Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease.

Background: Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson's disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms of PD. Objective: This study aimed to detect p-α-syn deposition characteristic in rare genetic PD patients with CHCHD2 or RAB39B mutations. Moreover, this study also aimed to describe peripheral alpha-synuclein prion-like activity in genetic PD patients, and acquire whether the cutaneous synucleinopathy characteristics of genetic PD are consistent with central neuropathologies. Methods: We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with CHCHD2 mutations, two patients with RAB39B mutations, 16 patients with PRKN mutations, 14 patients with LRRK2 mutations, five patients with GBA mutations, 100 iPD patients, and 20 healthy controls. We detected cutaneous synucleinopathies using immunofluorescence staining and a seeding amplification assay (SAA). A systematic literature review was also conducted, involving 64 skin biopsies and 205 autopsies of genetic PD patients with synucleinopathy. Results: P-α-syn was deposited in the peripheral cutaneous nerves of PD patients with CHCHD2, LRRK2, or GBA mutations but not in those with RAB39B or PRKN mutations. There were no significant differences in the location or rate of α-syn-positive deposits between genetic PD and iPD patients. Peripheral cutaneous synucleinopathy appears to well represent brain synucleinopathy of genetic PD, especially autosomal dominant PD (AD-PD). Cutaneous α-synuclein SAA analysis of iPD and LRRK2 and GBA mutation patients revealed prion-like activity. Conclusion: P-α-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.

A comprehensive study of clinicopathological and genetic features of neuronal intranuclear inclusion disease.

BACKGROUND: The discovery of skin intranuclear inclusions and GGC repeat expansion of NOTCH2NLC has greatly promoted the diagnosis of neuronal intranuclear inclusion disease (NIID). With highly heterogeneous clinical manifestations, NIID patients tend to be underdiagnosed at early stages. METHODS: This study comprehensively studied clinical manifestations, magnetic resonance imaging (MRI), and peripheral nerve conduction in 24 NIID and 166 other neurodegenerative disease (ND) subjects. The nomogram was plotted using the "rms" package, and the t-distributed stochastic neighbor embedding algorithm was performed. Associations between skin intranuclear inclusions and NOTCH2NLC GGC repeats were further analyzed. RESULTS: The clinical, MRI, and peripheral nerve conduction features seriously overlapped in NIID and ND patients; they were assigned variables according to their frequency and specificity in NIID patients. A nomogram that could distinguish NIID from ND was constructed according to the assigned variables and cutoff values of the above features. The occurrence of skin intranuclear inclusions and NOTCH2NLC GGC repeats ≥ 60 showed 100% consistency, and intranuclear inclusion frequency positively correlated with NOTCH2NLC GGC repeats. A hierarchical diagnostic flowchart for definite NIID was further established. CONCLUSION: We provide a novel nomogram with the potential to realize early identification and update the diagnostic flowchart for definitive diagnosis. Moreover, this is the first study to define the association between skin pathology and NOTCH2NLC genetics in NIID.

Cell Proliferation and Apoptosis-Related Genes Affect the Development of Human Nasopharyngeal Carcinoma Through PI3K/AKT Signaling Pathway.

Nasopharyngeal carcinoma (NPC) is one of the common malignant tumors in China, which occurs on the top and sidewalls of the nasopharyngeal cavity. The incidence of malignant tumors of the ear, nose and throat is the highest. However, little is known about the growth of the cells. Therefore, this study constructed a multi-regulator-driven NPC cell growth-related module, aiming to explore the mechanism of functional pathways regulating the proliferation of NPC cells in an all-round way. Firstly, differential expression analysis, co-expression analysis, enrichment analysis and connectivity analysis were synthesized to identify the intrinsic genes of expression disorder module. Subsequently, we analyzed the module by crosstalk, and observed the interaction between modules intuitively. Finally, based on hypergeometric test, the significance of multi-regulators on the regulation of potential modules is calculated. We obtained 17 cell growth-related expression disorder modules by 2148 gene modules focusing. These modules are mainly involved in the growth cycle of NPC cells, including cell proliferation, migration and apoptosis. At the same time, they mainly affect the proliferation and apoptosis of NPC cells through PI3K-AKT signaling pathway, NF-kappa B signaling pathway and Wnt signaling pathway. Based on the growth-related modules of NPC cells, we have obtained a series of non-coding RNAs (ncRNAs) including microRNA-92a-3p, microRNA-19a-3p and microRNA-130a-3p, play an important role in regulating the growth of NPC cells. Similarly, we also predicted transcription factors (involving E2F1, NFKB1, SP1, etc.) that may play a key role in cell growth-related modules. This study is based on cell growth-related expression disorder module to explore the regulatory role of its functional pathway on cell proliferation mechanism, which will help researchers to have a deeper understanding of the potential pathogenesis of NPC.

Comprehensive analysis of gene expression and DNA methylation for human nasopharyngeal carcinoma.

PURPOSE: Nasopharyngeal carcinoma (NPC) is one of the most malignant head and neck carcinomas with unique epidemiological features. In this study, we aimed to identify the novel NPC-related genes and biological pathways, shedding light on the potential molecular mechanisms of NPC. METHODS: Based on Gene Expression Omnibus (GEO) database, an integrated analysis of microarrays studies was performed to identify differentially expressed genes (DEGs) and differentially methylated genes (DMGs) in NPC compared to normal control. The genes which were both differentially expressed and differentially methylated were identified. Functional annotation and protein-protein interaction (PPI) network construction were used to uncover biological functions of DEGs. RESULTS: Two DNA methylation and five gene expression datasets were incorporated. A total of 1074 genes were up-regulated and 939 genes were down-regulated in NPC were identified. A total of 719 differential methylation CpG sites (DMCs) including 1 hypermethylated sites and 718 hypomethylated sites were identified. Among which, 11 genes were both DEGs and DMGs in NPC. Pathways in cancer, p53 signaling pathway and Epstein-Barr virus infection were three pathways significantly enriched pathways in DEmRNAs of NPC. The PPI network of top 50 DEGs were consisted of 191 nodes and 191 edges. CONCLUSIONS: Our study was helpful to elucidate the underlying mechanism of NPC and provide clues for therapeutic methods.

Genome­wide profiling of lncRNA and mRNA expression in CRSwNP.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most prevalent chronic diseases. In patients with CRSwNP, the present study performed comprehensive bioinformatics analyses to characterize the transcriptome profiles of mRNAs and long non­coding RNAs (lncRNAs). A total of 265 differentially expressed lncRNAs and 994 mRNAs were identified. The majority of up­ and downregulated differentially expressed genes were significantly enriched in the biological process of 'signal transduction'. The most significantly enriched molecular function was 'protein binding' and the most significantly enriched cellular component was 'membrane'. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis led to identification of several significantly enriched pathways [false discovery rate (FDR)<0.05], including 'cytokine­cytokine receptor interaction' (FDR=3.94x1016) and 'cell adhesion molecules' (CAMs) (FDR=1.28x10­5). Key differentially expressed lncRNAs were identified, including lncRNA XLOC_010280, which regulates chemokine (C­C motif) ligand 18 (CCL18) and inflammation, and RP11­798M19.6, which regulates polypeptide N­acetylgalactosaminyltransferase 7 (GALNT7) and cell proliferation. Based on the results of reverse transcription­quantitative polymerase chain reaction, except for CCL8, neural precursor cell expressed developmentally downregulated gene 4­like and GALNT7, the expression of 3 other selected genes was consistent with the results of integrated analysis. The results of the present study provide a foundation for future investigations into mRNAs and lncRNAs as diagnostic and therapeutic targets in CRSwNP.

Identification of miRNA/mRNA-Negative Regulation Pairs in Nasopharyngeal Carcinoma.

BACKGROUND Nasopharyngeal carcinoma (NPC) is a common malignancy in South-East Asia. NPC is characterized by distant metastasis and poor prognosis. The pathophysiological mechanism of nasopharyngeal carcinoma is unknown. This study aimed to identify the crucial miRNAs in nasopharyngeal carcinoma and their target genes, and to discover the potential mechanism of nasopharyngeal carcinoma development. MATERIAL AND METHODS Microarray expression profiling of miRNA and mRNA from the Gene Expression Omnibus database was downloaded, and we performed a significance analysis of differential expression. An interaction network of miRNAs and target genes was constructed. The underlying function of differentially expressed genes was predicted through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. To validate the microarray analysis data, significantly different expression levels of miRNAs and target genes were validated by quantitative real-time polymerase chain reaction. RESULTS We identified 27 differentially expressed miRNAs and 982 differentially expressed mRNAs between NPC and normal control tissues. 12 miRNAs and 547 mRNAs were up-regulated and 15 miRNAs and 435 mRNAs were down-regulated in NPC samples. We found a total of 1185 negative correlation pairs between miRNA and mRNA. Differentially expressed target genes were significantly enriched in pathways in cancer, cell cycle, and cytokine-cytokine receptor interaction signaling pathways. Significantly differentially expressed miRNAs and genes, such as hsa-miR-205, hsa-miR-18b, hsa-miR-632, hsa-miR-130a, hsa-miR-34b, PIGR, SMPD3, CD22, DTX4, and CDC6, may play essential roles in the development of nasopharyngeal carcinoma. CONCLUSIONS hsa-miR-205, hsa-miR-18b, hsa-miR-632, hsa-miR-130a, and hsa-miR-34b may be related to the development of nasopharyngeal carcinoma by regulating the genes involved in pathways in cancer and cell cycle signaling pathways.

Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.

IMPORTANCE: The current recommendation is for at least 12 months of dual antiplatelet therapy after implantation of a drug-eluting stent. However, the optimal duration of dual antiplatelet therapy with specific types of drug-eluting stents remains unknown. OBJECTIVE: To assess the clinical noninferiority of 3 months (short-term) vs 12 months (long-term) of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) with zotarolimus-eluting stents. DESIGN, SETTING, AND PATIENTS: The OPTIMIZE trial was an open-label, active-controlled, 1:1 randomized noninferiority study including 3119 patients in 33 sites in Brazil between April 2010 and March 2012. Clinical follow-up was performed at 1, 3, 6, and 12 months. Eligible patients were those with stable coronary artery disease or history of low-risk acute coronary syndrome (ACS) undergoing PCI with zotarolimus-eluting stents. INTERVENTIONS: After PCI with zotarolimus-eluting stents, patients were prescribed aspirin (100-200 mg daily) and clopidogrel (75 mg daily) for 3 months (n = 1563) or 12 months (n = 1556), unless contraindicated because of occurrence of an end point. MAIN OUTCOMES AND MEASURES: The primary end point was net adverse clinical and cerebral events (NACCE; a composite of all-cause death, myocardial infarction [MI], stroke, or major bleeding); the expected event rate at 1 year was 9%, with a noninferiority margin of 2.7%. Secondary end points were major adverse cardiac events (MACE; a composite of all-cause death, MI, emergent coronary artery bypass graft surgery, or target lesion revascularization) and Academic Research Consortium definite or probable stent thrombosis. RESULTS: NACCE occurred in 93 patients receiving short-term and 90 patients receiving long-term therapy (6.0% vs 5.8%, respectively; risk difference, 0.17 [95% CI, -1.52 to 1.86]; P = .002 for noninferiority). Kaplan-Meier estimates demonstrated MACE rates at 1 year of 8.3% (128) in the short-term group and 7.4% (114) in the long-term group (HR, 1.12 [95% CI, 0.87-1.45]). Between 91 and 360 days, no statistically significant association was observed for NACCE (39 [2.6%] vs 38 [2.6%] for the short- and long-term groups, respectively; HR, 1.03 [95% CI, 0.66-1.60]), MACE (78 [5.3%] vs 64 [4.3%]; HR, 1.22 [95% CI, 0.88-1.70]), or stent thrombosis (4 [0.3%] vs 1 [0.1%]; HR, 3.97 [95% CI, 0.44-35.49]). CONCLUSIONS AND RELEVANCE: In patients with stable coronary artery disease or low-risk ACS treated with zotarolimus-eluting stents, 3 months of dual antiplatelet therapy was noninferior to 12 months for NACCE, without significantly increasing the risk of stent thrombosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01113372.