pathway modules of somatic alterations, patient-specific pathway dysregulation status, and downstream regulon. In a trained ORN, the differentially expressed genes (DEGs) in each tumour can be explained by somatic mutations perturbing a pathway module. Furthermore, the ORN handles one of the most important properties of pathway perturbation in tumours, the mutual exclusivity. We have applied the ORN to lower-grade glioma (LGG) samples and liver hepatocellular carcinoma (LIHC) samples in TCGA and breast cancer samples from METABRIC. Both datasets have shown abnormal pathway activities related to immune response and cell cycles. In LGG samples, ORN identified pathway modules closely related to glioma development and revealed two pathways closely related to patient survival. We had similar results with LIHC samples. Additional results from the METABRIC datasets showed that ORN could characterize critical mechanisms of cancer and connect them to less studied somatic mutations (e.g., BAP1, MIR604, MICAL3, and telomere activities), which may generate novel hypothesis for targeted therapy.

BEM: Mining Coregulation Patterns in Transcriptomics via Boolean Matrix Factorization.

MOTIVATION: The matrix factorization is an important way to analyze coregulation patterns in transcriptomic data, which can reveal the tumor signal perturbation status and subtype classification. However, current matrix factorization methods do not provide clear bicluster structure. Furthermore, these algorithms are based on the assumption of linear combination, which may not be sufficient to capture the coregulation patterns. RESULTS: We presented a new algorithm for Boolean matrix factorization (BMF) via expectation maximization (BEM). BEM is more aligned with the molecular mechanism of transcriptomic coregulation and can scale to matrix with over 100 million data points. Synthetic experiments showed that BEM outperformed other BMF methods in terms of reconstruction error. Real-world application demonstrated that BEM is applicable to all kinds of transcriptomic data, including bulk RNA-seq, single-cell RNA-seq and spatial transcriptomic datasets. Given appropriate binarization, BEM was able to extract coregulation patterns consistent with disease subtypes, cell types or spatial anatomy. AVAILABILITY AND IMPLEMENTATION: Python source code of BEM is available on https://github.com/LifanLiang/EM_BMF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Integrating data and knowledge to identify functional modules of genes: a multilayer approach.

BACKGROUND: Characterizing the modular structure of cellular network is an important way to identify novel genes for targeted therapeutics. This is made possible by the rising of high-throughput technology. Unfortunately, computational methods to identify functional modules were limited by the data quality issues of high-throughput techniques. This study aims to integrate knowledge extracted from literature to further improve the accuracy of functional module identification. RESULTS: Our new model and algorithm were applied to both yeast and human interactomes. Predicted functional modules have covered over 90% of the proteins in both organisms, while maintaining a comparable overall accuracy. We found that the combination of both mRNA expression information and biomedical knowledge greatly improved the performance of functional module identification, which is better than those only using protein interaction network weighted with transcriptomic data, literature knowledge, or simply unweighted protein interaction network. Our new algorithm also achieved better performance when comparing with some other well-known methods, especially in terms of the positive predictive value (PPV), which indicated the confidence of novel discovery. CONCLUSION: Higher PPV with the multiplex approach suggested that information from both sources has been effectively integrated to reduce false positive. With protein coverage higher than 90%, our algorithm is able to generate more novel biological hypothesis with higher confidence.

Prediction of lncRNA-disease associations by integrating diverse heterogeneous information sources with RWR algorithm and positive pointwise mutual information.

BACKGROUND: Long non-coding RNAs play an important role in human complex diseases. Identification of lncRNA-disease associations will gain insight into disease-related lncRNAs and benefit disease diagnoses and treatment. However, using experiments to explore the lncRNA-disease associations is expensive and time consuming. RESULTS: In this study, we developed a novel method to identify potential lncRNA-disease associations by Integrating Diverse Heterogeneous Information sources with positive pointwise Mutual Information and Random Walk with restart algorithm (namely IDHI-MIRW). IDHI-MIRW first constructs multiple lncRNA similarity networks and disease similarity networks from diverse lncRNA-related and disease-related datasets, then implements the random walk with restart algorithm on these similarity networks for extracting the topological similarities which are fused with positive pointwise mutual information to build a large-scale lncRNA-disease heterogeneous network. Finally, IDHI-MIRW implemented random walk with restart algorithm on the lncRNA-disease heterogeneous network to infer potential lncRNA-disease associations. CONCLUSIONS: Compared with other state-of-the-art methods, IDHI-MIRW achieves the best prediction performance. In case studies of breast cancer, stomach cancer, and colorectal cancer, 36/45 (80%) novel lncRNA-disease associations predicted by IDHI-MIRW are supported by recent literatures. Furthermore, we found lncRNA LINC01816 is associated with the survival of colorectal cancer patients. IDHI-MIRW is freely available at https://github.com/NWPU-903PR/IDHI-MIRW .

The efflux pump inhibitor tetrandrine exhibits synergism with fluconazole or voriconazole against Candida parapsilosis.

In the last two decades, with the wide use of azoles, antifungal resistance among Candida parapsilosis has considered a matter of concern worldwide. The aim of this study is to evaluate the antifungal potentials of tetrandrine (TET) alone and in combination with fluconazole (FLC)/voriconazole (VRC) against C. parapsilosis. Susceptibility tests were performed by microdilution method, checkerboard assay, time-kill test, spot assay. Subsequently, rhodamine 6G efflux test and the expressions of transporter related genes, namely CDR1 and MDR1 for C. parapsilosis were analyzed by qRT-PCR. The susceptibility test showed that TET presented strong synergism with FLC and VRC with fractional inhibitory concentration index (FICI) in a range of 0.094-0.562. The susceptibility results were also confirmed by spot assay and time-kill studies. With TET treatment, a vast quantity of rhodamine 6G could not be pumped out from the cells as considerably intracellular red fluorescence was accumulated. Meanwhile, the expressions of efflux-associated genes presented varying degrees of inhibition. These results indicated that TET was a decent antifungal synergist to promote the antifungal efficacy of FLC/VRC, and the underlying antifungal mechanism might be associated with the inhibition of efflux pump and the elevation of intracellular drug content.

Combined effects of the BDNF rs6265 (Val66Met) polymorphism and environment risk factors on psoriasis vulgaris.

Smoking, alcohol consumption and higher body mass index (BMI) are well established risk factors for psoriasis and also associated with the clinical traits of the disease. And the genetic influences on these three risk factors indeed exist. Previously studies have demonstrated these risk factors related genetic variants may also play a role in the development of risk factors-related diseases. Then we performed a hospital-based study in order to evaluate the combined effect of the risk factors and their related polymorphism rs6265 in brain-derived neurotrophic factor (BDNF) gene on psoriasis vulgaris (PV) risk and clinic traits. The case-control study involved 660 subjects including 345 cases and 315 controls in Chinese Han population. The variant of rs6265 was typed by SNaPshot Multiplex Kit (Applied Biosystems Co., USA). We confirmed that higher BMI (≥25), smoking and alcohol consumption were risk factors for PV, and the estimated ORs were 1.63(95 % confidence interval (CI); 1.12-2.37), 2.09(95 % CI; 1.44-3.03) and 1.65(95 % CI; 1.15-2.37) respectively. Genotype and allele distributions did not differ significantly between case and control. However, we found combined effect of rs6265 genotype (GG) and higher BMI (≥25) increased risk of PV (OR = 2.09; 95 % CI, 1.02-4.28; P < 0.05; adjusted OR = 3.19; 95 % CI, 1.37-7.45; P < 0.05) and clinically severity of PV (OR = 2.71; 95 % CI, 1.09-6.72; P < 0.05; adjusted OR = 1.25; 95 % CI, 1.10-1.40; P < 0.05). But none such significant combined effect was observed between others genotype (AA and AG) and other risk factors. In conclusions, the combined effect of BDNF rs6265 genotype (GG) and higher BMI may increases the risk and clinical severity of PV in Chinese Han population.

Association analyses identifying two common susceptibility loci shared by psoriasis and systemic lupus erythematosus in the Chinese Han population.

BACKGROUND: Genome-wide association studies (GWASs) have revealed a large number of genetic risk loci for many autoimmune diseases. One clear finding emerging from the published genetic studies of autoimmunity is that different autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE), share susceptibility loci. Our study explores additional susceptibility loci shared by psoriasis and SLE in the Chinese Han population. METHODS: In total, 20 single nucleotide polymorphisms (SNPs) in 17 previously reported psoriasis susceptibility loci and 34 SNPs from 24 previously reported SLE susceptibility loci were investigated in our initial psoriasis and SLE GWAS dataset. Among these SNPs, we selected two SNPs (rs8016947 and rs4649203) with association values of p<5×10(-2) for both diseases in the GWAS data for further investigation in psoriasis (7260 cases and 9842 controls) and SLE (2207 cases and 9842 controls) using a Sequenom MassARRAY system. RESULTS: We found that these two SNPs (rs8016947 and rs4649203) in two loci (NFKBIA and IL28RA) were associated with psoriasis and SLE with genome-wide significance (Pcombined<5×10(-8) in psoriasis and Pcombined<5×10(-8) in SLE): rs8016947 at NFKBIA (Pcombined-psoriasis=3.90×10(-10), Pcombined-SLE=1.08×10(-13)) and rs4649203 at IL28RA (Pcombined-psoriasis=3.91×10(-12), Pcombined-SLE=9.90×10(-9)). CONCLUSIONS: These results showed that two common susceptibility loci (NFKBIA and IL28RA) are shared by psoriasis and SLE in the Chinese Han population.

Meta-analysis of IL12B polymorphisms (rs3212227, rs6887695) with psoriasis and psoriatic arthritis.

Interleukin 12 (IL-12) is a key player in model systems of autoimmunity. One of the most robust genetic findings is the association of variants in the IL12B gene with psoriasis and psoriatic arthritis (PsA). This study aims to assess whether combined evidence shows the association between IL12B polymorphisms and the susceptibility to psoriasis/PsA. We conducted a systematic review to examine the association between the IL12B rs3212227 (1188A > C) and rs6887695 and psoriasis/PsA. In addition, we used studies for which combined information from all genotypes was available to compare risks in dominant and recessive model. Potential publication bias was evaluated by Egger's linear regression test. Eleven articles met the inclusion criteria and contributed data to the meta-analyses. For rs3212227, the odds ratios the minor allele for psoriasis and PsA were 0.688 (95 % CI 0.650-0.729) and 0.707 (95 % CI 0.628-0.797), respectively. Then, for rs6887695, the pooled ORs were 0.704 (95 % CI 0.670-0.739) for psoriasis and 0.677 (95 % CI 0.599-0.767) for PsA. The overall ORs for all genotypes of rs3212227 and rs6887695 were all significantly associated with psoriasis. No publication bias was presented. Taken together, our results demonstrate a significant association between IL12B gene polymorphisms and psoriasis and PsA.

Prevalence and risk factors for latex glove allergy among female clinical nurses: a multicenter questionnaire study in China.

BACKGROUND: Natural rubber latex glove use is widespread in mainland China, but the prevalence and risk factors for latex glove allergy among clinical nurses have previously been unreported. METHODS: A questionnaire was used to collect information on latex glove-related allergy among clinical nursing staff in 35 hospitals of eight provinces in the southern, central southern, and northern regions of China, and the risk factors were calculated with logistic regression analysis. Some subjects with glove dermatitis were patch tested with a modified European standard series of allergens. RESULTS: Among 8485 female nurses in eight provinces of China, overall prevalence of latex glove allergy was 8.8%. Of 743 symptomatic nurses, 573 (77.1%) and 475 (63.9%) reported symptoms suggestive of glove dermatitis and type I latex allergy, respectively. Of 69 randomly selected subjects with glove dermatitis, 18 (26.1%) had a positive patch to rubber additives. Employment seniority, positive family and personal history of allergic diseases, and longer extent of time spent in a single hospital room were associated with latex allergy, while using >5 pairs of gloves per working day may be a protective factor. CONCLUSION: Chinese nurses are at high risk for latex sensitization. Nurses who develop latex-related symptoms after exposure to latex gloves should undergo screening tests for latex allergy. Low-protein, powder-free natural rubber latex gloves, or latex-free gloves should be widely adopted in China, along with other preventive measures.

Association of IL23R polymorphisms with psoriasis and psoriatic arthritis: a meta-analysis.

BACKGROUND: The association of variants in the IL23R gene with psoriasis and psoriatic arthritis (PsA) is a robust genetic finding OBJECTIVES: To assess whether combined evidence shows the association between IL23R polymorphisms and susceptibility to psoriasis/PsA. METHODS: We conducted a meta-analysis to examine the association between the IL23R rs11209026 (Q381R), rs7530511 (L310P), and rs2201841 polymorphisms and psoriasis/PsA. RESULTS: Thirteen articles met the inclusion criteria and contributed data to the meta-analysis. For rs11209026, the odds ratios (ORs) of minor alleles for psoriasis and PsA were 0.616 [95 % confidence interval (CI) 0.563-0.674] and 0.630 (95 % CI 0.524-0.757), respectively. For rs7530511, the pooled ORs were 0.820 (95 % CI 0.764-0.879) for psoriasis and 0.875 (95 % CI 0.766-1.000) for PsA; for rs2201841 the OR was 1.121 (95 % CI 1.031-1.219) for psoriasis. In genotypic analysis, the association of rs11209026 (A) and rs7530511 (T) were compatible with the dominant model (P < 0.0001, P = 0.001 respectively). The overall ORs for GG vs. AA (OR 1.339; 95 % CI 1.151-1.558), GG vs. GA (OR 1.143; 95 % CI 1.004-1.300), dominant (OR 1.226; 95 % CI 1.143-1.316), and recessive (OR 1.254; 95 % CI 1.115-1.411) models of rs2201841 were all significantly increased in psoriasis. No publication bias was present. CONCLUSIONS: Our results demonstrate a significant association between IL23R gene polymorphisms and psoriasis/PsA.

Polymorphisms at 16p13 are associated with systemic lupus erythematosus in the Chinese population.

BACKGROUND: Chromosomal region 16p13 has been reported to harbour variants associated with several autoimmune diseases, including type I diabetes, rheumatoid arthritis and multiple sclerosis. OBJECTIVE: To test whether variants in the 16p13 region are also associated with systemic lupus erythematosus (SLE) by performing a candidate locus study in the Chinese Han population. METHODS: Tag single nucleotide polymorphisms (SNPs) encompassing 50 kb upstream and downstream of the 250 kb linkage disequilibrium block, previously implicated in several autoimmune diseases, were analysed in 1047 patients with SLE and 1205 controls. The SNP showing the strongest association with SLE was then replicated in an independent cohort of 1643 cases and 5930 controls. RESULTS AND CONCLUSIONS: The association between SNP rs12599402 and SLE reached the genome-wide significance level (p<5 × 10⁻8). The SNP was likely to tag the same functional variant as previously reported in European populations. The results suggested that the chromosomal region at 16p13 contains common susceptibility genes for different immune-mediated disorders.

Meta-analysis of NOD2/CARD15 polymorphisms with psoriasis and psoriatic arthritis.

Psoriasis and psoriatic arthritis (PsA) is a complex autoimmune disease. NOD2/CARD15 gene has been suggested to play an important role in the pathogenesis of psoriasis and PsA. This study aims to assess the association between NOD2/CARD15 polymorphisms and the susceptibility to psoriasis/PsA. A meta-analysis was performed to survey studies on the NOD2/CARD15 polymorphisms and psoriasis/PsA using comprehensive PubMed, Embase, and Web of Science citation search. A total of 9 published studies were involved. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on fixed effects models or random effects models were depended on Cochran's Q-statistic. Potential publication bias was evaluated by Egger's linear regression test. As for R702W, the pooled ORs were 1.041 (95% CI 0.854-1.268, P = 0.693; 2,081 patients vs. 2,717 controls) for C allele and 0.886 (95% CI 0.565-1.391. P = 0.600; 1,222 patients vs. 1,818 controls) for genotype. Then for G908R, the pooled ORs were 1.042 (95% CI, 0.761-1.426, P = 0.799; 2,053 patients vs. 2,743 controls) for C allele and 0.942 (95% CI 0.708-1.254, P = 0.683; 1,226 patients vs. 1,824 controls) for the homozygous wild type. Then for Leu1007fsinsC allele polymorphism and genotype, the pooled ORs were 1.160 (95% CI, 0.893-1.507, P = 0.266; 2,279 patients vs. 3,067 controls) and 1.266 (95% CI 0.897-1.789, P = 0.180; 1,979 patients vs. 1,607 controls), respectively. No obvious publication bias was shown in the results. The association between NOD2/CARD15 polymorphisms and psoriasis/PsA was not found. Taken together, our results suggest that NOD2/CARD15 might not be a susceptibility gene for psoriasis and psoriatic arthritis.

Confirmation of C4 gene copy number variation and the association with systemic lupus erythematosus in Chinese Han population.

The distribution of complement component 4 (C4) gene copy number (GCN) has been validated in European populations. Meanwhile, C4 gene has been identified as a susceptibility gene for systemic lupus erythematosus (SLE). However, the association and the possible phenotype significance remain to be determined intensely in the Chinese population. This study was designed to validate the distribution of C4 GCNs in Chinese Han and the correlation between C4 GCNs and SLE using quantitative real-time polymerase chain reaction in 924 SLE patients and 1,007 controls. The results presented distribution of C4 GCNs in healthy populations and also showed that lower C4 GCN was a risk factor for SLE and higher C4 GCN was a protective factor against the disease susceptibility, which was similar to the report in the Caucasian population. Furthermore, we found the association between C4A GCN and disease subphenotypes of arthritis with SLE. We conclude that the association of C4 GCN with SLE was replicated in Chinese Han population, which highlighted the importance of C4 in SLE pathogenesis of diverse populations.

Successful treatment of a patient with cutaneous co-infection caused by Mucor irregularis and Klebsiella pneumoniae.

The authors report a rare case of primary cutaneous mucormycosis caused by Mucor irregularis and cutaneous Klebsiella pneumoniae infections in a 67-year-old Chinese woman. After the administration of liposomal amphotericin B combined with cefoperazone/sulbactam sodium, the patient recovered. Invasive fungal infection combined with cutaneous bacterial infection should receive attention.

Tetrandrine enhances the antifungal activity of fluconazole in a murine model of disseminated candidiasis.

BACKGROUND: Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications as an anti-inflammatory or anti-arrhythmic agent in the treatment of diverse diseases. In our previous study, TET exhibited the synergisitic action on azoles against pathogenic fungi. PURPOSE: In the current study, we examined whether TET can enhance the antifungal activity of FLC against disseminated candidiasis in mice. METHODS: BALB/c mice were inoculated intravenously with FLC-sensitive or FLC-resistant strains of Candida albicans, randomized and treated intraperitoneally with different doses of TET and/or FLC daily for 7 days. The treatment effectiveness, fungal burdens and the levels of the IFN-γ, IL-10, TGF-ß1 and IL-17A are determined in serum by ELISA and in the kidney by Real-time RT-PCR methods. RESULTS: We found that treatment with 45, 30 and 15 mg/kg of TET, enhanced the antifungal activities of a sub-critical dose (0.4 or 5 mg/kg) and minimal dose (0.8 or 10 mg/kg) of FLC against FLC-sensitive and FLC-resistant (respectively) infected mice. In the resistant strains the resistance mechanisms included MDR1 overexpression-and CDR1/CDR2 overexpression. Furthermore, when animals were treated with a sub-high dose (1.6-3.2 and 20-30 mg/kg) of FLC in the presence of fixed amounts of TET at 45, 30 and 15 mg/kg, the therapeutic doses of FLC could be substantially reduced in all strains tested. The findings in infected animal are consistent with the conclusion that TET exerts a synergistic effect on FLC against C. albicans by fractional inhibitory concentration index (FICI) and time-killing test in vitro. CONCLUSION: In summary, our data indicate that TET will enhance the antifungal activity of FLC against C. albicans infection in disseminated mice model.

The F1Fo-ATP Synthase ß Subunit Is Required for Candida albicans Pathogenicity Due to Its Role in Carbon Flexibility.

Previous work has explored link between mitochondrial biology and fungal pathogenicity in F1Fo-ATP synthase in Candida albicans. In this work we have detailed the more specific roles of the F1Fo-ATP synthase ß subunit, a key protein subunit of F1Fo-ATP synthase. The ability to assimilate alternative carbons in glucose-limited host niches is known to be a critical factor for infection caused by opportunistic pathogens including C. albicans. The function of the F1Fo-ATP synthase ß subunit was characterized through the construction of an ATP2 gene null mutant (atp2Δ/Δ) and the gene-reconstituted strain (atp2Δ/ATP2) in order to understand the link between carbon metabolism and C. albicans pathogenesis. Cell growth, viability, cellular ATP content, mitochondrial membrane potential (ΔΨm), and intracellular ROS were compared between null mutant and control strain. Results showed that growth of the atp2Δ/Δ mutant in synthetic medium was slower than in complex medium. However, the synthetic medium delayed the onset of reduced cell viability and kept cellular ATP content from becoming fully depleted. Consistent with these observations, we identified transcriptional changes in metabolic response that activated other ATP-generating pathways, thereby improving cell viability during the initial phase. Unlike glucose effects, the atp2Δ/Δ mutant exhibited an immediate and sharp reduction in cell viability on non-fermentable carbon sources, consistent with an immediate depletion of cellular ATP content. Along with a reduced viability in non-fermentable carbon sources, the atp2Δ/Δ mutant displayed avirulence in a murine model of disseminated candidiasis as well as lower fungal loads in mouse organs. Regardless of the medium, however, a decrease in mitochondrial membrane potential (ΔΨm) was found in the atp2Δ/Δ mutant but ROS levels remained in the normal range. These results suggest that the F1Fo-ATP synthase ß subunit is required for C. albicans pathogenicity and operates by affecting metabolic flexibility in carbon consumption.

Mitochondrial Complex V α Subunit Is Critical for Candida albicans Pathogenicity through Modulating Multiple Virulence Properties.

The α subunit (ATP1) is a vital component of mitochondrial complex V which counts for the majority of cellular ATP production in a living organism. Nevertheless, how the α subunit influences other cellular processes such as pathogenicity in Candida albicans remains poorly understood. To address this question, ATP1 mutant (atp1Δ/Δ) and the gene-reconstituted strain (atp1Δ/ATP1) have been constructed in this study and their pathogenicity-related traits are compared to those of wild type (WT). In a murine model of disseminated candidiasis, atp1Δ/Δ infected mice have a significantly higher survival rate and experience a lower fungal burden in tissues. In in vitro studies atp1Δ/Δ lose a capability to damage or destroy macrophages and endothelial cells. Furthermore, atp1Δ/Δ is not able to grow under either glucose-denial conditions or high H2O2 conditions, both of which are associated with the potency of the macrophages to kill C. albicans. Defects in filamentation and biofilm formation may impair the ability of atp1Δ/Δ to penetrate host cells and establish robust colonies in the host tissues. In concert with these pathogenic features, intracellular ATP levels of atp1Δ/Δ can drop to 1/3 of WT level. These results indicate that the α subunit of Complex V play important roles in C. albicans pathogenicity.

Synergistic Effects of Tetrandrine with Posaconazole Against Aspergillus fumigatus.

In our earlier in vitro and in vivo studies, synergistic effects were observed when itraconazole or voriconazole were combined with tetrandrine (TET) against Aspergillus fumigatus, and the synergistic mechanism was related to inhibition of the drug efflux pump. Posaconazole (PCZ) is a broad-spectrum triazole antifungal agent used for the treatment of diverse fungal infections, including aspergillosis and candidiasis. Herein, the antifungal effects of TET are further investigated in vitro and in vivo alone or combined with PCZ against 20 clinical isolates of A. fumigatus. We found that the minimal inhibitory concentrations (MICs) of PCZ were decreased one- to twofold and three- to fivefold across a series of concentration gradients in vitro in presence of TET. Time-killing curves revealed that the synergy was dependent on TET and PCZ concentrations as well as incubation time. The combination could further downregulate the expression of MDR2, MDR3, MDR4, and ATRF in PCZ-resistant strain, however, it has subtle effects on TET-synergized mechanism. In addition, TET in combination with PCZ significantly prolonged mice survival time and reduced kidney and brain tissue burdens in vivo. Our data in vitro and in vivo demonstrate that TET is an effective synergist with azoles against A. fumigates.

Variants of CARD14 gene and psoriasis vulgaris in southern Chinese cohort.

BACKGROUND: Recent mutation analysis identified several missense mutations in CARD14 in psoriasis. OBJECTIVES: We performed the genomic sequence analysis on CARD14 in southern Chinese Han Cantonese with Psoriasis Vulgaris (PsV) to reveal more causative missense mutations. METHODS: A total of 131 patients with PsV and 207 matched controls were included. We conducted sequence analysis of all the exon and exon-intron boundaries of CARD14 in the group of PsV patients and subsequent case control analysis of potential sequence variants of significance. RESULTS: We found five rare mutations and four of them are annotated or reported. Only the variant (c.1291C>G) has not been reported and annotated, but the variant was also found in controls. No significant difference was detected among all rare variant allele frequencies of patients and controls. CONCLUSION: None of the new definite variants were pathogenic. The other pathogenic mutations for PsV are still elusive in our cohort.

CARD14 gene polymorphism c.C2458T (p.Arg820Trp) is associated with clinical features of psoriasis vulgaris in a Chinese cohort.

Genome-wide association studies have found the single nucleotide polymorphism (SNP) c.C2458T, at the caspase recruitment domain family member 14 (CARD14) gene, to be associated with psoriasis. But little is known about the association of c.C2458T and clinical features of psoriasis vulgaris (PsV) in a Chinese cohort. This study was undertaken to further explore the relationship between c.C2458T and risk of psoriasis in southern Chinese subjects and to evaluate the SNP effect on the clinical features of psoriasis. A case-control study was performed involving 345 PsV patients and 206 controls. The variant of c.C2458T was typed using a SNaPshot assay. Statistical analysis was performed using SPSS version 13.0 software. In analysis of the basic situation of the sample, no difference was observed between cases and controls for age and sex. In the frequency distribution of genotypes and alleles in patients and controls, we found no association between the SNP and the risk of PsV. We performed a stratified analysis according to the age of onset, family history and Psoriasis Area and Severity Index (PASI) subphenotypes. We found that the CC genotype was associated significantly with an increased familial history of PsV. The main finding of our study was that the CC genotype was more common in familial cases than in sporadic cases. However, there were no significant differences found in other subphenotypes of age of onset or PASI between patients positive and those negative for a particular phenotype. In conclusion, the SNP c.C2458T may have significant effects on heritability of PsV in our Chinese population.