Novel Sulfonamide Derivatives Containing a Piperidine Moiety as New Bactericide Leads for Managing Plant Bacterial Diseases.

Plant bacterial diseases are an intractable problem due to the fact that phytopathogens have acquired strong resistances for traditional pesticides, resulting in restricting the quality and yield of agricultural products around the world. To develop new agrochemical alternatives, we prepared a novel series of sulfanilamide derivatives containing piperidine fragments and assessed their antibacterial potency. The bioassay results revealed that most molecules displayed excellent in vitro antibacterial potency towards Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac). In particular, molecule C4 exhibited outstanding inhibitory activity toward Xoo with EC50 value of 2.02 µg mL-1, which was significantly better than those of the commercial agents bismerthiazol (EC50 = 42.38 µg mL-1) and thiodiazole copper (EC50 = 64.50 µg mL-1). A series of biochemical assays confirmed that compound C4 interacted with dihydropteroate synthase, and irreversibly damaged the cell membrane. In vivo assays showed that the molecule C4 presented acceptable curative and protection activities of 34.78% and 39.83%, respectively, at 200 µg mL-1, which were greater than those of thiodiazole and bismerthiazol. This study highlights the valuable insights for the excavation and development of new bactericides that can concurrently target dihydropteroate synthase and bacterial cell membranes.

[Analysis of genetic variant in a Chinese pedigree affected with neurofibromatosis type I].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with neurofibromatosis type I (NF1). METHODS: Target capture high-throughput sequencing and Sanger sequencing were carried out to detect the pathological variant in a NF1 patient and his parents. RESULTS: The proband and his similarly affected father have both harbored a novel nonsense variant of c.2511G>A (p.trp837x) in the NF1 gene. The same variant was not found in his mother and 200 healthy controls. CONCLUSION: The heterozygous nonsense variant of c.2511G>A (p.trp837x) of the NF1 gene probably underlay the pathogenesis of NF1 in this pedigree.

Classical Disease-Specific Autoantibodies in Systemic Sclerosis: Clinical Features, Gene Susceptibility, and Disease Stratification.

Systemic sclerosis (SSc) is an autoimmune disease characterized by abnormalities in microcirculation, extracellular matrix accumulation, and immune activation. Autoantibodies are markers of immune abnormalities and provide diagnostic and predictive value in SSc. Anti-topoisomerase antibodies (ATAs), anticentromere antibodies (ACAs), and anti-RNA polymerase antibodies (ARAs) are the three classical specific antibodies with the highest availability and stability. In this review, we provide an overview of the recent progress in SSc research with respect to ATAs, ACAs, and ARAs, focusing on their application in distinguishing clinical phenotypes, such as malignancy and organ involvement, identifying genetic background in human leukocyte antigen (HLA) or non-HLA alleles, and their potential roles in disease pathogenesis based on the effects of antigen-antibody binding. We finally summarized the novel analysis using ATAs, ACAs, and ARAs on more detailed disease clusters. Considering these advantages, this review emphasizes that classical SSc-specific autoantibodies are still practical and have the potential for patient and risk stratification with applications in precise medicine for SSc.

Biologic TNF-alpha inhibitors in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a systemic review.

Background: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) is one of severe cutaneous adverse reactions with low morbidity but high mortality. Different systemic immunomodulating treatments are proposed but still remain controversial. Tumor necrosis factor (TNF)-alpha is long thought to be a vital mediator of epithelial cell death in SJS-TEN, indicating a potential target for therapy.Objective: The aim of this systemic review is to evaluate the efficacy and safety of biologic TNF-alpha inhibitors in the treatment of SJS-TEN.Methods: We reviewed the published literature by searching from PubMed, EMBASE, Web of Science and ClinicalTrial.gov. A total of 27 articles fulfilling our inclusion criteria were found and analyzed.Results: There were 21 case reports, four case series and two randomized controlled trials (RCTs) on the biologic TNF-alpha inhibitors for SJS-TEN therapy, comprising 91 patients. TNF-alpha inhibitors were used as monotherapy, second-line therapy or combination therapy. Among them, 79 patients (86.8%) responded well and discharged with few side effects and complications.Conclusions: Biologic TNF-alpha inhibitors are a safe and effective treatment for SJS-TEN. But further, larger RCTs need to be conducted to provide more evidence for clinical application.

Sublingual immunotherapy of atopic dermatitis in mite-sensitized patients: a multi-centre, randomized, double-blind, placebo-controlled study.

Allergen-specific immunotherapy is widely used for allergic rhinitis and asthma treatment worldwide. This study explored the efficacy and safety of sublingual immunotherapy (SLIT) with the extracts of Dermatophagoides Farinae (D. farinae Drops) on house dust mites (HDM)-induced atopic dermatitis (AD). 239 patients with HDM-induced AD were recruited and exposure to a multi-centre, randomized, double-blind, and placebo-controlled clinical trials for 36 weeks, which were randomly divided into placebo and sublingual D. farinae Drops groups (high-dose, medium-dose and low-dose), respectively. Statistical analysis was performed in three groups: Full Analysis Set, Per Protocol Set and Safety Set. 48 cases have withdrawn from the study before the end of study. As primary outcomes, significant decreases in scoring atopic dermatitis and total medication score were showed in medium-dose and high-dose D. farinae Drops groups. In the sixth visit, the skin lesion area showed a statistically significant difference between high-dose/medium-dose D. farinae Drops group and placebo group (p < .05). Most adverse events are slight, and no life-threatening adverse drug reaction happened. Our research demonstrates the beneficial effect of SLIT with high or medium dose D. farinae Drops on AD, and the treatment was well tolerated.

EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins.

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been frequently used in targeted therapy for lung cancer. However, the widespread use of gefitinib in targeted therapy for patients with lung cancer is hampered by its common skin toxicities. The present study aimed to investigate the mechanisms underlying the skin toxicities of gefitinib. Normal human epidermal keratinocytes (NHEKs) treated with gefitinib were used for a series of in vitro assays, including MTT, reverse transcription­quantitative polymerase chain reaction, western blot analysis, immunohistochemistry and transepithelial electrical resistance and paracellular permeability detection. In the present study, it was determined that the skin toxicities of gefitinib may be due to claudin (CLDN)1 and CLDN4 downregulation and CLDN2 upregulation in NHEKs. Additionally, Src and signal transducer and activator of transcription 3 pathways were involved in gefitinib­induced barrier function disruption in NHEKs. In conclusion, the present study may provide novel insights for improving skin toxicity of gefitinib in patients with lung cancer.

Prognostic value of neutrophil-to-lymphocyte ratio in melanoma: Evidence from a PRISMA-compliant meta-analysis.

BACKGROUND: A number of studies have investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with melanoma but the results were controversial. Therefore, we conducted a meta-analysis to explore the prognostic value of NLR in melanoma. METHODS: The databases of PubMed, Embase, and Web of Science were thoroughly searched. Associations between NLR and overall survival (OS) and progression-free survival (PFS) were investigated by pooling hazard ratio (HR) and 95% confidence interval (CI). RESULTS: A total of 12 studies comprising 3207 patients were finally included in the meta-analysis. The results showed that a high NLR was associated with poor OS (HR = 2.23, 95% CI = 1.64-3.04, P < .001, random-effects model) and PFS (HR = 2.19, 95% CI = 1.78-2.69, P < .001, fixed-effects model). Subgroup analyses demonstrated that NLR was still associated with poor OS and PFS for patients in Western countries who were treated with ipilimumab. No significant publication bias was found in this meta-analysis. CONCLUSION: This meta-analysis demonstrated that a high NLR was predictive of poor OS and PFS in patients with melanoma.

Silence of MACC1 decreases cell migration and invasion in human malignant melanoma through inhibiting the EMT.

Metastasis-associated colon cancer 1 (MACC1) has been demonstrated to promote metastasis of several cancers via regulating epithelial-mesenchymal transition (EMT). However, its biological behavior in human malignant melanoma remains unclear. In this study, MACC1 downregulation was established in two melanoma cell lines (A375 and G361 cells) using RNA interference, as confirmed by quantitative real time PCR (qRT-PCR) and Western blot analysis. Subsequently, we investigated the effects of MACC1 silencing on cell mobility, migration and invasion using scratch wound and Transwell assays. Our results indicated that knockdown of MACC1 significantly suppressed cell migration and invasion ability of both melanoma cell lines. Moreover, downregulation of MACC1 upregulated E-cadherin, N-cadherin and Vimentin, as confirmed by qRT-PCR, Western blot and immunofluorescent Staining analysis. These findings suggest MACC1 might serve as a new molecular target for the treatment of melanoma by a novel mechanism underlying the metastasis of melanoma cells.

Identification of candidate genes in atopic dermatitis based on bioinformatic methods.

BACKGROUND: Atopic dermatitis (AD) is a chronic or relapsing inflammatory disorder of the skin that frequently precedes asthma and allergic disorders. This study aimed to identify candidate genes related to AD using bioinformatic methods. METHODS: The microarray data of GSE32924, including 12 nonlesional AD (ANL) and 13 lesional AD (AL) skin samples obtained from 14 patients with AD as well as eight other normal human skin samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened in ANL and AL skin samples compared with normal controls, followed by gene ontology (GO) and pathway enrichment analyses. Furthermore, the selected overlapping DEGs were analyzed to identify co-expressed genes, and a co-expression network was established. GeneCodis database was selected for functional annotation of the differentially co-expressed genes and a regulatory network was constructed. RESULTS: Compared with normal controls, 438 DEGs were identified in ANL skin samples and were mainly enriched in two pathways and the GO terms associated with epidermis development. Besides, 779 DEGs were identified in AL skin samples and were mainly enriched in four pathways and GO terms associated with immune response. Stimulated by retinoic acid 13 (STRA13), presenilin enhancer gamma secretase subunit (PSENEN), and nucleosome assembly protein 1-like 2 (NAP1L2) were significantly enriched by integration analysis of the co-expression and regulatory network. CONCLUSION: Genes STRA13, PSENEN, and NAP1L2 were presumed to play critical roles in AD and they may serve as potential targets for the treatment of AD.

Multiple paraneoplastic syndromes: myasthenia gravis, vitiligo, alopecia areata, and oral lichen planus associated with thymoma.

Thymomas are associated with paraneoplastic autoimmune diseases at a high frequency. It is rare that four paraneoplastic autoimmune disorders co-occur in a single patient. We describe a thymoma patient with diagnoses of myasthenia gravis, vitiligo, alopecia areata, and oral lichen planus associated with a thymoma. After thymectomy, the weakness, vitiligo, alopecia and mucocutaneous lesions were improving progressively, possibly implicating the thymoma in initiating these autoimmune conditions. We believe that this is the first report of this particular combination of multiple paraneoplastic syndromes associated with thymoma.

Photodynamic therapy in the treatment of superficial mycoses: an evidence-based evaluation.

Photodynamic therapy (PDT) is effective in the destruction of fungi. In order to evaluate the efficacy and safety of PDT for superficial mycoses, we performed an evidence-based review of published literature. Database of MEDLINE, EMBASE, and Cochrane Library was searched until March 2010. English-language articles evaluating the efficacy and safety of PDT for superficial mycoses were included. No randomized clinical trials were found. Seven reports described the antifungal effect of PDT against 63 superficial mycoses patients. Eight of 10 (80%) tinea cruris patients and 6 of 10 (60%) tinea pedis were led to mycological cure after 1-3 treatments. Unfortunately, only 4 (40%) tinea cruris patients and 3 (30%) tinea pedis had a persist healing at the 8-week follow-up. Six of the 9 (66.7%) foot-interdigital mycoses patients recovered clinically and microbiologically after 1 or 4 treatments. Only 2 patients (22.2%) had a persist healing at the 8-week follow-up. Eleven of 30 (36.6%) onychomycosis patients were cure for 18 months after treatment, and 3 onychomycosis patients were all cure in other 2 reports. The therapeutic effect of PDT for one pityriasis versicolor patients was well. Overall tolerability of PDT was good. Therefore, it is unclear what PDT's place for superficial mycoses will be. Further clinical trials are needed to evaluate the efficacy of PDT to treat superficial mycoses. It is also important to optimize treatment protocols in order to cope with recurrence.

Matrine inhibits invasiveness and metastasis of human malignant melanoma cell line A375 in vitro.

BACKGROUND: Matrine is a traditional Chinese medicine with significant inhibitory activity against malignant tumors. Its effects on the invasiveness and metastasis of malignant tumors have rarely been reported. AIM: To investigate whether matrine can inhibit the metastasis-related activities of the human malignant melanoma cell line A375 in vitro. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and Annexin-V-fluorescein isothiocyanate/propidium iodide (Annexin-V-FITC/PI) affinity assay were used to examine the effects of matrine on the proliferation and apoptosis induction of A375 cells. The morphologic changes of A375 cells were observed by light and electron microscopy. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were performed to evaluate the expression of heparanase mRNA and protein. The effect of matrine on the adhesion ability and invasiveness of treated A375 cells was tested by cell-Matrigel adhesion assay and Matrigel invasion assay, respectively. RESULTS: Matrine showed significant inhibition of the proliferation of A375 cells in a dose- and time-dependent manner. It also induced apoptosis in a dose-dependent manner. Compared with the control group, the levels of heparanase mRNA and protein expression of A375 cells treated with different concentrations of matrine were decreased significantly, as were their adhesion ability and invasiveness. CONCLUSIONS: These findings indicate that matrine inhibits the invasiveness and metastasis of A375 cells in vitro. The mechanisms may be linked to the inhibition of cellular proliferation, induction of apoptosis, and downregulation of heparanase mRNA and protein expression.

Identification of a novel mutation and a de novo mutation in DKC1 in two Chinese pedigrees with Dyskeratosis congenita.

Dyskeratosis congenita (DKC) is a rare and fatal congenital syndrome characterized by the triad of reticular skin pigmentation, nail dystrophy and mucosal leukoplakia, and the predisposition to bone marrow failure and malignancies. Mutations in DKC1 gene encoding dyskerin are responsible for the X-linked dyskeratosis congenita. Here we report mutation analysis of two Chinese pedigrees with dyskeratosis congenita. The 15 coding exons of DKC1 and their flanking regions were amplified from genomic DNA by PCR. DNA sequencing and restriction endonuclease digestion were used for mutation detection. Transition mutation of 1226C-->T (P409L) found in the first pedigree is a novel mutation. In the second pedigree, the proband's mother phenotypically normal carried a de novo transition mutation of 1058C-->T (A353 V) in one allele, and transmitted the mutant allele to her two sons who had typical manifestations of dyskeratosis congenita.